Renal Oxygenation and Hemodynamics in Kidney Injury

Bullen, Alexander L.; Liu, Zhi Zhao; Hepokoski, Mark; Liu, Ying; Singh, Prabhleen

doi:10.1159/000477830

Cited by 29 publications

(20 citation statements)

References 30 publications

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“…It was discovered later that neurohumoral mediators released during mechanical ventilation also adversely alter renal blood flow from cortex to medulla which leads to sodium reabsorption and a reduction in the glomerular filtration rate (GFR). Sodium reabsorption in the kidney requires high oxygen utilization[6]; therefore, mechanical ventilation may decrease oxygen delivery through systemic hemodynamic effects while subsequently increasing oxygen utilization via neurohumoral mediators.…”

Section: Mechanisms and Current Approach To Mechanical Ventilation Inmentioning

confidence: 99%

Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention?

Hepokoski

Malhotra

Singh

et al. 2018

Nephron

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Mechanical ventilation is associated with significant increases in the risk of acute kidney injury (AKI). The rate of AKI due to mechanical ventilation and the associated mortality remain unacceptably high. Preventative and therapeutic strategies are clearly lacking. Ventilator-induced kidney injury is believed to occur due to changes in hemodynamics that impair renal perfusion, neurohumoral-mediated alterations in intra-renal blood flow, and systemic inflammatory mediators generated by ventilator-induced lung injury. The risk of injury to the kidney by these mechanisms may be modified by open lung protective ventilation with low tidal volumes and high positive end expiratory pressure. However, these strategies may also increase the risk of injury in some settings, and clinicians have limited means to identify the optimal ventilator strategy for each specific patient. Novel urinary biomarkers have demonstrated the ability to predict AKI prior to classic clinical signs such as decreased urine output and increased creatinine. These biomarkers may serve as an early indication to intensivists of an injurious ventilator strategy and failure of traditional management.

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Section: Mechanisms and Current Approach To Mechanical Ventilation Inmentioning

confidence: 99%

Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention?

Hepokoski

Malhotra

Singh

et al. 2018

Nephron

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“…While genetic compensation remains a possibility, collectively our results suggest that BRAF-kinase is not an essential gene in RTECs and vemurafenib nephrotoxicity is BRAF-independent. Though it is important to note that AKI is a multifaceted disease 2 that results from a complex interplay between epithelial 31,50,51 , immune 33 , and endothelial 52,53 cells. Thus, notwithstanding our studies with RTECs, further work is required to discern the role of immune and endothelial cells in vemurafenib nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Bai¹,

Kim²,

Jayne³

et al. 2021

Preprint

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A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal dysfunction through on and off-target mechanisms. Interestingly, among the small-molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenib-associated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by off-target FECH inhibition.Translational StatementBRAF is the most frequently mutated protein kinase and a critical oncogenic driver in human cancers. In melanoma and other cancers with BRAF activating mutations, BRAF targeted small-molecule therapeutics such as vemurafenib, and dabrafenib have shown remarkable clinical benefits. However, recent clinical studies have shown that a significant number of patients that receive vemurafenib develop AKI through mechanisms that remain unknown. The present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.

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“…Acute changes in serum creatinine may not accurately reflect the severity or nature of kidney injury due to the influence of factors such as age, sex, muscle mass, nutritional status, medication effects on creatinine kinetics, IV fluid administration, and hemodynamic changes with subsequent oxygen supply-demand mismatch. 7 Therefore, serum creatinine measured in the hospital setting can vary significantly and unpredictably. Further, elevations in serum creatinine are known to occur 48-72 hours following the episode of kidney injury.…”

Section: Introductionmentioning

confidence: 99%

Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery

Menez

Moledina

Garg

et al. 2021

Kidney International

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Renal Oxygenation and Hemodynamics in Kidney Injury

Cited by 29 publications

References 30 publications

Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention?

Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention?

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery

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