Disruption of Kidney–Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health

LaFavers, Kaice A.

doi:10.3390/ijms23031702

Cited by 18 publications

(9 citation statements)

References 94 publications

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“…It would be exciting to test these drugs in clinical trials for amelioration of both cisplatin-induced AKI and hearing loss. In addition, future studies can also address the possibility that these two drugs will have utility in other clinical settings associated with AKI, such as Fanconi-like syndrome, which can become a long-term sequela of cisplatin-induced kidney injury, 71,72 aminoglycoside-induced AKI, 73,74 ischemic injury, 75 sepsis, 76,77 and rhabdomyolysis. 78,79…”

Section: Discussionmentioning

confidence: 99%

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Pushpan,

Kresock,

Ingersoll

et al. 2023

JASN

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Background: Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects including acute kidney injury (AKI) and hearing loss. There are no FDA-approved drugs to treat both side effects. Recently, two anti-cancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin, and tested whether these drugs alleviate cisplatin-induced AKI. Methods: The HK-2 cell line and adult FVB mice were utilized to measure the protection from cisplatin-induced cell death and AKI by these drugs. Serum markers of kidney injury, BUN, creatinine, and NGAL, as well as histology of kidneys were analyzed. Levels of markers of kidney cell death including necroptosis and pyroptosis, pERK, and PCNA, were also examined by western blotting and immunofluorescence. Additionally, CDK2 KO mice were utilized to confirm AZD5438 protective effect is through CDK2 inhibition. Results: The drugs reduced cisplatin-induced cell death in the HK-2 cell line and attenuated cisplatin-induced AKI in mice. The drugs reduced serum kidney injury markers, inhibited cell death, and reduced levels of pERK and PCNA, all of which correlated with prolonged animal survival. CDK2 KO mice were resistant to cisplatin-induced AKI and AZD5438 conferred no additional protection in the KO mice. Conclusion: Cisplatin-induced damage to the inner ear and kidneys share similar cellular beneficial responses to AZD5438 and dabrafenib highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss.

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Section: Discussionmentioning

confidence: 99%

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Pushpan,

Kresock,

Ingersoll

et al. 2023

JASN

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“…Early sepsis is characterized by an organism's proinflammatory response mediated by neutrophils, macrophages, and other immune cells, referred to as the hyperdynamic phase. The organism subsequently enters a hypokinetic period marked by decreased tissue perfusion, impaired microcirculation, and exacerbated organ damage [ 23 ]. Meanwhile, sepsis-induced tissue damage increases inducible nitric oxide (NO) synthase activity while substantially suppressing endothelial NO synthase activity.…”

Section: Discussionmentioning

confidence: 99%

Clinical Value of Prognostic Nutritional Index and Neutrophil-to-Lymphocyte Ratio in Prediction of the Development of Sepsis-Induced Kidney Injury

et al. 2022

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Background. Sepsis-related acute kidney injury (S-AKI) is a frequent complication of hospitalized patients and is linked to increased morbidity and mortality. Early prediction and detection remain conducive to optimizing treatment strategies and limiting further insults. This study was aimed at evaluating the potential predictive value of the combined prognostic nutrition index (PNI) and neutrophil-to-lymphocyte ratio (NLR) to predict the risk of AKI in septic patients. Methods. In this retrospective study, 1238 adult patients with sepsis who were admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 2015 to June 2021 were enrolled. Patients were divided into two groups: the non-AKI group ( n = 731 ) and the S-AKI group ( n = 507 ). Univariate and multivariate logistic regression analyses were performed to screen the independent predictive factors of S-AKI. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of PNI and NLR. Results. Multivariate logistic regression analysis indicated that age, chronic liver disease, cardiovascular disease, respiratory rate (RR), white blood cells (WBC), blood urea nitrogen (BUN), creatinine (CRE), international normalized ratio (INR), neutrophil-to-lymphocyte ratio (NLR), and prognostic nutrition index (PNI) were independent prognostic factors of S-AKI. In the three models, the adjusted OR of PNI for S-AKI was 0.802 (0.776-0.829), 0.801 (0.775-0.829), and 0.717 (0.666-0.772), while that of NLR was 1.094 (1.078-1.111), 1.097 (1.080-1.114), and 1.044 (1.016-1.072), respectively. In addition, the area under the ROC curve of the PNI plus NLR group was significantly greater than that of the CRE plus BUN group (0.801, 95% CI: 0.775-0.827 vs. 0.750, 95% CI: 0.722-0.778, respectively; P < 0.001 ). Conclusions. PNI and NLR have been identified as readily available and independent predictors in septic patients with S-AKI. PNI, in combination with NLR, is of vital significance for early warning and efficient intervention of S-AKI and is superior to combined BUN and CRE.

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“…Additionally, vitamin D intervention could decrease the production of inflammatory cytokines such as IL-6, IL-8, IL-12, IL-17, tumor necrosis factor-α (TNF-α), and interferons-γ (IFN-γ), and thus prevent inflammation from progressing and damaging other organs, including the kidneys [55][56][57]. As a result, numerous preclinical studies have been conducted using vitamin D as a treatment for various types of AKI, such as sepsis-induced AKI, with promising results in mitigating both renal oxidative stress and the expression of inflammatory cytokines in kidney [58].…”

Section: Oxidative Stress Inflammation and Cytokine Stormmentioning

confidence: 99%

Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of “Kidney-Brain” Disorders

Zhang¹,

Wang²,

Zhang³

2023

Vitamin D Deficiency - New Insights

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Accumulating evidences have shown that serum 25-hydroxyvitamin D concentrations were inversely correlated with the incidence or severity of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and that vitamin D deficiency might be associated with an increased susceptibility to many of the complications accompanied by COVID-19, such as disorders in kidney and brain. Our previous experimental studies demonstrated that vitamin D and its analogs could protect from kidney diseases, neuroinflammation, and musculoskeletal disorders such as osteoporosis and muscle atrophy, through the suppressive effects on overactivation of the renin-angiotensin system (RAS) in tissues. Moreover, we published a review describing the therapeutic effects of traditional Chinese medicine (TCM) for organ injuries associated with COVID-19 by interfering with RAS. In the TCM principle “Kidney dredges brain,” this chapter will emphasize the potential preventive and therapeutic effects of vitamin D on both renal injuries and central nervous system disorders in COVID-19 patients and further elucidate the pharmacological effects with underlying mechanisms of vitamin D in “Kidney-Brain” disorders.

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Disruption of Kidney–Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health

Cited by 18 publications

References 94 publications

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Clinical Value of Prognostic Nutritional Index and Neutrophil-to-Lymphocyte Ratio in Prediction of the Development of Sepsis-Induced Kidney Injury

Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of “Kidney-Brain” Disorders

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