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Clinical Practice: Mini-Review

Free Access

A Role of Remote Organs Effect in Acute Kidney Injury Outcome

Dépret F.a, b · Prud'homme M.b · Legrand M.a, b

Author affiliations

aDepartment of Anesthesiology and Critical Care and Burn Unit, AP-HP, St-Louis-Lariboisière Hospital, University Paris Diderot, and bINSERM UMR-S 942, Institute National de la Santé et de la Recherche Médicale (INSERM), Lariboisière Hospital, FCRIN INICRCT Network, Paris, France

Corresponding Author

Dr. Matthieu Legrand

Department of Anesthesiology and Critical Care and Burn Unit

St-Louis Hospital, Assistance Publique-Hôpitaux de Paris

1 Avenue Claude Vellefaux, FR-75010 (France)

E-Mail matthieu.legrand@aphp.fr

Related Articles for ""

Nephron 2017;137:273–276

Abstract

Acute kidney injury (AKI) has been associated with both short- and long-term outcomes. To date, there is still a debate whether the increase risk of morbidity and mortality is directly due to AKI occurrence. There is, however, a potential causal impact of AKI on outcome, but evidence of this association is yet lacking. The hypothesis of remote organ damage and dysfunction (heart, lung, liver, brain, etc.) has emerged over the last decade and may explain the reason for the potential negative impact of AKI on outcome. The aim of this review was to describe findings concerning the remote effect of AKI in animal models and human studies.

© 2017 S. Karger AG, Basel


Introduction

Acute kidney injury (AKI) is a frequent event with an incidence from 1,811 per million/year [1] to 15,325 per million/year [2] among the general population. AKI has been associated with an increased risk of mortality [1,2,4,5] in various settings [3,6,7,8,9,10].

The hypothesis of remote organ damage and dysfunction has emerged over the last decade and may explain the reason for the potential negative impact of AKI on outcome. Animal models clearly indicate that AKI induces distant organ dysfunction through different identified pathways including inflammatory cascades, apoptosis, induction of remote oxidative stress, and differential molecular expression [11]. Most animal studies that found the presence of a remote effect of AKI were performed on rodents. Because rodents were used it may raise some concerns with respect to the generalizability of the results to other species [12]. Exploring the remote effect of AKI in humans is, however, highly challenging, since the burden of the underlying cause of AKI and comorbidities on other organs could not be separated from the occurrence of AKI. The aim of this mini review was to describe findings concerning the remote effect of AKI in animal models and human studies.

Remote Effect on the Lung

Animal Studies

In animal studies, the remote effect of AKI on the lung has been shown to involve different pathways: increased vascular permeability, transcriptomic changes, pro-inflammatory cytokine, apoptosis, and cell recruitment. A study performed on mice (C57BL/6) has focused on genes expression after renal ischemia/reperfusion (I/R) or nephrectomy. Authors identified an increased expression in genes at 6 and 36 h in the lung in the I/R group compared to the expression in the nephrectomy group. Downregulation was observed in other genes at 6 and 36 h in the I/R group compared to that in the nephrectomy group. Analysis revealed the significant activation of several pro-inflammatory and pro-apoptotic biological processes. Functional and transcriptional changes occur in the lung after renal I/R distinct from those induced by nephrectomy alone [13].

In another study, also using mice (C57BL/6), Brøchner et al. [14] compared 5 groups with different subtypes of AKI. This study revealed that Myeloperoxydase production (a marker of oxidative stress) in the lung was higher in the groups with AKI than in sham and limb ischemia groups. Furthermore, interleukin (IL)-6 and IL-10 blood levels were higher in the AKI groups compared to the levels in the sham group, suggesting a role of I/R to the systemic inflammatory response [14].

In the same line, Hoke et al. [15] observed that two different cytokine profiles between I/R injury and bilateral nephrectomy - keratinocyte-derived chemokine and GM-CSF (granulocyte macrophage colony-stimulating factor) - increased significantly after ischemic AKI but not after bilateral nephrectomy, while, IL-6, IL-1β, and IL-12 (p40), increased significantly after both renal I/R and bilateral nephrectomy. On the contrary, IL-10 and GM-CSF increased significantly after bilateral nephrectomy but not I/R. Furthermore, pulmonary injury after AKI from bilateral nephrectomy was prevented using IL-10 [15].

Deng et al. [16] evaluated the effect of an anti-inflammatory cytokine (α-melanocyte-stimulating hormone [α-MSH]). Renal I/R rapidly activated lung nuclear factor-kappaB, p38 mitogen-activated protein kinase, c-Jun and activator protein-1 pathways. Administration of α-MSH protected the kidney and lung from injury, prevented the activation of kidney and lung transcription factors and stress response genes, and lung intracellular adhesion molecule-1 and tumor necrosis factor (TNF)-α at early time points after renal I/R [16]. Pulmonary apoptosis after AKI was absent in TNFReceptors-/- mice, suggesting a role of TNF [17]. Caspase inhibition reduced lung microvascular changes in an animal model of acute respiratory distress syndrome (ARDS) induced by renal I/R. The inhibition of neutrophil extracellular traps (NETs) reduced kidney injury after renal I/R. Furthermore, NETs were detected in lungs only by immunofluorescence staining. NETs inhibition reduced lung injury also suggesting their involvement in lung remote injury after AKI [18].

Data in larger animals are very scarce and more inconsistent. In pigs, AKI associated with short-term lung tissue [Ca2+] increased. This largely resolved after 48 h, and no histopathology abnormalities, edema, apoptosis, or immune cell infiltration was noted in the lung in the short and longer term [19].

Human Studies

AKI and lung injury are frequently associated. Studies suggest that this association is not only due to shared comorbidities but that AKI itself could increase the risk of morbidity [20,21]. In a retrospective study, Darmon et al. [20] found that mechanical ventilation and ARDS were independently associated with AKI. On the contrary, in ICU patients, AKI has been associated with an increased duration of mechanical ventilation [22] and with an increased mortality [23]. However, to date, this link is only a statistical association without proof of causal relationship of AKI on lung injury.

Remote Consequences on the Heart

Animal Studies

In an animal study on rats, Kelly [24] observed an increased level of immunoreactive TNF-α and IL-1 and intercellular adhesion molecule-1 mRNA in the heart in the 48 first hours after renal I/R. This was accompanied by increases in myeloperoxidase activity in the heart. They also observed increases in left ventricular end diastolic diameter, left ventricular end systolic diameter, and decreased fractional shortening by echocardiography after renal I/R. The inhibition of TNF-α was associated with a decrease of cardiomyocyte apoptosis.

Long-term remote effects of AKI on the heart were also explored. In a subtotal nephrectomy on rats, animals receiving an angiotensin-converting enzyme inhibitor after AKI developed less left ventricular hypertrophy and less myocardial fibrosis, suggesting a role of renin angiotensin aldosterone system in remote cardiac effect after AKI [25].

In a mice model of angiotensin II (ANG II) induced-hypertension, González et al. [26] studied the effect of Galectine-3 (Gal-3), a mediator of fibrosis. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains (C57BL/6J and Gal-3 KO) when infused with ANG II. However, hypertensive C57BL/6J mice had impaired ejection and shortening fractions. The extent of myocardial fibrosis and macrophage infiltration was greater, and cardiac ICAM-1, as well as plasma IL-6, expression was higher in wild-type animals compared to Gal-3 KO mice [26]. This study suggests an implication of Gal-3 in ANG-II myocardial inflammation and fibrosis.

Human Studies

While cardiovascular consequences of chronic kidney disease have long been recognized, type 3 cardio renal syndrome (when AKI lead to acute cardiac failure) remains poorly explored and understood [27]. Acute cardiac failure can generate AKI through different pathways by increasing return venous pressure leading to renal congestion [28] or by decreasing renal arterial output or kidney perfusion pressure. It is less clear how AKI could be responsible for cardiac failure. One hypothesis is that AKI-induced systemic inflammatory response could affect myocardial structure, function and viability. Elevated levels of TNF and IL-6 are associated with the development of cardiac heart failure [29] and increases in modulators of apoptotic pathway are correlated with the severity of chronic heart failure [30].

In a human study after heart transplantation (HTx), Grupper et al. [31] studied the association of Gal-3 serum level, renal function and myocardial fibrosis before and after HTx. There was a significant inverse correlation between Gal-3 levels and glomerular filtration rate measured before and after HTx (p > 0.005). There was no association between Gal-3 serum level and Gal-3 staining of myocardial tissue or with the presence of myocyte hypertrophy and interstitial fibrosis post HTx (3 years after HTx). Elevated pre-HTx Gal-3 levels were not independently associated with reduced post-HTx exercise capacity after adjustment [31]. Of note, statistical power was low in this study due to the small sample size.

Liver Remote Effect

Animal Studies

In an animal study on rats (Wistar Male), hepatic levels of TNF-α increased significantly after 6 and 24 h of renal I/R (45 min of ischemia) or nephrectomy. Malondialdehyde, an index of lipid peroxidation, increased while total glutathione decreased, suggesting the activation of oxidative stress. The expression of liver spermine-spermidine acetyl transferase, an enzyme upregulated in the early phases of hepatic injury was significantly increased 6 h after AKI. Hepatocytes apoptosis increased in 24 h after nephrectomy. Authors also found histological evidence of hepatocyte injury following AKI. The infusion of reduced glutathione, before the induction of renal I/R, significantly improved liver architecture and was associated with a reduction in hepatic malondialdehyde and serum alanine transaminase levels [32]. Similar results were observed in another mice study showing rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration, and pro-inflammatory mRNA upregulation. The inhibition of TNF-α, IL-6, and IL-17A, protected mice against hepatic injury suggesting their involvement in hepatic injury after AKI [33].

In a recent study on pigs, authors assessed remote liver effects. AKI was associated with significant, short-term (24 h) increments in enzymes indicative of acute liver damage (e.g., AST: ALT ratio; p = 0.02). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver in the short and longer term [19].

Human Studies

Hepatorenal syndrome is a well-known and well-described syndrome leading to renal insufficiency secondary to local hemodynamics modifications [34]. On the contrary, the role of AKI in liver failure is less clear. Some studies suggest a modification of liver metabolism after AKI [35]. In a case-control study in ICU, an increased 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase gene activation in AKI patients compared to control patients without AKI was observed [36]. An observational study in cirrhotic patients found that the progression of AKI was independently associated with an increased mortality [37]. To date, there is no human study showing a long-term remote effect on liver after AKI.

Conclusions

Several experimental studies have highlighted the existence of a remote organs effect of AKI in rodents. This effect seems to involve many pathways: increased vascular permeability, transcriptomic changes, pro-inflammatory cytokine, apoptosis, cell recruitment, and so on. In humans, to date, proofs are weak and indirect. Further studies are needed to explore the short- and long-term remote effect of AKI that could be involved in the morbi-mortality of AKI.

Disclosure Statement

The authors have no conflicts of interest to declare.


References

  1. Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, et al: Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007;18:1292-1298.
  2. Bedford M, Stevens PE, Wheeler TW, Farmer CK: What is the real impact of acute kidney injury? BMC Nephrol 2014;15:95.
  3. Ostermann M, Chang RW: Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007;35:1837-1843.
  4. De Corte W, Dhondt A, Vanholder R, De Waele J, Decruyenaere J, Sergoyne V, et al: Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study. Crit Care 2016;20:256.
  5. Sawhney S, Marks A, Fluck N, Levin A, Prescott G, Black C: Intermediate and long-term outcomes of survivors of acute kidney injury episodes: a large population-based cohort study. Am J Kidney Dis 2017;69:18-28.
  6. Wang HE, Muntner P, Chertow GM, Warnock DG: Acute kidney injury and mortality in hospitalized patients. Am J Nephrol 2012;35:349-355.
  7. Cruz DN, Bolgan I, Perazella MA, Bonello M, de Cal M, Corradi V, et al: North east Italian prospective hospital renal outcome survey on acute kidney injury (NEiPHROS-AKI): targeting the problem with the RIFLE criteria. Clin J Am Soc Nephrol 2007;2:418-425.
  8. Liangos O, et al: Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006;1:43-51.
  9. Chertow GM, et al: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.
  10. Choi AI, Li Y, Parikh C, Volberding PA, Shlipak MG: Long-term clinical consequences of acute kidney injury in the HIV-infected. Kidney Int 2010;78:478-485.
  11. Grams ME, Rabb H: The distant organ effects of acute kidney injury. Kidney Int 2012;81:942-948.
  12. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al: Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci 2013;110:3507-3512.
  13. Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, et al: Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007;293:F30-F40.
  14. Brøchner AC, Dagnaes-Hansen F, Højberg-Holm J, Toft P: The inflammatory response in blood and in remote organs following acute kidney injury. APMIS 2014;122:399-404.
  15. Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, et al: Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2007;18:155-164.
  16. Deng J, Hu X, Yuen PS, Star RA: Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004;169:749-756.
  17. Hassoun HT, Lie ML, Grigoryev DN, Liu M, Tuder RM, Rabb H: Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 2009;297:F125-F137.
  18. Nakazawa D, Kumar SV, Marschner J, Desai J, Holderied A, Rath L, et al: Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J Am Soc Nephrol 2017;pii:ASN.2016080925.
  19. Gardner DS, De Brot S, Dunford LJ, Grau-Roma L, Welham SJ, Fallman R, et al: Remote effects of acute kidney injury in a porcine model. Am J Physiol Renal Physiol 2016;310:F259-F271.
  20. Darmon M, Clec'h C, Adrie C, Argaud L, Allaouchiche B, Azoulay E, et al: Acute respiratory distress syndrome and risk of AKI among critically ill patients. Clin J Am Soc Nephrol 2014;9:1347-1353.
  21. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-1494.
  22. Vieira JM Jr, Castro I, Curvello-Neto A, Demarzo S, Caruso P, Pastore L, et al: Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 2007;35:184-191.
  23. Liu KD, Glidden DV, Eisner MD, Parsons PE, Ware LB, Wheeler A, et al: Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med 2007;35:2755-2761.
  24. Kelly KJ: Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003;14:1549-1558.
  25. Burchill L, Velkoska E, Dean RG, Lew RA, Smith AI, Levidiotis V, et al: Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression. Exp Physiol 2008;93:622-630.
  26. González GE, Rhaleb NE, D'Ambrosio MA, Nakagawa P, Liao TD, Peterson EL, et al: Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 2016;311:H1287-H1296.
  27. Di Lullo L, Bellasi A, Russo D, Cozzolino M, Ronco C: Cardiorenal acute kidney injury: epidemiology, presentation, causes, pathophysiology and treatment. Int J Cardiol 2017;227:143-150.
  28. Gambardella I, Gaudino M, Ronco C, Lau C, Ivascu N, Girardi LN: Congestive kidney failure in cardiac surgery: the relationship between central venous pressure and acute kidney injury. Interact Cardiovasc Thorac Surg 2016;23:800-805.
  29. Vasan RS: Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003;107:1486-1491.
  30. Setsuta K, Seino Y, Ogawa T, Ohtsuka T, Seimiya K, Takano T: Ongoing myocardial damage in chronic heart failure is related to activated tumor necrosis factor and Fas/Fas ligand system. Circ J 2004;68:747-750.
  31. Grupper A, Nativi-Nicolau J, Maleszewski JJ, Geske JR, Kremers WK, Edwards BS, et al: Circulating galectin-3 levels are persistently elevated after heart transplantation and are associated with renal dysfunction. JACC Heart Fail 2016;4:847-856.
  32. Golab F, Kadkhodaee M, Zahmatkesh M, Hedayati M, Arab H, Schuster R, et al: Ischemic and non-ischemic acute kidney injury cause hepatic damage. Kidney Int 2009;75:783-792.
  33. Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D'Agati VD, et al: Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 2011;91:63-84.
  34. Baraldi O, Valentini C, Donati G, Comai G, Cuna V, Capelli I, et al: Hepatorenal syndrome: update on diagnosis and treatment. World J Nephrol 2015;4:511-520.
  35. Lane K, Dixon JJ, MacPhee IA, Philips BJ: Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? Nephrol Dial Transplant 2013;28:1634-1647.
  36. Johnson AC, Ware LB, Himmelfarb J, Zager RA: HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury. Clin J Am Soc Nephrol 2011;6:2108-2113.
  37. Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al: Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753-762.

Author Contacts

Dr. Matthieu Legrand

Department of Anesthesiology and Critical Care and Burn Unit

St-Louis Hospital, Assistance Publique-Hôpitaux de Paris

1 Avenue Claude Vellefaux, FR-75010 (France)

E-Mail matthieu.legrand@aphp.fr


Article / Publication Details

First-Page Preview
Abstract of Clinical Practice: Mini-Review

Received: March 03, 2017
Accepted: April 21, 2017
Published online: June 07, 2017
Issue release date: Published online first

Number of Print Pages: 4
Number of Figures: 0
Number of Tables: 0

ISSN: 1660-8151 (Print)
eISSN: 2235-3186 (Online)

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References

  1. Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, et al: Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol 2007;18:1292-1298.
  2. Bedford M, Stevens PE, Wheeler TW, Farmer CK: What is the real impact of acute kidney injury? BMC Nephrol 2014;15:95.
  3. Ostermann M, Chang RW: Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007;35:1837-1843.
  4. De Corte W, Dhondt A, Vanholder R, De Waele J, Decruyenaere J, Sergoyne V, et al: Long-term outcome in ICU patients with acute kidney injury treated with renal replacement therapy: a prospective cohort study. Crit Care 2016;20:256.
  5. Sawhney S, Marks A, Fluck N, Levin A, Prescott G, Black C: Intermediate and long-term outcomes of survivors of acute kidney injury episodes: a large population-based cohort study. Am J Kidney Dis 2017;69:18-28.
  6. Wang HE, Muntner P, Chertow GM, Warnock DG: Acute kidney injury and mortality in hospitalized patients. Am J Nephrol 2012;35:349-355.
  7. Cruz DN, Bolgan I, Perazella MA, Bonello M, de Cal M, Corradi V, et al: North east Italian prospective hospital renal outcome survey on acute kidney injury (NEiPHROS-AKI): targeting the problem with the RIFLE criteria. Clin J Am Soc Nephrol 2007;2:418-425.
  8. Liangos O, et al: Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006;1:43-51.
  9. Chertow GM, et al: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.
  10. Choi AI, Li Y, Parikh C, Volberding PA, Shlipak MG: Long-term clinical consequences of acute kidney injury in the HIV-infected. Kidney Int 2010;78:478-485.
  11. Grams ME, Rabb H: The distant organ effects of acute kidney injury. Kidney Int 2012;81:942-948.
  12. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al: Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci 2013;110:3507-3512.
  13. Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, et al: Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007;293:F30-F40.
  14. Brøchner AC, Dagnaes-Hansen F, Højberg-Holm J, Toft P: The inflammatory response in blood and in remote organs following acute kidney injury. APMIS 2014;122:399-404.
  15. Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, et al: Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2007;18:155-164.
  16. Deng J, Hu X, Yuen PS, Star RA: Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004;169:749-756.
  17. Hassoun HT, Lie ML, Grigoryev DN, Liu M, Tuder RM, Rabb H: Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 2009;297:F125-F137.
  18. Nakazawa D, Kumar SV, Marschner J, Desai J, Holderied A, Rath L, et al: Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J Am Soc Nephrol 2017;pii:ASN.2016080925.
  19. Gardner DS, De Brot S, Dunford LJ, Grau-Roma L, Welham SJ, Fallman R, et al: Remote effects of acute kidney injury in a porcine model. Am J Physiol Renal Physiol 2016;310:F259-F271.
  20. Darmon M, Clec'h C, Adrie C, Argaud L, Allaouchiche B, Azoulay E, et al: Acute respiratory distress syndrome and risk of AKI among critically ill patients. Clin J Am Soc Nephrol 2014;9:1347-1353.
  21. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-1494.
  22. Vieira JM Jr, Castro I, Curvello-Neto A, Demarzo S, Caruso P, Pastore L, et al: Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 2007;35:184-191.
  23. Liu KD, Glidden DV, Eisner MD, Parsons PE, Ware LB, Wheeler A, et al: Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med 2007;35:2755-2761.
  24. Kelly KJ: Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003;14:1549-1558.
  25. Burchill L, Velkoska E, Dean RG, Lew RA, Smith AI, Levidiotis V, et al: Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression. Exp Physiol 2008;93:622-630.
  26. González GE, Rhaleb NE, D'Ambrosio MA, Nakagawa P, Liao TD, Peterson EL, et al: Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 2016;311:H1287-H1296.
  27. Di Lullo L, Bellasi A, Russo D, Cozzolino M, Ronco C: Cardiorenal acute kidney injury: epidemiology, presentation, causes, pathophysiology and treatment. Int J Cardiol 2017;227:143-150.
  28. Gambardella I, Gaudino M, Ronco C, Lau C, Ivascu N, Girardi LN: Congestive kidney failure in cardiac surgery: the relationship between central venous pressure and acute kidney injury. Interact Cardiovasc Thorac Surg 2016;23:800-805.
  29. Vasan RS: Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003;107:1486-1491.
  30. Setsuta K, Seino Y, Ogawa T, Ohtsuka T, Seimiya K, Takano T: Ongoing myocardial damage in chronic heart failure is related to activated tumor necrosis factor and Fas/Fas ligand system. Circ J 2004;68:747-750.
  31. Grupper A, Nativi-Nicolau J, Maleszewski JJ, Geske JR, Kremers WK, Edwards BS, et al: Circulating galectin-3 levels are persistently elevated after heart transplantation and are associated with renal dysfunction. JACC Heart Fail 2016;4:847-856.
  32. Golab F, Kadkhodaee M, Zahmatkesh M, Hedayati M, Arab H, Schuster R, et al: Ischemic and non-ischemic acute kidney injury cause hepatic damage. Kidney Int 2009;75:783-792.
  33. Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D'Agati VD, et al: Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 2011;91:63-84.
  34. Baraldi O, Valentini C, Donati G, Comai G, Cuna V, Capelli I, et al: Hepatorenal syndrome: update on diagnosis and treatment. World J Nephrol 2015;4:511-520.
  35. Lane K, Dixon JJ, MacPhee IA, Philips BJ: Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? Nephrol Dial Transplant 2013;28:1634-1647.
  36. Johnson AC, Ware LB, Himmelfarb J, Zager RA: HMG-CoA reductase activation and urinary pellet cholesterol elevations in acute kidney injury. Clin J Am Soc Nephrol 2011;6:2108-2113.
  37. Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al: Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753-762.
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