Increased Plasma Creatinine Research Articles

Temporary bilateral clamping of renal arteries induces ischemia-reperfusion: A new pig model of acute kidney injury using total intravenous anesthesia.

Ischemia-reperfusion (IR) is a leading cause of acute kidney injury (AKI), and pigs are commonly used in preclinical AKI models. However, existing models often vary in the methods used to induce ischemia, and the resulting AKI tends to be mild-to-moderate. Moreover, follow-up is often performed under volatile anesthesia, which, in contrast to total intravenous anesthesia (TIVA), can induce malignant hyperthermia and cause hemodynamic instability. Here we present a novel surgical model of IR-induced AKI using bilateral renal artery clamping under TIVA. Anesthesia was induced via TIVA with diazepam, ketamine, and morphine. After retroperitoneal exposure, the renal arteries were isolated and clamped with a plastic tube for 90 min, followed by 8 h of reperfusion. The IR group (n = 6) was compared with a Sham group (n = 5) that underwent the same procedure without IR. The IR group developed moderate-to-severe AKI as evidenced by reduced glomerular filtration, a 158% increase in plasma creatinine versus 21% in the Sham group, and elevated neutrophil gelatinase-associated lipocalin levels (+280% in IR vs. 0% in Sham), indicating tubular injury. Histopathology confirmed these findings. Thus, this preclinical model successfully induced moderate-to-severe AKI in pigs. The TIVA anesthetic protocol offered several advantages compared to halogenated gas anesthesia.

Western diet exacerbates a murine model of Balkan nephropathy.

Aristolochic acid (AA) ingestion causes Balkan nephropathy, characterized by tubular injury and progression to chronic kidney disease (CKD). AA is taken up by proximal tubule cells via organic anion transport and induces p21-mediated DNA damage response, but little is known about dietary modulating factors. Western diet (WD) is rich in saturated fats and sugars and can promote metabolic disorders and CKD progression. Here, we determined the impact of WD on AA-induced kidney injury. Five-week-old male C57BL/6J mice were fed WD or normal chow (NC) for 8 wk, followed by administration of AA every 3 days for 3 wk. Measurements were performed after the last injection and following a 3-wk recovery. Independent of dosing AA by body weight (3 mg/kg/day) or same dose/mouse (0.1125 mg/day), the AA-induced increase in plasma creatinine and reduction of hematocrit were greater in WD versus NC. This was associated with increased kidney gene expression in WD vs. NC of markers of DNA damage (p21), injury (Kim1 and Ngal), and inflammation (Tnfa) and kidney fibrosis staining. WD alone increased fractional excretion of indoxyl sulfate by 7.5-fold, indicating enhanced kidney organic anion transport. Kidney proteomics identified further WD-induced changes that could increase kidney sensitivity to AA and contribute to the altered response to AA including weakening of energy metabolism, potentiation of immune and infection pathways, and disruption in RNA regulation. In conclusion, WD can increase the susceptibility of mice to Balkan nephropathy, possibly in part through facilitating kidney uptake of the organic anion AA.NEW & NOTEWORTHY This study shows that a Western diet (WD) aggravates a murine model of Balkan nephropathy induced by the application of the organic anion and nephrotoxin aristolochic acid (AA). Mechanistically, this may involve WD-induced kidney organic anion secretion, which can facilitate the AA uptake into proximal tubular cells and thereby contribute to the injury. Kidney proteomics identified further changes induced by feeding a WD that could have increased the sensitivity of the kidney to stress and injury.

Evaluation of Xanthine Oxidase Inhibitors Febuxostat and Allopurinol on Kidney Dysfunction and Histological Damage in Two-Kidney, One-Clip (2K1C) Rats.

In chronic kidney disease (CKD), hyperuricemia is a common phenomenon, presumably due to reduced renal clearance of uric acid. This study investigated the effect of xanthine oxidase (XO) inhibitors allopurinol and febuxostat to prevent oxidative stress in the kidney of two-kidney, one-clip (2K1C) rats. In this investigation, 2K1C rats were used as an experimental animal model for kidney dysfunction. 2K1C rats were provided with food and drinking water and received febuxostat at a dose of 10 mg/kg or allopurinol at 100 mg/kg, respectively. After the treatment completion, all rats were sacrificed, and tissue samples were collected. 2K1C rats exhibited increased plasma creatinine, uric acid level, and glomerular injury assessed based on microscopic findings. Both allopurinol and febuxostat significantly normalized creatinine and uric acid levels. Furthermore, 2K1C rats showed increased lipid peroxidation (LPO), nitric oxide (NO), and advanced oxidation protein products (AOPP) alongside decreased superoxide dismutase (SOD) and catalase activity. Again, both drug treatments ameliorated these elevated oxidative stress parameters in 2K1C rats. The antioxidant genes such as Nrf-2, HO-1, and SOD were also restored in the kidneys of 2K1C rats by allopurinol and febuxostat treatment. 2K1C rats also showed increased IL-1β, IL-6, TNF-α, and NF-кB mRNA expression in the kidneys which were normalized by allopurinol and febuxostat treatment. Thus, the data suggest that XO inhibition protects kidney function potentially by restoring antioxidant enzyme function and suppressing inflammation.

Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice.

Extracellular ATP plays an important role in renal physiology as well as the pathogenesis of acute kidney injury induced by renal ischemia and reperfusion (IR). Expression of the purinergic P2Y2 receptor has been shown on inflammatory and structural cells of the kidney, and P2Y2R is preferably activated by ATP (or UTP). Here, we investigated the molecular mechanism of P2Y2R during IR injury by using P2Y2R knockout (KO) mice and a selective P2Y2R agonist, MRS2768. After renal IR, P2Y2R KO mice showed greater increases in plasma creatinine, tubular damage and neutrophil infiltration, and significant induction of proinflammatory cytokines and apoptotic markers than wild-type (WT) mice. In contrast, treatment with MRS2768 reduced plasma creatinine levels, tubular damage and inflammation, and renal apoptosis in mice subjected to renal IR. In cultured human proximal tubular HK-2 cells, MRS2768 upregulated P2Y2R mRNA levels and decreased TNF-α/cycloheximide-induced apoptosis and inflammation. Importantly, P2Y2R activation by MRS2768 increased the phosphorylation of protein kinase C (PKC), Src, and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, the inhibition of PI3K/Akt abolished the protective effects of MRS2768 against TNF-α/cycloheximide-induced apoptosis and inflammation in HK-2 cells. In conclusion, activation of P2Y2R protects against tubular apoptosis and inflammation during renal IR via the PKC/Src/Akt pathway, suggesting P2Y2R is a promising therapeutic target for acute kidney injury.

Investigating the cause of cardiovascular dysfunction in chronic kidney disease: capillary rarefaction and inflammation may contribute to detrimental cardiovascular outcomes

Myocardial ischemia–reperfusion (IR) injury is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The most frequently used and representative experimental model is the rat dietary adenine-induced CKD, which leads to CKD-associated CVD. However, the continued intake of adenine is a potential confounding factor. This study investigated cardiovascular dysfunction following brief adenine exposure, CKD development and return to a normal diet. Male Wistar rats received a 0.3% adenine diet for 10 weeks and normal chow for an additional 8 weeks. Kidney function was assessed by urinalysis and histology. Heart function was assessed by echocardiography. Sensitivity to myocardial IR injury was assessed using the isolated perfused rat heart (Langendorff) model. The inflammation profile of rats with CKD was assessed via cytokine ELISA, tissue histology and RNA sequencing. Induction of CKD was confirmed by a significant increase in plasma creatinine and albuminuria. Histology revealed extensive glomerular and tubular damage. Diastolic dysfunction, measured by the reduction of the E/A ratio, was apparent in rats with CKD even following a normal diet. Hearts from rats with CKD had significantly larger infarcts after IR injury. The CKD rats also had statistically higher levels of markers of inflammation including myeloperoxidase, KIM-1 and interleukin-33. RNA sequencing revealed several changes including an increase in inflammatory signaling pathways. In addition, we noted that CKD induced significant cardiac capillary rarefaction. We have established a modified model of adenine-induced CKD, which leads to cardiovascular dysfunction in the absence of adenine. Our observations of capillary rarefaction and inflammation suggest that these may contribute to detrimental cardiovascular outcomes.

Comparison of sGC activator and sGC stimulator in 5/6 nephrectomized rats on high-salt-diet.

Soluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies. We conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41-8543 and the sGC activator BAY 60-2770 in CKD progression. BAY 41-8543 (1mg/kg; twice daily) and BAY 60-2770 (1mg/kg; once daily) were administered by gavage for 11 weeks. The 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41-8543 and BAY 60-2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60-2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41-8543 did not. These antifibrotic effects of BAY 60-2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60-2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group. In contrast, BAY 41-8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure.

Gastrointestinal permeability and kidney injury risk during hyperthermia in young and older adults.

We tested whether older adults, compared with young adults, exhibit greater gastrointestinal permeability and kidney injury during heat stress. Nine young (32±3 years) and nine older (72±3 years) participants were heated using a model of controlled hyperthermia (increasing core temperature by 2°C via a water-perfused suit). Gastrointestinal permeability was assessed using a multi-sugar drink test containing lactulose, sucrose and rhamnose. Blood and urine samples were assayed for markers of intestinal barrier injury [plasma intestinal fatty acid binding protein (I-FABP), plasma lipopolysaccharide binding protein (LBP) and plasma soluble cluster of differentiation 14 (sCD14)], inflammation (serum cytokines), kidney function (plasma creatinine and cystatin C) and kidney injury [urine arithmetic product of IGFBP7 and TIMP-2 (TIMP-2 × IGFBP7), neutrophil gelatinase-associated lipocalin and kidney injury molecule-1]. The lactulose-to-rhamnose ratio was increased in both young and older adults (group-wide: Δ0.11±0.11), but the excretion of sucrose was increased only in older adults (Δ1.7±1.5). Young and older adults showed similar increases in plasma LBP (group-wide: Δ0.65±0.89µg/mL), but no changes were observed for I-FABP or sCD14. Heat stress caused similar increases in plasma creatinine (group-wide: Δ0.08±0.07mg/dL), cystatin C (group-wide: Δ0.16±0.18mg/L) and urinary IGFBP7×TIMP-2 [group-wide: Δ0.64±0.95 (pg/min)2] in young and older adults. Thus, the level of heat stress used herein caused modest increases in gastrointestinal permeability, resulting in a mild inflammatory response in young and older adults. Furthermore, our data indicate that older adults might be more at risk for increases in gastroduodenal permeability, as evidenced by the larger increases in sucrose excretion in response to heat stress. Finally, our findings show that heat stress impairs kidney function and elevates markers of kidney injury; however, these responses are not modulated by age.

Early metabolic and hemodynamic indicators of kidney dysfunction in mice offspring from parental low protein diet

BackgroundParental malnutrition, particularly a low-protein diet (LPD), causes oligonephropathy at birth and predisposes offspring to hypertension and chronic kidney disease later in life. The onset of adult kidney disease varies based on genetics and environmental factors, often with subclinical alterations in kidney function being overlooked. This study aimed to examine changes in kidney morphology before significant kidney function decline in the offspring of mice fed a low-protein diet.MethodsUsing a combination of histological analysis, kidney metabolic and hemodynamic panel assessments, and advanced statistical techniques such as Linear Discriminant Analysis (LDA) and Principal Component Analysis (PCA), we investigated the initial impact of a maternal low-protein diet (LPD) on kidney development and function. Our study utilized 12-week-old F1 mice from F0 parents fed either a low-protein diet (LPD) or a normal-protein diet (NPD) before the onset of hypertension.ResultsThe offspring (F1 generation) of parents (F0 generation) fed an LPD show reduced body weight from birth to P20. The kidney weight was also reduced compared to F1 offspring from parents fed an NPD. At 12 weeks of age, body weight normalized, but kidney weight remained low. Offspring of parents fed an LPD displayed abnormal kidney morphology, including dilated tubules, oligonephropathy, and fluid-filled cysts which had worsened with age. A kidney metabolic panel analysis at 12 weeks revealed a slight but consistent increase in urine albumin, plasma creatinine, mean urea, and BUN concentrations. Although no significant changes in hemodynamic variables were observed, 2/12 mice, both males, showed alterations in systolic blood pressure, suggesting sex-specific effects when comparing F1 mice from F0 fed either diet. Overall, kidney metabolic changes were strongly correlated to parental LPD.ConclusionOur findings indicate that significant kidney damage must accumulate in the F1 generation from parents fed an LPD before any detectable changes in blood pressure occur. Our study suggests that small variations in kidney metabolic function may point to early kidney damage and should not be overlooked in the offspring of these malnourished mice and likely humans.

Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease

ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.

#1973 Factors conditioning cisplatin nephrotoxicity

Abstract Background and Aims Cisplatin is an antitumor drug whose use is significantly limited by its nephrotoxicity. Knowledge of the factors that determine or condition the pathogenesis of cisplatin-induced AKI will help to prevent or reduce nephrotoxic outcomes and improve safety during cisplatin treatment. Specifically, we aimed to study the impact of different factors (dehydration, hypertension, age and combinations of the former) on a pre-clinical model of AKI induced by a low dose of cisplatin. Method Young Wistar rats, young spontaneously hypertensive rats (SHR), and aged Wistar rats were divided into two experimental groups: Blood and 24-hour urine samples were collected, and renal function (plasma creatinine, plasma urea and urine protein levels) and dehydration parameters (weight loss, skin elasticity, haematocrit, plasma osmolality, urine flow and urine concentration) were monitored for each animal at three different timepoints: basal time (B), at the end of the dehydration period (D0), and 4 days after cisplatin administration (D4, day of maximum kidney damage). Results After 48 h water deprivation, dehydration was evinced by loss of weight, reduced skin elasticity, increases in plasma osmolality and haematocrit, urine flow reduction and highly concentrated urine (with elevated density and osmolality). A single, low dose of cisplatin induced minimal loss of renal function in young normohydrated Wistar rats that was not worsened by previous acute dehydration resulting from 48 h water deprivation. Interestingly, although renal function was fully preserved when cisplatin was administered to hypertensive rats under normohydrated conditions, a cisplatin-induced AKI (with significant increases in plasma creatinine, plasma urea and proteinuria) was developed in hypertensive rats when animals were previously forced to dehydration. Aged Wistar rats with free access to drinking water showed an important loss of renal function after cisplatin administration (as supported by increases in plasma creatinine and urea concentration). This effect was significantly amplified when aged animals were dehydrated at the time of cisplatin administration. Conclusion Our results suggest that age is an important factor conditioning cisplatin nephrotoxicity. Hypertension or dehydration in fully competent young rats are not in itself significant risk factors for AKI. However, when dehydration is combined with other comorbidity (age or hypertension) the risk of cisplatin-induced AKI is significantly increased. In perspective, our animal models reproducing conditions of increased vulnerability to cisplatin-induced AKI provide useful tools not only for the identification of predictive biomarkers pre-emptively detecting individuals at high risk, but also to assess preventive strategies potentially useful for vulnerable individuals. This study was supported by Project PI21/01226, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and a grant from the Consejería de Educación, Junta de Castilla y León (IES160P20), Spain, co-funded by FEDER funds. Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU/PRTR”.

Risk factors and implications associated with ultrasound-diagnosed nephrocalcinosis in cats with chronic kidney disease.

Microscopic nephrocalcinosis is a common pathological feature of chronic kidney disease (CKD) in cats. Detection of macroscopic nephrocalcinosis using ultrasonography and its implications remain unexplored. Identify risk factors associated with ultrasound-diagnosed nephrocalcinosis and evaluate the influence of nephrocalcinosis on CKD progression. Thirty-six euthyroid client-owned cats with CKD. Prospective cohort study. Cats with CKD with and without ionized hypercalcemia were enrolled for renal ultrasonography. Cats were categorized according to the presence or absence of ultrasound-diagnosed nephrocalcinosis. Binary logistic regression was performed to identify nephrocalcinosis risk factors. The influence of nephrocalcinosis on CKD progression was assessed using linear mixed models. Ultrasound-diagnosed nephrocalcinosis was evident in 61% of CKD cats overall, with increased prevalence (81%) in those with hypercalcemia. At enrollment, higher blood ionized calcium concentration (odds ratio [OR], 1.27 per 0.1 mg/dL; P = .01), plasma phosphate concentration (OR, 1.16 per 0.1 mg/dL; P = .05), plasma creatinine concentration (OR, 1.29 per 0.1 mg/dL; P = .02) and alanine aminotransferase activity (OR, 2.08 per 10 U/L; P = .04) were independent nephrocalcinosis risk factors. The rate of change in log-transformed fibroblast growth factor-23 differed significantly between groups (P = .04). Cats with CKD and nephrocalcinosis had increasing plasma creatinine concentrations (.03 ± .01 mg/dL/month; P = .04) and phosphate concentrations (.06 ± .02 mg/dL/month; P < .001) and decreasing body weight (.02 ± .01 kg/month; P < .001) over time. Nephrocalcinosis is prevalent in cats with CKD, especially in those with hypercalcemia. This pathological feature appears to be associated with CKD progression in cats.

Predictors and Prognostic Impact of Early Acute Kidney Injury in Cardiogenic Shock: Results from a Monocentric, Prospective Registry

Introduction: The presence of acute kidney injury (AKI) was shown to increase the risk of mortality following acute myocardial infarction; however, data regarding the prognostic impact of early AKI in patients with concomitant cardiogenic shock (CS) is limited. The study investigates predictors and the prognostic impact of AKI in patients with CS. Methods: Consecutive patients with CS from 2019 to 2021 were included at one institution. Laboratory values were retrieved from day of disease onset (day 1) and days 2, 3, 4, and 8 thereafter. Predictors for AKI (defined as an increase of plasma creatinine >50% within 48 h referring to pre-admission or baseline creatinine on day 1 and/or the need for continuous veno-venous hemodiafiltration [CVVHDF]) and the prognostic impact of early AKI with regard to 30-day all-cause mortality were assessed. Statistical analyses included t test, Spearman’s correlation, C-statistics, Kaplan-Meier, and Cox proportional regression analyses. Results: A total of 219 CS patients were included with an incidence of early CS-related AKI of 52%. With an area under the curve of up to 0.689 (p = 0.001), creatine discriminated 30-day mortality in CS. Increasing lactate levels (OR = 1.194; 95% CI: 1.083–1.316; p = 0.001; per increase of 1 mmol/L) was associated with the occurrence of AKI. The presence of AKI was associated with an increased risk of 30-day all-cause mortality (63% vs. 36%; HR = 2.138; 95% CI: 1.441–3.171; p = 0.001), even after multivariable adjustment (HR = 1.861; 95% CI: 1.207–2.869; p = 0.005). Finally, highest risk of all-cause mortality was observed in patients with AKI requiring CVVHDF (75% vs. 44%; log rank p = 0.001; HR = 2.211; 95% CI: 1.315–3.718; p = 0.003). Conclusion: Early AKI affects more than half of patients with CS and is independently associated with 30-day all-cause mortality in CS, with highest risk of death among patients with AKI requiring CVVHDF.

Association of Glutamate Infusion With Risk of Acute Kidney Injury After Coronary Artery Bypass Surgery

Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality, and measures to prevent AKI have had limited success. Glutamate has been reported to enhance natural postischemic recovery of the heart, but not among animals and humans with diabetes. To summarize pooled results from the GLUTAMICS (Glutamate for Metabolic Intervention in Coronary Surgery) trials regarding the effect of glutamate on postoperative AKI among patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Data on a total of 791 patients without diabetes from 2 prospective, randomized, double-blind multicenter trials performed at 5 cardiac surgery centers in Sweden between October 4, 2005, and November 12, 2009, and between November 15, 2015, and September 30, 2020, were pooled. Patients had acute coronary syndrome, left ventricular ejection fraction of 0.30 or less, or a European System for Cardiac Risk Evaluation II score of 3.0 or more and underwent CABG with or without additional valve procedure. Statistical analysis was performed from May to November 2023. Intravenous infusion of 0.125-M l-glutamic acid or saline at 1.65 mL/kg/h for 2 hours during reperfusion, after which the infusion rate was halved and an additional 50 mL was given. The primary end point was AKI, defined as postoperative increase of plasma creatinine of 50% or more, corresponding to the Risk stage or higher in the Risk, Injury, Failure, Loss, and End-Stage kidney disease (RIFLE) criteria. A total of 791 patients without diabetes (391 who received glutamate [mean (SD) age, 69.3 (9.1) years; 62 women (15.9%)] and 400 controls [mean (SD) age, 69.6 (9.5) years; 73 women (18.3%)]) were randomized. Baseline data did not differ between groups. Glutamate was associated with a significantly lower risk of AKI (relative risk, 0.49 [95% CI, 0.29-0.83]). Dialysis was required for 2 patients in the glutamate group and 5 patients in the control group. In multivariable analysis, glutamate remained significantly associated with a protective effect against AKI (odds ratio, 0.47 [95% CI, 0.26-0.86]). In the glutamate and control groups, the rate of postoperative mortality at 30 days or less was 0.5% (2 of 391) vs 1.0% (4 of 400), and the rate of stroke at 24 hours or less was 0.8% (3 of 391) vs 1.8% (7 of 400). In this pooled analysis of 2 randomized clinical trials, infusion of glutamate was associated with a markedly lower risk of AKI after CABG among patients without diabetes. The findings are exploratory and need to be confirmed in prospective trials. ClinicalTrials.gov Identifiers: NCT00489827 and NCT02592824.

Assessing donor kidney function: the role of CIRBP in predicting delayed graft function post-transplant.

Delayed graft function (DGF) shortens the survival time of transplanted kidneys and increases the risk of rejection. Current methods are inadequate in predicting DGF. More precise tools are required to assess kidney suitability for transplantation. Cold-inducible RNA-binding protein (CIRBP) expression has been linked to acute kidney injury, suggesting its potential as a new biomarker for transplanted kidney function. We included deceased donors and recipients who had undergone successful kidney transplantation between 2016 and 2019. Recipients and their paired donors are assigned to either the DGF or immediate graft function (IGF) group, based on the recipient's recovery of graft renal function. Donor plasma CIRBP levels were measured using an enzyme-linked immunosorbent assay kit to assess their relationships with DGF. Donor plasma CIRBP concentrations in the DGF group were approximately twice as high as those in the IGF group (6.82 vs. 3.44; P<0.001). DGF occurred in all cases where CIRBP concentrations exceeded 7.92 ng/mL. Furthermore, univariate and multivariate analyses (odds ratio [OR]=1.660; P<0.001) confirmed that donor plasma CIRBP level was an independent risk factor for DGF. Additionally, higher CIRBP levels were associated with increased plasma creatinine at 6 months (R²=0.08; P<0.001), and survival analysis showed shorter kidney survival in recipients with DGF (P=0.002). This study demonstrated that donor plasma CIRBP levels can effectively predict the occurrence of DGF. CIRBP is a potential novel biomarker for evaluating transplanted kidney function. https://clinicaltrials.gov, identifier NCT06641622.

Olive oil Ameliorates renal Ischemia-reperfusion-mediated hepatic and renal changes in stressed rats

Background: Renal ischemia-reperfusion injury (IRI) does not only affect kidneys, but also affects remote organs especially the liver. Stress may lead to further progression of renal and hepatic insults. This study was planned to explore the efficacy of olive oil (OO) on the assumed renal and hepatic changes of immobilization stress following renal IRI. Methods: Seventy-seven adult male Wistar albino rats were divided into the following five groups; Sham-Operated Control group, Renal Ischemia-Reperfusion group, Stressed Renal Ischemia-Reperfusion group, OO-Supplemented Renal Ischemia-Reperfusion group) and OO-Supplemented Stressed Renal Ischemia-Reperfusion Group (OO+Stressed+IR). All animals were subjected to determination of renal and hepatic biochemical functions and histopathological examination. Results: Renal IR significantly increased plasma creatinine and urea levels. This was associated with significant rise in serum levels of both ALT and AST, total bilirubin together with plasma level of TNF-[Formula: see text], whereas the plasma level of albumin (ALB) was significantly reduced. In addition, histological disruptions of kidneys and livers were observed. Chronic immobilization stress aggravated the effects of renal IR. Also, renal and hepatic morphological changes were more worsened. Whilst, OO supplementation resulted in significant amelioration of renal and hepatic functions. Also, the kidney and liver morphologic lesions were attenuated. Conclusion: Renal IR not only affected the renal functional and structural integrity but also the remote organ, the liver. Chronic immobilization stress rendered the kidney and liver more prone to injury. OO improved renal and hepatic dysfunction and morphological damage mediated by renal IRI, in control rats and in those exposed to chronic stress which can be exerted partially via its antioxidant, anti- inflammatory and nitric oxide (NO) reducing activities.

Heat-treated and/or lysozyme-treated Enterococcus faecalis (FK-23) improves the progression of renal disease in a unilateral ischemia-reperfusion injury rat model

The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated Enterococcus faecalis (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed ad libitum as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumulation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that Enterococcus faecalis ingredients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.

Mitochondrial Impairment and Oxidative Stress Are Essential Mechanisms Involved in the Pathogenesis of Acute Kidney Injury

Acute kidney injury (AKI) is an emergency condition that requires restrictive and appropriate clinical interventions. Identifying mechanisms of organ injury is a critical step in developing clinical interventions. Unilateral ureter obstruction (UUO) is widely used as an animal model for investigating AKI. The current study was designed to evaluate the role of mitochondrial impairment and oxidative stress in the pathogenesis of renal injury in UUO model. Mice underwent UUO surgery. Then, kidney tissue histopathological changes, plasma biomarkers of renal injury, oxidative stress, and different renal mitochondrial indices were evaluated at scheduled time intervals (3, 7, 14, and 21 days after UUO surgical procedure). Significant increase in plasma creatinine and blood urea nitrogen levels was evident in UUO mice. The UUO surgery induced severe kidney tissue histopathological alterations, including necrosis, severe tubular atrophy, and interstitial inflammation. Moreover, kidney biomarkers of oxidative stress included reactive oxygen species formation, lipid peroxidation, protein carbonylation, decreased glutathione reservoirs (GSH), and increased oxidized glutathione (GSSG) observed in UUO mice. On the other hand, significant mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and decreased adenosine triphosphate and GSH/GSSG levels were discovered in mitochondria isolated from the kidneys of UUO mice. The data obtained from the current study demonstrated a pivotal and interconnected role for oxidative stress and mitochondrial dysfunction in the pathogenesis of renal injury in UUO model. Therefore, these directions could serve as therapeutic targets in animal models or patients of acute renal failure.

Sustained activation of 12/15 lipoxygenase (12/15 LOX) contributes to impaired renal recovery post ischemic injury in male SHR compared to females

BackgroundAcute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females.Methods13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography–mass spectrometry (LC/MS).ResultsMale SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR.ConclusionOur data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

Proximal tubular uptake of aristolochic acid (AA) forms aristolactam (AL)-DNA adducts, which cause a p53/p21-mediated DNA damage response and acute tubular injury. Recurrent AA exposure causes kidney function loss and fibrosis in humans (Balkan endemic nephropathy) and mice and is a model of (acute kidney injury) AKI to chronic kidney disease (CKD) transition. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. C57BL/6J mice (15-wk-old) were administered vehicle or AA every 3 days for 3 wk (10 and 3 mg/kg ip in females and males, respectively). Dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. All dapa effects were sex independent, including a robust glycosuria. Dapa lowered urinary kidney-injury molecule 1 (KIM-1) and albumin (both normalized to creatinine) after the last AA injection and kidney mRNA expression of early DNA damage response markers (p53 and p21) 3 wk later at the study end. Dapa also attenuated AA-induced increases in plasma creatinine as well as AA-induced up-regulation of renal pro-senescence, pro-inflammatory and pro-fibrotic genes, and kidney collagen staining. When assessed 1 day after a single AA injection, dapa pretreatment attenuated AL-DNA adduct formation by 10 and 20% in kidney and liver, respectively, associated with reduced p21 expression. Initiating dapa application after the last AA injection also improved kidney outcome but in a less robust manner. In conclusion, the first evidence is presented that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.NEW & NOTEWORTHY Recurrent exposure to aristolochic acid (AA) causes kidney function loss and fibrosis in mice and in humans, e.g., in the form of the endemic Balkan nephropathy. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. Here we provide the first evidence in a murine model that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.

Impact of procedure-related increase in plasma creatinine after transcatheter aortic valve implantation: a nationwide study

Abstract Background In patients undergoing transcatheter aortic valve implantation (TAVI), the impact of plasma creatinine (PCreat) increase on the prognosis and on future kidney function is sparsely examined and data from large, nationwide cohorts are warranted. Purpose To examine the long-term risk of dialysis treatment, mortality, and major adverse kidney event according to PCreat level increments in the periprocedural setting of TAVI. Methods With Danish nationwide registries, we identified all patients undergoing TAVI from 2014–2021. According to two PCreat blood samples (the latest measured value between 365–7 days prior to TAVI and the highest measured value within 21 days after TAVI), patients were classified according to percent increase in PCreat: 1) &amp;lt;25%, 2) 25–49%, and 3) ≥50%. With a maximum of one year of follow-up, we used Aalen-Johanson estimator to examine the cumulative incidence frequency (CIF) of first-time dialysis treatment and major adverse kidney event and Kaplan-Meier estimates to assess all-cause mortality. Major adverse kidney event was defined as either of three: initiation of dialysis treatment, mortality, or an admission with a diagnosis code of acute kidney injury. Adjusted rates of outcomes were assessed, using multivariable Cox analysis, with patients with &amp;lt;25% PCreat increase serving as reference. Results We identified 4,029 patients undergoing a first-time TAVI procedure (57.0% male, median age 81 year); 3,343 (83.0%) patients with &amp;lt;25% PCreat increase, 462 (11.5%) with 25–49% PCreat increase, and 224 (5.6%) with ≥50% PCreat increase. Compared with &amp;lt;25% PCreat increase, the adjusted one-year rate of dialysis treatment showed no statistical difference in patients with 25-49% PCreat increase (hazard ratio [HR] 1.52 [95%CI, 0.74–3.11]), while patients with ≥50% PCreat increase had an increased associated one-year rate of dialysis treatment (HR 3.62 [95%CI, 1.90–6.90]) (Figure). The adjusted one-year rate of mortality was increased in both patients with 25-49% PCreat increase (HR 1.78 [95%CI, 1.29–2.45]) and ≥50% PCreat increase (HR 2.87 [95%CI, 1.97–4.18]). The adjusted one-year rate of major adverse kidney event was increased in both patients with 25-49% PCreat increase (HR 1.69 [95%CI, 1.25–2.28]) and ≥50% PCreat increase (HR 3.03 [95%CI, 2.17–4.23]). Conclusion In patients undergoing TAVI, a PCreat increase of ≥25% was associated with increased one-year rates of mortality and major adverse kidney event, while an increase ≥50% carried a more than threefold increased rate of incident dialysis treatment and increased rates of mortality and major adverse kidney event.