Acta Physiol 2015, 215, 73–75
ExActa Acute kidney injury Both demographic trends and the current rise in the number and complexity of diagnostic and surgical procedures have let acute kidney injury (AKI) grow into an enormous medical challenge and common clinical complication among hospitalized patients. In these populations, AKI is an important cause of morbidity and mortality, with rising incidence (Zarjou et al. 2012, Rabadi & Lee 2015). AKI is characterized by a sudden reduction in renal function, ranging from a small decrease in glomerular filtration rate (GFR) to complete loss of renal function (Srisawat & Kellum 2011) and often results in chronic loss of renal function or end-stage kidney disease. There is growing evidence that AKI is associated with an increased risk for the development of chronic kidney disease (CKD), depending on AKI severity and the underlying pathophysiological mechanism (Coca 2013). In their recent meta-analysis of AKI association with CKD and endstage renal disease, Coca et al. investigated renal and non-renal outcomes of patients who survived AKI. AKI patients not only have a higher risk of CKD, but also to develop further complications in organ systems such as the heart, lung and liver. Renal fibrosis, permanent impairment of renal function and complications in non-renal organs apparently contribute to CKD development (Coca et al. 2012). As numerous different definitions of AKI existed in parallel, the 2004 developed RIFLE (risk, injury, failure, loss and end-stage kidney disease) system was introduced to standardize AKI classification in patient care and research (Bellomo et al. 2004). This well-validated system was further modified in the year 2008 and is based on GFR and urine output (Zappitelli 2008). The closely related AKIN (Acute Kidney Injury Network) classification is based on serum creatinine (SCr) and on urinary output. SCr is, in general, only useful as a late indicator for AKI, as detectable changes in SCr require that the kidney already lost 50% of the GFR (Zarjou et al. 2012). This is in line with our knowledge from basic physiology that the (measured) GFR is better suited to detect early changes in loss of kidney function in contrast to SCr. The practical advantages of the scoring systems were and are under investigation in clinical studies. Unfortunately, none of the scoring systems is able to characterize AKI as pre-renal, post-renal or intrinsic. New sensitive and specific biomarkers are urgently needed to support the current, yet insufficient
diagnostic ‘gold standard’. Urinary calprotectin and neutrophil-gelatinase-associated lipocalin (NGAL) showed promising results in a study by Seibert et al. (2013) with high sensitivity and specificity values for calprotectin. NGAL for instance is produced by injured epithelial cells and is upregulated very early in animal models of AKI (Zarjou et al. 2012). Kidney injury molecule-1 (KIM-1) is released into the urine during proximal tubular injury in different models of AKI (Vaidya et al. 2008), and interestingly so by those very cells that are commonly injured in AKI. The leading causes of AKI are ischaemia/reperfusion injury (IRI), rhabdomyolysis, hepatic malfunction, sepsis and nephrotoxic substances (Persson 2013). Strong research efforts in animal models of AKI have, during the last years, lead to a better understanding of the cellular and molecular basis of this complex disease. Ischaemia/reperfusion injury, the restriction of blood supply to an organ followed by reperfusion, leads to tubular and endothelial necrosis and apoptosis. The tissue damage is exacerbated by the initiated inflammatory response after reperfusion and re-oxygenation of the kidney. The complex serial events during IRI include the release of reactive oxygen species (ROS) and pro-inflammatory cytokines and chemokines and lead to the activation of apoptotic pathways, intracellular Ca2+ accumulation and tubular cell injury (Shokeir et al. 2014, Malek & Nematbakhsh 2015). The detoxification of ROS during oxidative stress is essential for recovery of the kidney and is, for instance, regulated by the transcription nuclear factor erythroid 2-related factor (Nrf2) that accumulates in the nucleus and activates the transcription of phase 2 enzyme genes, such as haeme-oxygenase-1, glutathione reductase and glutathione peroxidase. Shokeir et al. investigated the impact of ischaemic pre- and postconditioning on the expression of Nrf2 and dependent genes in the kidney. Ischaemic pre-conditioning (Ipre) improved renal function as measured by SCr and blood urea nitrogen, whereas ischaemic post-conditioning (Ipost) did not lead to a significant improvement. Furthermore, Ipre caused an increase in the immediate expression of Nrf2 and dependent genes in proximal convoluted tubular cells. This supports the idea of Nrf2 as the mediator of the renoprotective effect of Ipre and Ipost. In addition, caloric restriction enhances the cellular adaption to hypoxia via Sirt1 pathway, provides protection against acute tissue
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
73
ExActa
· S Reuter and R Mrowka
injury and improves survival and kidney function after acute IRI (Mitchell et al. 2010, Lempi€ ainen et al. 2013). The hypoxic environment of the renal medulla renders it extremely vulnerable to changes in blood flow and oxygen supply (Liu et al. 2013). Increases in medullary blood flow (MBF) wash out the cortico-medullary osmotic gradient, whereas decreases in MBF lead to hypoxia and IRI, followed by tissue necrosis and CKD (Kennedy-Lydon et al. 2013). Kennedy-Lydon et al. intensively discuss controversial data of MBF regulation from different rat models. They shed light on the role of pericytes in the context of the fact that a passive MBF regulation is the accepted mechanism. Those smooth muscle-like cells on the abluminal side of the endothelium wrap their claw-like processes around microvessels and contribute to vessel stabilization, endothelial cell regulation, angiogenesis and phagocytosis. Despite different peptide and hormonal vasoactive agents, pericytes respond to acetylcholine, ATP and noradrenaline, so it seems likely that the release of these substances by adjacent sympathetic nerve terminals contributes to the regulation of MBF. Pericytes seem to bridge tubular and endothelial cell signalling by detecting vasoactive stimuli – and responding through regulation of vasa recta diameter and MBF. Although heavily discussed, pericytes could be, by de-differentiation and migration, one source of myofibroblasts in the kidney. Myofibroblasts initiate renal fibrosis by producing large amounts of extracellular matrix components. The identification of decisive signalling molecules and pathways activated by hypoxia is the central issue of a number of excellent AKI-related studies published in Acta Physiologica. During haemorrhagic shock, when arterial pressure falls below the autoregulatory region, filtration pressure and perfusion of the kidney decrease, leading to hypoxia and kidney injury with reduced GFR. Major systems that maintain arterial pressure, worsen the hypoxic environment in the kidney by enhancing oxygen consumption in the kidney and lowering renal perfusion to protect heart and brain (Hultstr€ om 2013). Hultstr€ om describes the neuro-hormonal interactions between the sympathetic nervous system, the renin-angiotensin-aldosteron system (RAAS) and vasopressin during shock. Interventions to protect the kidney have to maintain blood pressure during inhibition of one of the mentioned systems. A careful use of RAAS inhibitors is suggested by Hultstr€ om as experimental data from several studies showed their reno-protective effects in AKI through IRI. Hypoxia-inducible transcription factor (HIF) activates the transcription of more than 100 genes and is 74
Acta Physiol 2015, 215, 73–75
involved in erythropoiesis, angiogenesis, regulation of vascular tone, iron metabolism, anaerobic metabolism, regulation of cell proliferation and apoptosis. Renal prolyl 4-hydroxylases (P4Hs) are the cellular oxygen sensors that regulate HIF stability. Selective pharmacological inhibition of P4Hs showed beneficial effects in different rodent models of IRI (Myllyharju 2013); nevertheless, potential unwanted side effects need to be studied further. Other promising pharmaceutical targets in AKI are transient receptor potential vanilloid-1 and 4 (TRPV1,4) with potential reno-protective role in IRI (Kassmann et al. 2013). Activation of TRPV1 by capsaicin and other agonists ameliorated IR-induced renal dysfunction. The authors discuss that catheter-based renal denervation of hypertensive patients could affect the ischaemic response of those individuals; thus, renal denervation of sensory neurones in rats exacerbates ischaemic renal injury. Nevertheless, over-activity of the sympathetic nervous system is involved in hypertension-associated kidney failure (Khan et al. 2014) and is caused by neurohormonal signalling by the kidney itself. In a model of cisplatin-induced kidney injury in rats, Kahn et al. showed a blunted high-pressure baroreflex regulation of renal sympathetic nerve activity (RSNA). Renal denervation helped to normalize the baroreflex regulation of RSNA. Due to the wide range of agents and conditions causing AKI, numerous pathways have been identified in animal models that seemed to be promising for pharmaceutical interventions, as, for instance, inhibition of inflammation. Unfortunately, none of them has so far been translated into a therapeutic option for human AKI (Zarjou et al. 2012). Studies on renal detoxification mechanisms identified haeme-oxygenase-1 as an attractive target (Haines et al. 2012). This enzyme indirectly contributes to detoxification of ROS and is for instance induced by HIF. It ameliorated renal injury in a mouse model of IRI-induced AKI. In addition, cell-based strategies such as the therapeutic application of mesenchymal stem cells (MSCs) are under intensive investigation. MSCs are a multipotent cell population found in bone marrow, where they are easily isolated from. They promote the functional repair of nephrons through paracrine and endocrine mechanisms. Intravenous administration of exogenous MSCs protected for instance from cisplatin-induced kidney dysfunction (Humphreys & Bonventre 2008), and are currently tested in clinical trials. New treatment procedures in combination with new early detection markers of AKI hopefully offer a chance to improve the outcome of AKI and ultimately contribute to the prevention of CKD.
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
Acta Physiol 2015, 215, 73–75
Conflict of interest None.
S. Reuter and R. Mrowka Klinik f€ ur Innere Medizin III, AG Experimentelle Nephrologie, Universit€ atsklinikum Jena, Jena, Germany E-mail: [email protected]
References Bellomo, R., Ronco, C., Kellum, J.A., Mehta, R.L., Palevsky, P. & Acute Dialysis Quality Initiative workgroup 2004. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8, R204–R212. Coca, S.G. 2013. Ongoing controversies on the relationship between AKI and CKD. NephSAP 12, 77–82. Coca, S.G., Singanamala, S. & Parikh, C.R. 2012. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 81, 442–448. Haines, D., Lekli, I., Teissier, P., Bak, I. & Tosaki, A. 2012. Role of haeme oxygenase-1 in resolution of oxidative stress-related pathologies: focus on cardiovascular, lung, neurological and kidney disorders. Acta Physiol (Oxf) 204, 487–501. Hultstr€ om, M. 2013. Neurohormonal interactions on the renal oxygen delivery and consumption in haemorrhagic shock-induced acute kidney injury. Acta Physiol (Oxf) 209, 11–25. Humphreys, B.D. & Bonventre, J.V. 2008. Mesenchymal stem cells in acute kidney injury. Annu Rev Med 59, 311–325. Kassmann, M., Harteneck, C., Zhu, Z., N€ urnberg, B., Tepel, M. & Gollasch, M. 2013. Transient receptor potential vanilloid 1 (TRPV1), TRPV4, and the kidney. Acta Physiol (Oxf) 207, 546–564. Kennedy-Lydon, T.M., Crawford, C., Wildman, S.S.P. & Peppiatt-Wildman, C.M. 2013. Renal pericytes: regulators of medullary blood flow. Acta Physiol (Oxf) 207, 212–225. Khan, S.A., Sattar, M.A., Rathore, H.A., Abdulla, M.H., Ud Din Ahmad, F., Ahmad, A., Afzal, S., Abdullah, N.A. & Johns, E.J. 2014. Renal denervation restores the baroreflex control of renal sympathetic nerve activity and heart rate in Wistar-Kyoto rats with cisplatin-induced renal failure. Acta Physiol (Oxf) 210, 690–700. Lempi€ainen, J., Finckenberg, P., Mervaala, E.E., Sankari, S., Levijoki, J. & Mervaala, E.M. 2013. Caloric restriction
S Reuter and R Mrowka
· ExActa
ameliorates kidney ischaemia/reperfusion injury through PGC-1a-eNOS pathway and enhanced autophagy. Acta Physiol (Oxf) 208, 410–421. Liu, N., Patzak, A. & Sendeski, M.M. 2013. Nitric oxide and reactive oxygen species in renal medulla pathophysiology – so small yet so special: the renal medulla. Acta Physiol (Oxf) 208, 144–147. Malek, M. & Nematbakhsh, M. 2015. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev 4, 20–27. Mitchell, J.R., Verweij, M., Brand, K., van de Ven, M., Goemaere, N., van den Engel, S., Chu, T., Forrer, F., M€ uller, C., de Jong, M., van IJcken, W., IJzermans, J.N.M., Hoeijmakers, J.H.J. & de Bruin, R.W.F. 2010. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 9, 40–53. Myllyharju, J. 2013. Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol (Oxf) 208, 148–165. Persson, P.B. 2013. Mechanisms of acute kidney injury. Acta Physiol (Oxf) 207, 430–431. Rabadi, M.M. & Lee, H.T. 2015. Adenosine receptors and renal ischaemia reperfusion injury. Acta Physiol (Oxf) 213, 222–231. Seibert, F.S., Pagonas, N., Arndt, R., Heller, F., Dragun, D., Persson, P., Schmidt-Ott, K., Zidek, W. & Westhoff, T.H. 2013. Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury. Acta Physiol (Oxf) 207, 700–708. Shokeir, A.A., Hussein, A.M., Barakat, N., Abdelaziz, A., Elgarba, M. & Awadalla, A. 2014. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf-2dependent genes by ischaemic pre-conditioning and postconditioning: new adaptive endogenous protective responses against renal ischaemia/reperfusion injury. Acta Physiol (Oxf) 210, 342–353. Srisawat, N. & Kellum, J.A. 2011. Acute kidney injury: definition, epidemiology, and outcome. Curr Opin Crit Care 17, 548–555. Vaidya, V.S., Waikar, S.S., Ferguson, M.A., Collings, F.B., Sunderland, K., Gioules, C., Bradwin, G., Matsouaka, R., Betensky, R.A., Curhan, G.C. & Bonventre, J.V. 2008. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci 1, 200–208. Zappitelli, M. 2008. Epidemiology and diagnosis of acute kidney injury. Semin Nephrol 28, 436–446. Zarjou, A., Sanders, P.W., Mehta, R.L. & Agarwal, A. 2012. Enabling innovative translational research in acute kidney injury. Clin Transl Sci 5, 93–101.
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
75
ExActa Acute kidney injury Both demographic trends and the current rise in the number and complexity of diagnostic and surgical procedures have let acute kidney injury (AKI) grow into an enormous medical challenge and common clinical complication among hospitalized patients. In these populations, AKI is an important cause of morbidity and mortality, with rising incidence (Zarjou et al. 2012, Rabadi & Lee 2015). AKI is characterized by a sudden reduction in renal function, ranging from a small decrease in glomerular filtration rate (GFR) to complete loss of renal function (Srisawat & Kellum 2011) and often results in chronic loss of renal function or end-stage kidney disease. There is growing evidence that AKI is associated with an increased risk for the development of chronic kidney disease (CKD), depending on AKI severity and the underlying pathophysiological mechanism (Coca 2013). In their recent meta-analysis of AKI association with CKD and endstage renal disease, Coca et al. investigated renal and non-renal outcomes of patients who survived AKI. AKI patients not only have a higher risk of CKD, but also to develop further complications in organ systems such as the heart, lung and liver. Renal fibrosis, permanent impairment of renal function and complications in non-renal organs apparently contribute to CKD development (Coca et al. 2012). As numerous different definitions of AKI existed in parallel, the 2004 developed RIFLE (risk, injury, failure, loss and end-stage kidney disease) system was introduced to standardize AKI classification in patient care and research (Bellomo et al. 2004). This well-validated system was further modified in the year 2008 and is based on GFR and urine output (Zappitelli 2008). The closely related AKIN (Acute Kidney Injury Network) classification is based on serum creatinine (SCr) and on urinary output. SCr is, in general, only useful as a late indicator for AKI, as detectable changes in SCr require that the kidney already lost 50% of the GFR (Zarjou et al. 2012). This is in line with our knowledge from basic physiology that the (measured) GFR is better suited to detect early changes in loss of kidney function in contrast to SCr. The practical advantages of the scoring systems were and are under investigation in clinical studies. Unfortunately, none of the scoring systems is able to characterize AKI as pre-renal, post-renal or intrinsic. New sensitive and specific biomarkers are urgently needed to support the current, yet insufficient
diagnostic ‘gold standard’. Urinary calprotectin and neutrophil-gelatinase-associated lipocalin (NGAL) showed promising results in a study by Seibert et al. (2013) with high sensitivity and specificity values for calprotectin. NGAL for instance is produced by injured epithelial cells and is upregulated very early in animal models of AKI (Zarjou et al. 2012). Kidney injury molecule-1 (KIM-1) is released into the urine during proximal tubular injury in different models of AKI (Vaidya et al. 2008), and interestingly so by those very cells that are commonly injured in AKI. The leading causes of AKI are ischaemia/reperfusion injury (IRI), rhabdomyolysis, hepatic malfunction, sepsis and nephrotoxic substances (Persson 2013). Strong research efforts in animal models of AKI have, during the last years, lead to a better understanding of the cellular and molecular basis of this complex disease. Ischaemia/reperfusion injury, the restriction of blood supply to an organ followed by reperfusion, leads to tubular and endothelial necrosis and apoptosis. The tissue damage is exacerbated by the initiated inflammatory response after reperfusion and re-oxygenation of the kidney. The complex serial events during IRI include the release of reactive oxygen species (ROS) and pro-inflammatory cytokines and chemokines and lead to the activation of apoptotic pathways, intracellular Ca2+ accumulation and tubular cell injury (Shokeir et al. 2014, Malek & Nematbakhsh 2015). The detoxification of ROS during oxidative stress is essential for recovery of the kidney and is, for instance, regulated by the transcription nuclear factor erythroid 2-related factor (Nrf2) that accumulates in the nucleus and activates the transcription of phase 2 enzyme genes, such as haeme-oxygenase-1, glutathione reductase and glutathione peroxidase. Shokeir et al. investigated the impact of ischaemic pre- and postconditioning on the expression of Nrf2 and dependent genes in the kidney. Ischaemic pre-conditioning (Ipre) improved renal function as measured by SCr and blood urea nitrogen, whereas ischaemic post-conditioning (Ipost) did not lead to a significant improvement. Furthermore, Ipre caused an increase in the immediate expression of Nrf2 and dependent genes in proximal convoluted tubular cells. This supports the idea of Nrf2 as the mediator of the renoprotective effect of Ipre and Ipost. In addition, caloric restriction enhances the cellular adaption to hypoxia via Sirt1 pathway, provides protection against acute tissue
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
73
ExActa
· S Reuter and R Mrowka
injury and improves survival and kidney function after acute IRI (Mitchell et al. 2010, Lempi€ ainen et al. 2013). The hypoxic environment of the renal medulla renders it extremely vulnerable to changes in blood flow and oxygen supply (Liu et al. 2013). Increases in medullary blood flow (MBF) wash out the cortico-medullary osmotic gradient, whereas decreases in MBF lead to hypoxia and IRI, followed by tissue necrosis and CKD (Kennedy-Lydon et al. 2013). Kennedy-Lydon et al. intensively discuss controversial data of MBF regulation from different rat models. They shed light on the role of pericytes in the context of the fact that a passive MBF regulation is the accepted mechanism. Those smooth muscle-like cells on the abluminal side of the endothelium wrap their claw-like processes around microvessels and contribute to vessel stabilization, endothelial cell regulation, angiogenesis and phagocytosis. Despite different peptide and hormonal vasoactive agents, pericytes respond to acetylcholine, ATP and noradrenaline, so it seems likely that the release of these substances by adjacent sympathetic nerve terminals contributes to the regulation of MBF. Pericytes seem to bridge tubular and endothelial cell signalling by detecting vasoactive stimuli – and responding through regulation of vasa recta diameter and MBF. Although heavily discussed, pericytes could be, by de-differentiation and migration, one source of myofibroblasts in the kidney. Myofibroblasts initiate renal fibrosis by producing large amounts of extracellular matrix components. The identification of decisive signalling molecules and pathways activated by hypoxia is the central issue of a number of excellent AKI-related studies published in Acta Physiologica. During haemorrhagic shock, when arterial pressure falls below the autoregulatory region, filtration pressure and perfusion of the kidney decrease, leading to hypoxia and kidney injury with reduced GFR. Major systems that maintain arterial pressure, worsen the hypoxic environment in the kidney by enhancing oxygen consumption in the kidney and lowering renal perfusion to protect heart and brain (Hultstr€ om 2013). Hultstr€ om describes the neuro-hormonal interactions between the sympathetic nervous system, the renin-angiotensin-aldosteron system (RAAS) and vasopressin during shock. Interventions to protect the kidney have to maintain blood pressure during inhibition of one of the mentioned systems. A careful use of RAAS inhibitors is suggested by Hultstr€ om as experimental data from several studies showed their reno-protective effects in AKI through IRI. Hypoxia-inducible transcription factor (HIF) activates the transcription of more than 100 genes and is 74
Acta Physiol 2015, 215, 73–75
involved in erythropoiesis, angiogenesis, regulation of vascular tone, iron metabolism, anaerobic metabolism, regulation of cell proliferation and apoptosis. Renal prolyl 4-hydroxylases (P4Hs) are the cellular oxygen sensors that regulate HIF stability. Selective pharmacological inhibition of P4Hs showed beneficial effects in different rodent models of IRI (Myllyharju 2013); nevertheless, potential unwanted side effects need to be studied further. Other promising pharmaceutical targets in AKI are transient receptor potential vanilloid-1 and 4 (TRPV1,4) with potential reno-protective role in IRI (Kassmann et al. 2013). Activation of TRPV1 by capsaicin and other agonists ameliorated IR-induced renal dysfunction. The authors discuss that catheter-based renal denervation of hypertensive patients could affect the ischaemic response of those individuals; thus, renal denervation of sensory neurones in rats exacerbates ischaemic renal injury. Nevertheless, over-activity of the sympathetic nervous system is involved in hypertension-associated kidney failure (Khan et al. 2014) and is caused by neurohormonal signalling by the kidney itself. In a model of cisplatin-induced kidney injury in rats, Kahn et al. showed a blunted high-pressure baroreflex regulation of renal sympathetic nerve activity (RSNA). Renal denervation helped to normalize the baroreflex regulation of RSNA. Due to the wide range of agents and conditions causing AKI, numerous pathways have been identified in animal models that seemed to be promising for pharmaceutical interventions, as, for instance, inhibition of inflammation. Unfortunately, none of them has so far been translated into a therapeutic option for human AKI (Zarjou et al. 2012). Studies on renal detoxification mechanisms identified haeme-oxygenase-1 as an attractive target (Haines et al. 2012). This enzyme indirectly contributes to detoxification of ROS and is for instance induced by HIF. It ameliorated renal injury in a mouse model of IRI-induced AKI. In addition, cell-based strategies such as the therapeutic application of mesenchymal stem cells (MSCs) are under intensive investigation. MSCs are a multipotent cell population found in bone marrow, where they are easily isolated from. They promote the functional repair of nephrons through paracrine and endocrine mechanisms. Intravenous administration of exogenous MSCs protected for instance from cisplatin-induced kidney dysfunction (Humphreys & Bonventre 2008), and are currently tested in clinical trials. New treatment procedures in combination with new early detection markers of AKI hopefully offer a chance to improve the outcome of AKI and ultimately contribute to the prevention of CKD.
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
Acta Physiol 2015, 215, 73–75
Conflict of interest None.
S. Reuter and R. Mrowka Klinik f€ ur Innere Medizin III, AG Experimentelle Nephrologie, Universit€ atsklinikum Jena, Jena, Germany E-mail: [email protected]
References Bellomo, R., Ronco, C., Kellum, J.A., Mehta, R.L., Palevsky, P. & Acute Dialysis Quality Initiative workgroup 2004. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8, R204–R212. Coca, S.G. 2013. Ongoing controversies on the relationship between AKI and CKD. NephSAP 12, 77–82. Coca, S.G., Singanamala, S. & Parikh, C.R. 2012. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 81, 442–448. Haines, D., Lekli, I., Teissier, P., Bak, I. & Tosaki, A. 2012. Role of haeme oxygenase-1 in resolution of oxidative stress-related pathologies: focus on cardiovascular, lung, neurological and kidney disorders. Acta Physiol (Oxf) 204, 487–501. Hultstr€ om, M. 2013. Neurohormonal interactions on the renal oxygen delivery and consumption in haemorrhagic shock-induced acute kidney injury. Acta Physiol (Oxf) 209, 11–25. Humphreys, B.D. & Bonventre, J.V. 2008. Mesenchymal stem cells in acute kidney injury. Annu Rev Med 59, 311–325. Kassmann, M., Harteneck, C., Zhu, Z., N€ urnberg, B., Tepel, M. & Gollasch, M. 2013. Transient receptor potential vanilloid 1 (TRPV1), TRPV4, and the kidney. Acta Physiol (Oxf) 207, 546–564. Kennedy-Lydon, T.M., Crawford, C., Wildman, S.S.P. & Peppiatt-Wildman, C.M. 2013. Renal pericytes: regulators of medullary blood flow. Acta Physiol (Oxf) 207, 212–225. Khan, S.A., Sattar, M.A., Rathore, H.A., Abdulla, M.H., Ud Din Ahmad, F., Ahmad, A., Afzal, S., Abdullah, N.A. & Johns, E.J. 2014. Renal denervation restores the baroreflex control of renal sympathetic nerve activity and heart rate in Wistar-Kyoto rats with cisplatin-induced renal failure. Acta Physiol (Oxf) 210, 690–700. Lempi€ainen, J., Finckenberg, P., Mervaala, E.E., Sankari, S., Levijoki, J. & Mervaala, E.M. 2013. Caloric restriction
S Reuter and R Mrowka
· ExActa
ameliorates kidney ischaemia/reperfusion injury through PGC-1a-eNOS pathway and enhanced autophagy. Acta Physiol (Oxf) 208, 410–421. Liu, N., Patzak, A. & Sendeski, M.M. 2013. Nitric oxide and reactive oxygen species in renal medulla pathophysiology – so small yet so special: the renal medulla. Acta Physiol (Oxf) 208, 144–147. Malek, M. & Nematbakhsh, M. 2015. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev 4, 20–27. Mitchell, J.R., Verweij, M., Brand, K., van de Ven, M., Goemaere, N., van den Engel, S., Chu, T., Forrer, F., M€ uller, C., de Jong, M., van IJcken, W., IJzermans, J.N.M., Hoeijmakers, J.H.J. & de Bruin, R.W.F. 2010. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell 9, 40–53. Myllyharju, J. 2013. Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol (Oxf) 208, 148–165. Persson, P.B. 2013. Mechanisms of acute kidney injury. Acta Physiol (Oxf) 207, 430–431. Rabadi, M.M. & Lee, H.T. 2015. Adenosine receptors and renal ischaemia reperfusion injury. Acta Physiol (Oxf) 213, 222–231. Seibert, F.S., Pagonas, N., Arndt, R., Heller, F., Dragun, D., Persson, P., Schmidt-Ott, K., Zidek, W. & Westhoff, T.H. 2013. Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury. Acta Physiol (Oxf) 207, 700–708. Shokeir, A.A., Hussein, A.M., Barakat, N., Abdelaziz, A., Elgarba, M. & Awadalla, A. 2014. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf-2dependent genes by ischaemic pre-conditioning and postconditioning: new adaptive endogenous protective responses against renal ischaemia/reperfusion injury. Acta Physiol (Oxf) 210, 342–353. Srisawat, N. & Kellum, J.A. 2011. Acute kidney injury: definition, epidemiology, and outcome. Curr Opin Crit Care 17, 548–555. Vaidya, V.S., Waikar, S.S., Ferguson, M.A., Collings, F.B., Sunderland, K., Gioules, C., Bradwin, G., Matsouaka, R., Betensky, R.A., Curhan, G.C. & Bonventre, J.V. 2008. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci 1, 200–208. Zappitelli, M. 2008. Epidemiology and diagnosis of acute kidney injury. Semin Nephrol 28, 436–446. Zarjou, A., Sanders, P.W., Mehta, R.L. & Agarwal, A. 2012. Enabling innovative translational research in acute kidney injury. Clin Transl Sci 5, 93–101.
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12555
75
