Preconditioning against renal ischaemia reperfusion injury: the failure to translate to the clinic

O‘Kane, Dermot; Baldwin, Graham S.; Bolton, Damien; Ischia, Joseph; Patel, Oneel

doi:10.1007/s40620-019-00582-6

Cited by 13 publications

(10 citation statements)

References 79 publications

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“…Ischemic preconditioning is the application of short periods of ischemia and reperfusion to an organ before prolonged ischemia whereas in remote preconditioning cycles of brief ischemia are applied to a remote organ (e.g., the lower limb) before prolonged ischemia of the target organ. Studies with both techniques have shown some reduction in renal I/R injury (Hu et al, 2016; Veighey et al, 2019), however, their application is extremely limited and sometimes impractical (O'Kane, Baldwin, Bolton, Ischia, & Patel, 2019; Zhou et al, 2017). Numerous pharmacological modalities and substances have been studied to reduce I/R‐induced mortality, however, none have been entirely successful (Nazir et al, 2017; S. Wang, Liu, et al, 2018; Yip et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Involvement of GPX4 in irisin's protection against ischemia reperfusion‐induced acute kidney injury

Zhang

Ren

et al. 2020

Journal Cellular Physiology

100

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Ischemia reperfusion (I/R)-induced acute kidney injury (AKI) is a common and serious condition. Irisin, an exercise-induced hormone, improves mitochondrial function and reduces reactive oxygen species (ROS) production. Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis and its inactivation aggravates renal I/R injury by inducing ROS production. However, the effect of irisin on GPX4 and I/Rinduced AKI is still unknown. To study this, male adult mice were subjected to renal I/R by occluding bilateral renal hilum for 30 min, which was followed by 24 hr reperfusion. Our results showed serum irisin levels were decreased in renal I/R mice. Irisin (250 μg/kg) treatment alleviated renal injury, downregulated inflammatory response, improved mitochondrial function, and reduced ER stress and oxidative stress after renal I/R, which were associated with upregulation of GPX4. Treated with RSL3 (a GPX4 inhibitor) abolished irisin's protective effect. Thus, irisin attenuates I/R-induced AKI through upregulating GPX4.

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Section: Discussionmentioning

confidence: 99%

Involvement of GPX4 in irisin's protection against ischemia reperfusion‐induced acute kidney injury

Zhang

Ren

et al. 2020

Journal Cellular Physiology

100

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“…Knowledge on normal calorie intake in this population is very limited. Furthermore, blinding of CR is difficult and this fact can lead to undesired dietary adaptation in the control group [24][25][26]. Taken together, an improved knowledge of the molecular mechanisms underlying the impact of CR on resilience is an important pre-requisite for clinical translation of its potential.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury

Hoyer-Allo

Späth

Hanßen

et al. 2021

IJMS

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Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

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“…Nevertheless, the translation of new therapies to patients is very poor, and despite significant renoprotective properties in rodents, many drug candidates have failed to show significant protective effects in clinical trials (O'Kane et al, 2019). The failure to translate from the bench to the bedside has been attributed, in part, to the more complicated architecture of human kidneys than animal kidneys, to differences in the primary endpoints between clinical and animal studies and poor-quality and irreproducible preclinical results (O'Kane et al, 2019). Indeed, some recent studies have claimed that a major portion of published results are not reproducible (Baker & Penny, 2016;Begley & Ioannidis, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Despite continuing advances in the field of renal medicine, to date, there is no clinically used effective pharmacotherapy to decrease ischemia‐reperfusion (I‐R)‐induced kidney damage (O'Kane et al., 2019; Zuk & Bonventre, 2016). Thus, the search for new renoprotective substances is still important.…”

Section: Introductionmentioning

confidence: 99%

“…For decades, various preclinical in vivo models with different modifications have been used to study the pathogenic mechanisms of ischemic AKI and to search for novel renoprotective substances (Wei & Dong, 2012). Nevertheless, the translation of new therapies to patients is very poor, and despite significant renoprotective properties in rodents, many drug candidates have failed to show significant protective effects in clinical trials (O'Kane et al., 2019). The failure to translate from the bench to the bedside has been attributed, in part, to the more complicated architecture of human kidneys than animal kidneys, to differences in the primary endpoints between clinical and animal studies and poor‐quality and irreproducible preclinical results (O'Kane et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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Rats with congenital hydronephrosis show increased susceptibility to renal ischemia‐reperfusion injury

et al. 2020

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Many drug candidates have shown significant renoprotective effects in preclinical models; however, there is no clinically used effective pharmacotherapy for acute kidney injury. The failure to translate from bench to bedside could be due to misleading results from experimental animals with undetected congenital kidney defects. This study was performed to assess the effects of congenital hydronephrosis on the functional capacity of tubular renal transporters as well as kidney sensitivity to ischemia‐reperfusion (I‐R)‐induced injury in male Wistar rats. Ultrasonography was used to distinguish healthy control rats from rats with hydronephrosis. L‐carnitine or furosemide was administered, and serial blood samples were collected and analyzed to assess the effects of hydronephrosis on the pharmacokinetic parameters. Renal injury was induced by clamping the renal pedicles of both kidneys for 30 min with subsequent 24 hr reperfusion. The prevalence of hydronephrosis reached ~30%. The plasma concentrations after administration of L‐carnitine or furosemide were similar in both groups. I‐R induced more pronounced renal injury in the hydronephrotic rats than the control rats, which was evident by a significantly higher kidney injury molecule‐1 concentration and lower creatinine concentration in the urine of the hydronephrotic rats than the control rats. After I‐R, the gene expression levels of renal injury markers were significantly higher in the hydronephrotic kidneys than in the kidneys of control group animals. In conclusion, our results demonstrate that hydronephrotic kidneys are more susceptible to I‐R‐induced damage than healthy kidneys. Unilateral hydronephrosis does not affect the pharmacokinetics of substances secreted or absorbed in the renal tubules.

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Preconditioning against renal ischaemia reperfusion injury: the failure to translate to the clinic

Cited by 13 publications

References 79 publications

Involvement of GPX4 in irisin's protection against ischemia reperfusion‐induced acute kidney injury

Involvement of GPX4 in irisin's protection against ischemia reperfusion‐induced acute kidney injury

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury

Rats with congenital hydronephrosis show increased susceptibility to renal ischemia‐reperfusion injury

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