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Acute kidney injury: preclinical innovations, challenges, and opportunities for translation.

Silver SA, Cardinal H, Colwell K, Burger D, Dickhout JG - Can J Kidney Health Dis (2015)

Bottom Line: MEDLINE, ISI Web of Science.As such, it does not represent a systematic review of all of the AKI literature.Translation of findings from biomedical research into AKI therapy presents several challenges.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Canada.

ABSTRACT

Background: Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice.

Objective: This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice.

Sources of information: MEDLINE, ISI Web of Science.

Findings: This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition.

Limitations: This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature.

Implications: Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations.

No MeSH data available.


Related in: MedlinePlus

Acute kidney injury due to acute tubular necrosis. Acute tubular necrosis can be the result of nephrotoxins or ischemia to the kidney. Nephrotoxic drugs, such as tunicmycin, can induce ER stress caused by protein misfolding; while a lack of blood supply to the kidney can cause oxidative stress in the mitochondria. Both ER stress and oxidative stress have been shown to generate reactive oxygen species, ultimately leading to acute kidney injury
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Fig2: Acute kidney injury due to acute tubular necrosis. Acute tubular necrosis can be the result of nephrotoxins or ischemia to the kidney. Nephrotoxic drugs, such as tunicmycin, can induce ER stress caused by protein misfolding; while a lack of blood supply to the kidney can cause oxidative stress in the mitochondria. Both ER stress and oxidative stress have been shown to generate reactive oxygen species, ultimately leading to acute kidney injury

Mentions: The process of ER stress has been linked to AKI from a variety of causes, such as ischemia, nephrotoxic drugs or contrast media [15–19]. ER stress is caused by the accumulation of misfolded proteins in the ER [19]. It has become clear that ER stress induction in the kidney generates AKI [19, 20]. The process of ER and oxidative stress leading to loss of renal function in AKI is summarized in Fig. 2. Diverse physiological and environmental stressors are also regulated through heat shock proteins (HSPs), which are molecular chaperones that are induced in response to cellular stresses that cause protein misfolding [21]. HSPs transiently bind to polypeptides to facilitate correct protein folding by preventing the aggregation of misfolded proteins. In rodent models of IRI-induced AKI, HSP induction was shown to provide protection against the increase in BUN and creatinine levels, preventing the increase in BUN from normal levels, and reducing the tubular necrosis and cast formation index from extensive to mild [22]. The beneficial effects of HSPs were time dependent, and function most efficiently when increased within 6 hours of the AKI-inducing insult. HSPs 70s and 90s are of particular importance in the regulation of protein folding, including the protein GRP78 [21]. ER stress-induced AKI has been shown to be associated with neutral lipid accumulation [23]. GRP78 overexpression reduces lipid accumulation generated by ER stress [23]. Low molecular weight chemical chaperones have been used to reduce ER stress and inhibit AKI due to nephrotoxins [20] and IRI [24].Fig. 2


Acute kidney injury: preclinical innovations, challenges, and opportunities for translation.

Silver SA, Cardinal H, Colwell K, Burger D, Dickhout JG - Can J Kidney Health Dis (2015)

Acute kidney injury due to acute tubular necrosis. Acute tubular necrosis can be the result of nephrotoxins or ischemia to the kidney. Nephrotoxic drugs, such as tunicmycin, can induce ER stress caused by protein misfolding; while a lack of blood supply to the kidney can cause oxidative stress in the mitochondria. Both ER stress and oxidative stress have been shown to generate reactive oxygen species, ultimately leading to acute kidney injury
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4556308&req=5

Fig2: Acute kidney injury due to acute tubular necrosis. Acute tubular necrosis can be the result of nephrotoxins or ischemia to the kidney. Nephrotoxic drugs, such as tunicmycin, can induce ER stress caused by protein misfolding; while a lack of blood supply to the kidney can cause oxidative stress in the mitochondria. Both ER stress and oxidative stress have been shown to generate reactive oxygen species, ultimately leading to acute kidney injury
Mentions: The process of ER stress has been linked to AKI from a variety of causes, such as ischemia, nephrotoxic drugs or contrast media [15–19]. ER stress is caused by the accumulation of misfolded proteins in the ER [19]. It has become clear that ER stress induction in the kidney generates AKI [19, 20]. The process of ER and oxidative stress leading to loss of renal function in AKI is summarized in Fig. 2. Diverse physiological and environmental stressors are also regulated through heat shock proteins (HSPs), which are molecular chaperones that are induced in response to cellular stresses that cause protein misfolding [21]. HSPs transiently bind to polypeptides to facilitate correct protein folding by preventing the aggregation of misfolded proteins. In rodent models of IRI-induced AKI, HSP induction was shown to provide protection against the increase in BUN and creatinine levels, preventing the increase in BUN from normal levels, and reducing the tubular necrosis and cast formation index from extensive to mild [22]. The beneficial effects of HSPs were time dependent, and function most efficiently when increased within 6 hours of the AKI-inducing insult. HSPs 70s and 90s are of particular importance in the regulation of protein folding, including the protein GRP78 [21]. ER stress-induced AKI has been shown to be associated with neutral lipid accumulation [23]. GRP78 overexpression reduces lipid accumulation generated by ER stress [23]. Low molecular weight chemical chaperones have been used to reduce ER stress and inhibit AKI due to nephrotoxins [20] and IRI [24].Fig. 2

Bottom Line: MEDLINE, ISI Web of Science.As such, it does not represent a systematic review of all of the AKI literature.Translation of findings from biomedical research into AKI therapy presents several challenges.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Canada.

ABSTRACT

Background: Acute kidney injury (AKI) is a clinically important condition that has attracted a great deal of interest from the biomedical research community. However, acute kidney injury AKI research findings have yet to be translated into significant changes in clinical practice.

Objective: This article reviews many of the preclinical innovations in acute kidney injury AKI treatment, and explores challenges and opportunities to translate these finding into clinical practice.

Sources of information: MEDLINE, ISI Web of Science.

Findings: This paper details areas in biomedical research where translation of pre-clinical findings into clinical trials is ongoing, or nearing a point where trial design is warranted. Further, the paper examines ways that best practice in the management of AKI can reach a broader proportion of the patient population experiencing this condition.

Limitations: This review highlights pertinent literature from the perspective of the research interests of the authors for new translational work in AKI. As such, it does not represent a systematic review of all of the AKI literature.

Implications: Translation of findings from biomedical research into AKI therapy presents several challenges. These may be partly overcome by targeting populations for interventional trials where the likelihood of AKI is very high, and readily predictable. Further, specific clinics to follow-up with patients after AKI events hold promise to provide best practice in care, and to translate therapies into treatment for the broadest possible patient populations.

No MeSH data available.


Related in: MedlinePlus