A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation.

BACKGROUND: Nephrotoxicity remains the most serious side effect of cisplatin therapy. Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and affects up to 20% of patients. Several possible interventions such as magnesium supplementation may prevent CIN. This study aimed to review different types of hydration protocols and we conducted a meta-analysis of magnesium supplementation to understand its effect in protecting against CIN. METHODS: A search of the PubMed, Embase, and Cochrane databases was performed. Trials were eligible if they enrolled patients who received cisplatin and different hydration protocols to prevent CIN. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the efficacy of different protocols. RESULTS: We initially identified 1113 different studies and included 33 of them which met the selection criteria. A meta-analysis of 11 retrospective studies that examined magnesium supplementation during hydration showed that this treatment provided significant protection against CIN (OR = 0.22, 95% CI = 0.14 to 0.35). CONCLUSION: There has been uncertainty regarding the best method to prevent CIN. Our results highlight the potentially protective effect of magnesium supplementation during hydration. This study is registered in PROSPERO, CRD42020212682.

Acute Kidney Injury after Multiple Cycles of Cisplatin Chemotherapy: A Nomogram for Risk Assessment.

INTRODUCTION: Acute kidney injury (AKI) caused by cisplatin is common and has a higher incidence of multiple use, resulting in a poor short- and long-term prognosis for patients. There is currently no good premedication AKI risk assessment tool. The aim of this study was to establish an AKI risk assessment nomogram for patients with multiple cisplatin applications. METHODS: This study was a retrospective analysis of patients who were treated with non-first-time cisplatin chemotherapy regimen at Changzhou Second People's Hospital affiliated to Nanjing Medical University from January 2016 to January 2022. All data from the development group were used to screen the impact factors of AKI via univariate and multivariate analyses. A nomogram was developed based on these impact factors and verified with verification group. The area under the curve (AUC) of receiver operating characteristic (ROC) curve, calibration curves, and decision curve analyses (DCAs) were used to evaluate the nomogram. RESULTS: Among the 256 patients enrolled in 450 cycles of chemotherapy, 282 were in the development cohort (97 AKI), and 168 were in the validation cohort (61 AKI). Multivariate logistic regression revealed that age, hypertension, diabetes, serum cystatin C (sCysC), urinary kidney injury molecule-1 (uKim1), and a single dose of cisplatin were independently associated with AKI. The results showed that our model yielded satisfied diagnostic performance with an AUC value of 0.887 and 0.906 using the development group and on verification group. The calibration plots and DCA showed the superior clinical applicability of the nomogram. These results were verified in the validation cohort. CONCLUSION: A nomogram combining functional (sCysC) and tubular (uKim1) injury biomarkers with conventional clinical factors might assess the risk of AKI after multiple cycles of cisplatin chemotherapy.

Altered spontaneous brain activities in maintenance hemodialysis patients with cognitive impairment and the construction of cognitive function prediction models.

OBJECTIVE: The brain neuromechanism in maintenance hemodialysis patients (MHD) with cognitive impairment (CI) remains unclear. The study aimed to probe the relationship between spontaneous brain activity and CI by using resting-state functional magnetic resonance imaging (rs-fMRI) data. METHODS: Here, 55 MHD patients with CI and 28 healthy controls were recruited. For baseline data, qualitative data were compared between groups using the χ2 test; quantitative data were compared between groups using the independent samples t-test, ANOVA test, Mann-Whitney U-test, or Kruskal-Wallis test. Comparisons of ALFF/fALFF/ReHo values among the three groups were calculated by using the DPABI toolbox, and then analyzing the correlation with clinical variables. p < .05 was considered a statistically significant difference. Furthermore, back propagation neural network (BPNN) was utilized to predict cognitive function. RESULTS: Compared with the MHD-NCI group, the patients with MHD-CI had more severe anemia and higher urea nitrogen levels, lower mALFF values in the left postcentral gyrus, lower mfALFF values in the left inferior temporal gyrus, and greater mALFF values in the right caudate nucleus (p < .05). The above-altered indicators were correlated with MOCA scores. BPNN prediction models indicated that the diagnostic efficacy of the model which inputs were hemoglobin, urea nitrogen, and mALFF value in the left central posterior gyrus was optimal (R2 = 0.8054), validation cohort (R2 = 0.7328). CONCLUSION: The rs-fMRI can reveal the neurophysiological mechanism of cognitive impairment in MHD patients. In addition, it can serve as a neuroimaging marker for diagnosing and evaluating cognitive impairment in MHD patients.

The Effects of Febuxostat on Urine NGAL and Urine KIM-1 in Patients with Hyperuricemia.

Retrospective analysis of the effects of febuxostat on urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in patients with hyperuricemia was performed. From January 2018 to June 2018, there were 45 patients with asymptomatic hyperuricemia in the outpatient or inpatient of Changzhou Second People's Hospital, which were divided into the febuxostat group (25 cases) and the control group (20 cases). We collected the patients' baseline indicators and testing indicators after three months of treatment, including blood urea nitrogen, blood creatinine, blood uric acid, urine microalbumin, urine NGAL, urine KIM-1, and other indicators. The subjects in both groups were given lifestyle intervention, instructed to drink more water, and given a low-purine diet. The patients in the febuxostat group took febuxostat 40 mg/D or 80 mg/D. We used SPSS 25.0 statistical software for statistical analysis. Baseline indexes between the febuxostat group and the control group and indexes after treatment between two groups were both performed by independent sample t-test, and paired t-test was used for self-comparison between the groups before and after treatment. There was no significant difference in age, sex, body mass index (BMI), urea nitrogen, creatinine, uric acid, urine microalbumin/creatinine, urine NGAL/creatinine, and urine KIM-1/creatinine between the two groups before treatment (P > 0.05). Compared with before treatment, after 3 months of intervention, the levels of serum uric acid, urine microalbumin/creatinine, urine NGAL/creatinine, and urine KIM-1/creatinine were significantly decreased in the febuxostat group (P < 0.05), while the changes of blood urea nitrogen, serum creatinine, and epidermal growth factor receptor (eGFR) were not statistically significant (P > 0.05). After 3 months of intervention, the control group had no significant changes in blood urea nitrogen, creatinine, eGFR, uric acid, microalbumin/creatinine, urine NGAL/creatinine, and urine KIM-1/creatinine (P > 0.05). After 3 months of intervention, compared with the control group, the serum uric acid, microalbumin/creatinine, urine NGAL/creatinine, and urine KIM-1/creatinine were significantly decreased in the febuxostat group (P < 0.05), but there was no significant difference in blood urea nitrogen, creatinine, and eGFR (P > 0.05). Febuxostat can reduce urine NGAL/creatinine and urine KIM-1/creatinine levels in patients with hyperuricemia and has the protective effects on renal tubular injury caused by hyperuricemia, which can provide evidences for the early prevention and treatment of asymptomatic hyperuricemia.

The influence of dusts on radiation and temperature over the eastern Asia with a regional climate model.

In order to investigate the climate effects of dusts, a regional climate model (RegCM 4.6) with the dust scheme was used to simulate the direct radiative forcing and air temperature response at 2 m near surface of dusts over the eastern Asia. Two sets of experiments were conducted, one with and one without dust aerosols. The experiment covered the main dust occurrence months from March to May for 8 years (2011-2018), and the simulation results were evaluated against ground station, reanalysis and satellite data. The model captured the spatiotemporal distribution of dust AOD and mass loading over the eastern Asia. However, it tended to underestimate the dust AOD and mass loading over the downwind of the dust source region and the Taklimakan Desert, and overestimate them over the north Xinjiang. The direct net radiative forcing including shortwave and longwave was up to -20 W·m-2 at the surface and -10 W·m-2 at the TOA over the dust source region due to the dominant negative shortwave forcing. The only exception of positive forcing at the TOA was observed along the western boundaries of the Tibetan Plateau due to the semi-persistent ice and snow cover. The dusts tended to warm the atmosphere more than 18 W·m-2 and cool the surface locally up to -0.7 °C. Among the 5 sub-areas, the largest averaged regional direct radiative forcing induced by dusts appeared over the central Inner Mongolia in May with the value of -3.0 ± 2.1, -12.2 ± 4.1 and 9.2 ± 4.4 W·m-2 at the TOA, surface and in the atmosphere, respectively. The results indicated that the model simulation for dusts should be further improved and the dust effects should be included in the estimates of climate change over the eastern Asia.

The accuracy improvement of clear-sky surface shortwave radiation derived from CERES SSF dataset with a simulation analysis.

Towards the Xiaotang region along the northern margin of the China's largest desert, a quantitative assessment of the precision of clear-sky satellite observations (the Single Scanner Footprint TOA/Surface Fluxes and Clouds downward surface shortwave radiation product of Clouds and the Earth's Radiant Energy System (CERES), DSSRCER) is conducted, the localized inversion mode of "absolutely clear-sky" downward surface shortwave radiation (DSSR) is established, and the "absolutely clear-sky" DSSR in Xiaotang during 2005-2018 is simulated by the Santa Barbara Discrete Atmospheric Radiative Transfer (SBDART) model. In general, under the "absolutely clear-sky" condition of Xiaotang region, there is a significant error in DSSRCER, and the simulated results of SBDART (DSSRSBD) with same input parameters as DSSRCER is better and more comparable. Single scattering albedo (SSA), asymmetry parameter (ASY) and aerosol optical depth (AOD) play crucial roles in deciding the accuracy of DSSR, and after parameter adjustment, the DSSRSBD is better than the initial, which is improved remarkably with all indexes of the fitting results greatly improved. The temporal variation of the DSSR during 2005-2018 indicates that the highest annual average value is found in 2008 (770.00 W·m-2), while the lowest appears in 2010 (600.97 W·m-2). Besides, the highest seasonal mean DSSR appears in summer, which between 860.6 and 935.07 W·m-2, while reaches the lowest in winter (403.79-587.53 W·m-2). Moreover, the monthly average DSSR changes as a curve with a single peak and is close to normal distribution, the highest appears in June (934.61 W·m-2), while the minimum with the value of 390.34 W·m-2 is found in December. All of the solar elevation angle, the characteristics of climate and aerosol particles in different seasons may contribute to the temporal variation.

Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury.

PURPOSE: Contrast-induced acute kidney injury (CI-AKI) resulting from administration of iodinated contrast media (CM) is the third leading cause of hospital-acquired acute kidney injury and is associated with substantial morbidity and mortality. Deteriorated renal microcirculation plays an important role in CI-AKI. Limb ischemic preconditioning (LIPC), where brief and non-injurious ischemia/reperfusion is applied to a limb prior to the administration of the contrast agent, is emerging as a promising strategy for CI-AKI prevention. However, it is not known whether the renal protection of LIPC against CI-AKI is mediated by regulation of renal microcirculation and the molecular mechanisms remain largely unknown. METHODS: In this study, we examined the renal cortical and medullary blood flow in a stable CI-AKI model using 5/6-nephrectomized (NE) rat. The LIPC and sham procedures were performed prior to the injection of CM. Furthermore, we analyzed renal medulla hypoxia using in vivo labeling of hypoxyprobe. Pharmacological inhibitions and western blotting were used to determine the underlying molecular mechanisms. RESULTS: In this study, we found LIPC significantly ameliorated CM-induced reduction of medullary blood flow and attenuated CM-induced hypoxia. PI3K inhibitor (wortmannin) treatment blocked the regulation of medullary blood flow and the attenuation of hypoxia of LIPC. Phosphorylation of Akt/eNOS was significantly decreased via wortmannin treatment compared with LIPC. Nitric oxide synthase-inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] treatment abolished the above effects and decreased phosphorylation of eNOS, but not Akt. CONCLUSIONS: Collectively, the results demonstrate that LIPC ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/eNOS signaling pathway.

Remote Ischemic Preconditioning Protects Cisplatin-Induced Acute Kidney Injury through the PTEN/AKT Signaling Pathway.

Although cisplatin (Cis) is an effective chemotherapeutic agent in treatment of various cancers, its adverse effect of nephrotoxicity limits the clinical application. Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury by applying transient, brief episodes of ischemia. However, whether RIPC exerts protective effect on Cis-induced renal injury remains unclear. In this study, we showed that RIPC significantly alleviated the renal functional and histopathological damage of Cis-induced acute kidney injury (AKI) mice. Furthermore, RIPC substantially reversed the downregulation of miR-144 and upregulation of PTEN in renal tissues of Cis-induced AKI mice and alleviated tubular cell apoptosis via activating PTEN/AKT signaling. In mechanism, we demonstrated that miR-144 directly targets the 3'-UTR of PTEN mRNA, and then the elevation of miR-144 in RIPC activates PTEN/AKT signaling by downregulating PTEN expression to achieve its antiapoptosis effect. Collectively, our results indicate that RIPC may be a potential therapeutic strategy in Cis-induced AKI, and provide insights on the underlying molecular mechanisms of cisplatin's nephrotoxicity.

Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats.

Contrast-induced acute kidney injury (CI-AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI-AKI. O-linked ß-N-acetylglucosamine (O-GlcNAc) is a post-translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O-GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O-GlcNAc signaling via glucosamine on CI-AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3-kinase (PI3K)/Akt signaling. We used a novel and reliable CI-AKI model consisting of 5/6 nephrectomized (NE) rats, and a low-osmolar contrast media (iohexol, 10mL/kg, 3.5gI) injected via the tail vein after dehydration for 48h. The results showed that augmented O-GlcNAc signaling by glucosamine prevented the kidneys against iohexol-induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O-GlcNAc transferase inhibitor. Augmented O-GlcNAc signaling also increased the protein expression levels of phospho-Akt (Ser473, but not Thr308 and Thr450), phospho-GSK-3ß, Nrf2, and Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O-GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed that Akt was modified by O-GlcNAcylation, and glucosamine pretreatment increased the O-GlcNAcylation of Akt. Collectively, the results demonstrate that glucosamine induces renoprotection against CI-AKI through augmented O-GlcNAc and activation of PI3K/Akt signaling, making it a promising strategy for preventing CI-AKI.

Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a state of Klotho deficiency. The Klotho expression may be suppressed due to DNA hypermethylation in cancer cells so we have investigated the effects and possible mechanisms by which Klotho expression is regulated in human aortic smooth muscle cells (HASMCs). The vascular Klotho hypermethylation in radial arteries of patients with end-stage renal disease was described. Cultured HASMCs and 5/6-nephrectomized Sprague Dawley (SD) rats treated with indoxyl sulfate (IS) were used as in vitro and in vivo models, respectively. IS increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in HASMCs, and potentiated HASMCs calcification. The expression of DNA methyltransferase (DNMT) 1 and 3a in HASMCs treated with IS was significantly increased and specific inhibition of DNA methyltransferase 1 by 5-aza-2'-deoxycytidine(5Aza-2dc) caused demethylation of the Klotho gene and increased Klotho expression. In rats, injection of IS potentiated vascular calcification, increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in the aortic medial layer and all of these changes could be reverted by 5Aza-2dc treatment. Transcriptional suppression of vascular Klotho gene expression by IS and epigenetic modification of Klotho by IS may be an important pathological mechanism of vascular calcification in CKD.

Limb ischemic preconditioning protects against contrast-induced acute kidney injury in rats via phosphorylation of GSK-3ß.

Contrast-induced acute kidney injury (CI-AKI) resulting from the use of intravascular iodinated contrast media for diagnostic and interventional cardiovascular procedures is associated with substantial morbidity and mortality. Despite preventative measures intended to mitigate the risk of CI-AKI, there remains a need for a novel and effective therapeutic approach. Limb ischemic preconditioning (LIPC), where short-term ischemia/reperfusion is applied to an arm prior to administration of the contrast agent, has been shown in several trials to preserve renal function in patients at high risk for CI-AKI. However, the underlying mechanism by which this procedure provides renoprotection against contrast media insults is not known. Here, we explored the molecular mechanism(s) of LIPC-induced protection of the kidneys from CI-AKI, particularly the role of phosphorylated glycogen synthase kinase-3ß (GSK-3ß). We used a novel CI-AKI model consisting of 5/6 nephrectomized (NE) rats at 6 weeks after the ablative surgery. LIPC- or sham-treated rats were administered iohexol (10 ml/kg, 3.5 gI) via the tail vein. The results showed that LIPC protected the kidneys against iohexol-induced injury. This protective effect was accompanied by the attenuation of renal dysfunction, tubular damage, apoptosis, mitochondrial swelling, oxidative stress, and inflammation. Furthermore, LIPC-induced renoprotection was blocked via treatment with inhibitors of PI3K (wortmannin or LY294002), but not ERK (U0126 or PD98059). LIPC also increased the protein expression levels of phospho-Akt, phospho-GSK-3ß, and nuclear Nrf2, and decreased the levels of nuclear NF-κB. A specific GSK-3ß inhibitor (SB216763) mimicked this effect of LIPC, by inhibiting the opening of the mitochondrial permeability transition pore and reducing the levels of oxidative stress and inflammation via activation of Nrf2 and suppression of NF-κB. The above results demonstrate that LIPC induces protection against CI-AKI, making this procedure a promising strategy for preventing CI-AKI. In particular, this renoprotective effect involves the phosphorylation of GSK-3ß.

A novel contrast-induced acute kidney injury model based on the 5/6-nephrectomy rat and nephrotoxicological evaluation of iohexol and iodixanol in vivo.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress. In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. Iohexol induced more severe CI-AKI than iodixanol in this model.

Atorvastatin improves survival of implanted stem cells in a rat model of renal ischemia-reperfusion injury.

AIMS: To investigate the impacts of combinatorial atorvastatin (Ator) perioperative administration and mesenchymal stem cell (MSC) implantation on therapeutic effects in the rat experimental acute kidney injury. METHODS: The model of renal ischemia-reperfusion (I/R) injury was induced by the release of bilateral renal pedicle clamps following 45 min of occlusion. Immediately after reperfusion, CM-Dil-labeled MSCs (1 × 10(6) cells) or vehicles only were administered through the carotid artery of the animals pretreated with or without Ator. RESULTS: The combined treatment with Ator and MSCs (Ator+MSCs) markedly reduced the elevated levels of serum creatinine and blood urea nitrogen, as well as the severity of renal damage 24 h after I/R injury. In addition, we also observed inhibition of renal tubular cell apoptosis and promotion of proliferation in the Ator+MSCs group compared with the other groups. Consistent with the improvement in renal function and morphology, Ator pretreatment significantly ameliorated oxidative stress, inhibited inflammation response, and increased the viability of implanted MSCs. With regard to the further mechanism, we found that the expression of Toll-like receptor 4 (TLR4) and high-mobility group box 1, potential mediators of innate immunity, was significantly decreased in the Ator-treated groups. CONCLUSION: Ator treatment may protect the kidney undergoing I/R injury through suppression of TLR4 signaling, creating a better environment for the survival of grafted MSCs. The extra benefit of the Ator+MSCs combined therapy may result from the Ator-mediated inhibition of oxidative stress and inflammation in the ischemic kidney.