Mechanisms and consequences of injury and repair in older organ transplants.
Authors:
Journal: Transplantation
Publication Type: Editorial
Date: 2014
DOI: NIHMS557622
ID: 24646769
Abstract
Donor organ scarcity remains a significant clinical challenge in transplantation. Older organs, increasingly utilized to meet the growing demand for donor organs, have been linked to inferior transplant outcomes. Susceptibility to organ injury, reduced repair capacity, and increased immunogenicity are interrelated and impacted by physiological and pathological aging processes. Insights into the underlying mechanisms are needed to develop age-specific interventional strategies with regards to organ preservation, immunosuppression, and allocation. In this overview, we summarize current knowledge of injury and repair mechanisms and the effects of aging relevant to transplantation.
Chemical List
- Heat-Shock Proteins|||Ubiquitin|||Proteasome Endopeptidase Complex
Reference List
- Noppakun K, Cosio FG, Dean PG, Taler SJ, Wauters R, Grande JP. Living donor age and kidney transplant outcomes. Am J Transplant. 2011 Jun;11(6):1279–86.|||Moers C, Kornmann NS, Leuvenink HG, Ploeg RJ. The influence of deceased donor age and old-for-old allocation on kidney transplant outcome. Transplantation. 2009 Aug 27;88(4):542–52.|||de Fijter JW, Mallat MJ, Doxiadis II, Ringers J, Rosendaal FR, Claas FH, et al. Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol. 2001 Jul;12(7):1538–46.|||Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med. 2011 Apr 7;364(14):1369–70.|||Yarlagadda SG, Coca SG, Formica RN, Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: A systematic review and meta-analysis. Nephrol Dial Transplant. 2009 Mar;24(3):1039–47.|||Guedes AM, Malheiro J, Fonseca I, Martins LS, Pedroso S, Almeida M, et al. Over ten-year kidney graft survival determinants. Int J Nephrol. 2012;2012:302974.|||Chavalitdhamrong D, Gill J, Takemoto S, Madhira BR, Cho YW, Shah T, et al. Patient and graft outcomes from deceased kidney donors age 70 years and older: An analysis of the organ procurement transplant Network/United network of organ sharing database. Transplantation. 2008 Jun 15;85(11):1573–9.|||Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant. 2006 Apr;6(4):783–90.|||Cameron AM, Ghobrial RM, Hiatt JR, Carmody IC, Gordon SA, Farmer DG, et al. Effect of nonviral factors on hepatitis C recurrence after liver transplantation. Ann Surg. 2006 Oct;244(4):563–71.|||Machicao VI, Bonatti H, Krishna M, Aqel BA, Lukens FJ, Nguyen JH, et al. Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C. Transplantation. 2004 Jan 15;77(1):84–92.|||Berenguer M, Aguilera V, Prieto M, Ortiz C, Rodriguez M, Gentili F, et al. Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C: Impact of donor age and baseline cirrhosis. Liver Transpl. 2009 Jul;15(7):738–46.|||Stehlik J, Feldman DS, Brown RN, VanBakel AB, Russel SD, Ewald GA, et al. Interactions among donor characteristics influence post-transplant survival: A multi-institutional analysis. J Heart Lung Transplant. 2010 Mar;29(3):291–8.|||Axelrod DA, Sung RS, Meyer KH, Wolfe RA, Kaufman DB. Systematic evaluation of pancreas allograft quality, outcomes and geographic variation in utilization. Am J Transplant. 2010 Apr;10(4):837–45.|||Bittle GJ, Sanchez PG, Kon ZN, Claire Watkins A, Rajagopal K, Pierson RN, 3rd, et al. The use of lung donors older than 55 years: A review of the united network of organ sharing database. J Heart Lung Transplant. 2013 Aug;32(8):760–8.|||Dahlman S, Jeppsson A, Schersten H, Nilsson F. Expanding the donor pool: Lung transplantation with donors 55 years and older. Transplant Proc. 2006 Oct;38(8):2691–3.|||Pizanis N, Heckmann J, Tsagakis K, Tossios P, Massoudy P, Wendt D, et al. Lung transplantation using donors 55 years and older: Is it safe or just a way out of organ shortage? Eur J Cardiothorac Surg. 2010 Aug;38(2):192–7.|||Campisi J, d’Adda di Fagagna F. Cellular senescence: When bad things happen to good cells. Nat Rev Mol Cell Biol. 2007 Sep;8(9):729–40.|||Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007 Jan;128(1):36–44.|||Westhoff JH, Schildhorn C, Jacobi C, Homme M, Hartner A, Braun H, et al. Telomere shortening reduces regenerative capacity after acute kidney injury. J Am Soc Nephrol. 2010 Feb;21(2):327–36.|||Braun H, Schmidt BM, Raiss M, Baisantry A, Mircea-Constantin D, Wang S, et al. Cellular senescence limits regenerative capacity and allograft survival. J Am Soc Nephrol. 2012 Sep;23(9):1467–73.|||Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232–6.|||Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. an evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000 Jun;908:244–54.|||Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, et al. Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev. 2007 Jan;128(1):83–91.|||Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: Basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R18–36.|||Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxid Redox Signal. 2006 Mar-Apr;8(3–4):572–81.|||Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010 Mar;10(3):210–5.|||Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009 Aug;11(8):973–9.|||Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP) Cell Signal. 2012 Apr;24(4):835–45.|||Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. myocyte loss and reactive cellular hypertrophy. Circ Res. 1991 Jun;68(6):1560–8.|||Wynne HA, Cope LH, Mutch E, Rawlins MD, Woodhouse KW, James OF. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology. 1989 Feb;9(2):297–301.|||Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992 Feb;232(2):194–201.|||Barbari A, Stephan A, Masri MA, Kamel G, Karam A, Kilani H, et al. Nephron mass in kidney transplantation. Transplant Proc. 2002 Sep;34(6):2401–2.|||Terasaki PI, Koyama H, Cecka JM, Gjertson DW. The hyperfiltration hypothesis in human renal transplantation. Transplantation. 1994 May 27;57(10):1450–4.|||De Vusser K, Lerut E, Kuypers D, Vanrenterghem Y, Jochmans I, Monbaliu D, et al. The predictive value of kidney allograft baseline biopsies for long-term graft survival. J Am Soc Nephrol. 2013 Aug 15;|||Braun H, Schmidt BM, Raiss M, Baisantry A, Mircea-Constantin D, Wang S, et al. Cellular senescence limits regenerative capacity and allograft survival. J Am Soc Nephrol. 2012 Sep;23(9):1467–73.|||Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009 Aug;51(2):371–9.|||Vetelainen R, van Vliet A, Gouma DJ, van Gulik TM. Steatosis as a risk factor in liver surgery. Ann Surg. 2007 Jan;245(1):20–30.|||Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, et al. The registry of the international society for heart and lung transplantation: 29th official adult heart transplant report--2012. J Heart Lung Transplant. 2012 Oct;31(10):1052–64.|||Nagji AS, Hranjec T, Swenson BR, Kern JA, Bergin JD, Jones DR, et al. Donor age is associated with chronic allograft vasculopathy after adult heart transplantation: Implications for donor allocation. Ann Thorac Surg. 2010 Jul;90(1):168–75.|||Schmauss D, Weis M. Cardiac allograft vasculopathy: Recent developments. Circulation. 2008 Apr 22;117(16):2131–41.|||Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy PM, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: Evidence from intravascular ultrasound. Circulation. 2001 Jun 5;103(22):2705–10.|||Li H, Tanaka K, Anzai H, Oeser B, Lai D, Kobashigawa JA, et al. Influence of pre-existing donor atherosclerosis on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients. J Am Coll Cardiol. 2006 Jun 20;47(12):2470–6.|||Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229–317.|||Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol. 2007 Feb;292(2):C670–86.|||Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5618–23.|||Lagouge M, Larsson NG. The role of mitochondrial DNA mutations and free radicals in disease and ageing. J Intern Med. 2013 Jun;273(6):529–43.|||Lesnefsky EJ, Hoppel CL. Ischemia-reperfusion injury in the aged heart: Role of mitochondria. Arch Biochem Biophys. 2003 Dec 15;420(2):287–97.|||Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 Sep 13;357(11):1121–35.|||Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009 Jun;46(6):821–31.|||Haworth RA, Hunter DR. The Ca2+-induced membrane transition in mitochondria. II. nature of the Ca2+ trigger site. Arch Biochem Biophys. 1979 Jul;195(2):460–7.|||Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+ overloading, trigger pH- and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2006 May;290(5):H2024–34.|||Ananthakrishnan R, Kaneko M, Hwang YC, Quadri N, Gomez T, Li Q, et al. Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H333–41.|||Pi Y, Goldenthal MJ, Marin-Garcia J. Mitochondrial channelopathies in aging. J Mol Med (Berl) 2007 Sep;85(9):937–51.|||Chen GY, Nunez G. Sterile inflammation: Sensing and reacting to damage. Nat Rev Immunol. 2010 Dec;10(12):826–37.|||Mills KH. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011 Nov 18;11(12):807–22.|||Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, et al. Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3390–5.|||Palmer SM, Burch LH, Mir S, Smith SR, Kuo PC, Herczyk WF, et al. Donor polymorphisms in toll-like receptor-4 influence the development of rejection after renal transplantation. Clin Transplant. 2006 Jan-Feb;20(1):30–6.|||Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S. Altered innate immune functioning of dendritic cells in elderly humans: A role of phosphoinositide 3-kinase-signaling pathway. J Immunol. 2007 Jun 1;178(11):6912–22.|||Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV, Sapey E, et al. Senescence in innate immune responses: Reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol. 2001 Dec;70(6):881–6.|||Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol. 2001 Nov;117(5):1027–35.|||Aprahamian T, Takemura Y, Goukassian D, Walsh K. Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol. 2008 Jun;152(3):448–55.|||Morelli AE, Larregina AT. Apoptotic cell-based therapies against transplant rejection: Role of recipient’s dendritic cells. Apoptosis. 2010 Sep;15(9):1083–97.|||Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D, Hernanz-Falcon P, et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009 Apr 16;458(7240):899–903.|||Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 2010 Mar;20(3):332–40.|||Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009 Aug;5(8):e1000602.|||Agrawal A, Tay J, Yang GE, Agrawal S, Gupta S. Age-associated epigenetic modifications in human DNA increase its immunogenicity. Aging (Albany NY) 2010 Mar 20;2(2):93–100.|||Castle SC, Uyemura K, Crawford W, Wong W, Makinodan T. Antigen presenting cell function is enhanced in healthy elderly. Mech Ageing Dev. 1999 Mar 1;107(2):137–45.|||Ordemann R, Hutchinson R, Friedman J, Burakoff SJ, Reddy P, Duffner U, et al. Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease. J Clin Invest. 2002 May;109(9):1249–56.|||Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ, et al. MicroRNA changes in human arterial endothelial cells with senescence: Relation to apoptosis, eNOS and inflammation. Exp Gerontol. 2012 Jan;47(1):45–51.|||Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med. 2011 Aug;32(4–6):279–304.|||Hahn JS, Hu Z, Thiele DJ, Iyer VR. Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol Cell Biol. 2004 Jun;24(12):5249–56.|||Kelly KJ. Heat shock (stress response) proteins and renal ischemia/reperfusion injury. Contrib Nephrol. 2005;148:86–106.|||Kourtis N, Tavernarakis N. Cellular stress response pathways and ageing: Intricate molecular relationships. EMBO J. 2011 May 17;30(13):2520–31.|||Macario AJ, Conway de Macario E. Sick chaperones, cellular stress, and disease. N Engl J Med. 2005 Oct 6;353(14):1489–501.|||Okaya T, Blanchard J, Schuster R, Kuboki S, Husted T, Caldwell CC, et al. Age-dependent responses to hepatic ischemia/reperfusion injury. Shock. 2005 Nov;24(5):421–7.|||Ollinger R, Pratschke J. Role of heme oxygenase-1 in transplantation. Transpl Int. 2010 Nov;23(11):1071–81.|||Kotsch K, Martins PN, Klemz R, Janssen U, Gerstmayer B, Dernier A, et al. Heme oxygenase-1 ameliorates ischemia/reperfusion injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal. 2007 Dec;9(12):2049–63.|||Ferenbach DA, Nkejabega NC, McKay J, Choudhary AK, Vernon MA, Beesley MF, et al. The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney Int. 2011 May;79(9):966–76.|||Tullius SG, Nieminen-Kelha M, Reutzel-Selke A, Bachmann U, Jonas S, Pratschke J, et al. Improvement of long-term function in renal allografts from ‘marginal donors’ following the induction of heme-oxygenase-1. Transplant Proc. 2001 Feb-Mar;33(1–2):1160–1.|||Broere F, van der Zee R, van Eden W. Heat shock proteins are no DAMPs, rather ‘DAMPERs’. Nat Rev Immunol. 2011 Jul 25;11(8):565. author reply 565.|||Wachstein J, Tischer S, Figueiredo C, Limbourg A, Falk C, Immenschuh S, et al. HSP70 enhances immunosuppressive function of CD4(+)CD25(+)FoxP3(+) T regulatory cells and cytotoxicity in CD4(+)CD25(−) T cells. PLoS One. 2012;7(12):e51747.|||Borges TJ, Porto BN, Teixeira CA, Rodrigues M, Machado FD, Ornaghi AP, et al. Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells. PLoS One. 2010 Dec 8;5(12):e14264.|||Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: Cell life and death decisions. J Clin Invest. 2005 Oct;115(10):2656–64.|||Brodsky JL. Cleaning up: ER-associated degradation to the rescue. Cell. 2012 Dec 7;151(6):1163–7.|||Haynes CM, Ron D. The mitochondrial UPR - protecting organelle protein homeostasis. J Cell Sci. 2010 Nov 15;123(Pt 22):3849–55.|||Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006 Sep;7(9):880–5.|||Inagi R. Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol. 2009;112(1):e1–9.|||Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis. 2007 Nov;27(4):367–77.|||Toth A, Nickson P, Mandl A, Bannister ML, Toth K, Erhardt P. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets. 2007 Sep;7(3):205–18.|||Naidoo N. ER and aging-protein folding and the ER stress response. Ageing Res Rev. 2009 Jul;8(3):150–9.|||Breusing N, Grune T. Regulation of proteasome-mediated protein degradation during oxidative stress and aging. Biol Chem. 2008 Mar;389(3):203–9.|||Ishihara Y, Hamaguchi A, Sekine M, Hirakawa A, Shimamoto N. Accumulation of cytochrome P450 induced by proteasome inhibition during cardiac ischemia. Arch Biochem Biophys. 2012 Nov 1;527(1):16–22.|||Tian Z, Zheng H, Li J, Li Y, Su H, Wang X. Genetically induced moderate inhibition of the proteasome in cardiomyocytes exacerbates myocardial ischemia-reperfusion injury in mice. Circ Res. 2012 Aug 17;111(5):532–42.|||Huber JM, Tagwerker A, Heininger D, Mayer G, Rosenkranz AR, Eller K. The proteasome inhibitor bortezomib aggravates renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2009 Aug;297(2):F451–60.|||Pye J, Ardeshirpour F, McCain A, Bellinger DA, Merricks E, Adams J, et al. Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H919–26.|||Glembotski CC. Clarifying the cardiac proteasome paradox: Protein quality control. Circ Res. 2012 Aug 17;111(5):509–12.|||Walsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int. 2012 Jun;81(11):1067–74.|||Murrow L, Debnath J. Autophagy as a stress-response and quality-control mechanism: Implications for cell injury and human disease. Annu Rev Pathol. 2013 Jan 24;8:105–37.|||Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 2012 Dec;82(12):1271–83.|||Wang JH, Ahn IS, Fischer TD, Byeon JI, Dunn WA, Jr, Behrns KE, et al. Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology. 2011 Dec;141(6):2188, 2199.e6.|||Sala-Mercado JA, Wider J, Undyala VV, Jahania S, Yoo W, Mentzer RM, Jr, et al. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation. 2010 Sep 14;122(11 Suppl):S179–84.|||Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011 Aug 26;333(6046):1109–12.|||Wang JH, Behrns KE, Leeuwenburgh C, Kim JS. Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy. 2012 Jan;8(1):140–1.|||Karp SJ. Clinical implications of advances in the basic science of liver repair and regeneration. Am J Transplant. 2009 Sep;9(9):1973–80.|||Nelson PJ, Rees AJ, Griffin MD, Hughes J, Kurts C, Duffield J. The renal mononuclear phagocytic system. J Am Soc Nephrol. 2012 Feb;23(2):194–203.|||Humphreys BD, Bonventre JV. Mesenchymal stem cells in acute kidney injury. Annu Rev Med. 2008;59:311–25.|||Liu KD, Brakeman PR. Renal repair and recovery. Crit Care Med. 2008 Apr;36(4 Suppl):S187–92.|||Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007 Nov;213(2):286–300.|||Basile DP. The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int. 2007 Jul;72(2):151–6.|||Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res. 2010 May 1;86(2):236–42.|||Leonard EC, Friedrich JL, Basile DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol. 2008 Dec;295(6):F1648–57.|||Regner KR, Roman RJ. Role of medullary blood flow in the pathogenesis of renal ischemia-reperfusion injury. Curr Opin Nephrol Hypertens. 2012 Jan;21(1):33–8.|||Shiraha H, Gupta K, Drabik K, Wells A. Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors. J Biol Chem. 2000 Jun 23;275(25):19343–51.|||Tran KT, Rusu SD, Satish L, Wells A. Aging-related attenuation of EGF receptor signaling is mediated in part by increased protein tyrosine phosphatase activity. Exp Cell Res. 2003 Oct 1;289(2):359–67.|||Komi-Kuramochi A, Kawano M, Oda Y, Asada M, Suzuki M, Oki J, et al. Expression of fibroblast growth factors and their receptors during full-thickness skin wound healing in young and aged mice. J Endocrinol. 2005 Aug;186(2):273–89.|||Patschan D, Patschan S, Muller GA. Endothelial progenitor cells in acute ischemic kidney injury: Strategies for increasing the cells’ renoprotective competence. Int J Nephrol. 2011;2011:828369.|||Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007 Mar 1;109(5):1801–9.|||Togel F, Isaac J, Hu Z, Weiss K, Westenfelder C. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int. 2005 May;67(5):1772–84.|||Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med. 2008 Feb 18;205(2):479–90.|||Patschan D, Backhaus R, Elle HJ, Schwarze K, Henze E, Becker JU, et al. Angiopoietin-2 modulates eEOC-mediated renoprotection in AKI in a dose-dependent manner. J Nephrol. 2013 Mar;6:0.|||Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ Res. 2007 Dec 7;101(12):1310–8.|||Kyriakou C, Rabin N, Pizzey A, Nathwani A, Yong K. Factors that influence short-term homing of human bone marrow-derived mesenchymal stem cells in a xenogeneic animal model. Haematologica. 2008 Oct;93(10):1457–65.|||Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest. 2012 Mar 1;122(3):787–95.|||Lech M, Anders HJ. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta. 2013 Jul;1832(7):989–97.|||Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol. 2011 Feb;22(2):317–26.|||Menke J, Iwata Y, Rabacal WA, Basu R, Yeung YG, Humphreys BD, et al. CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest. 2009 Aug;119(8):2330–42.|||Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4194–9.|||Mahbub S, Deburghgraeve CR, Kovacs EJ. Advanced age impairs macrophage polarization. J Interferon Cytokine Res. 2012 Jan;32(1):18–26.|||Diehl AM, Chute J. Underlying potential: Cellular and molecular determinants of adult liver repair. J Clin Invest. 2013 May 1;123(5):1858–60.|||Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab. 2009 May;20(4):171–6.|||Baddour JA, Sousounis K, Tsonis PA. Organ repair and regeneration: An overview. Birth Defects Res C Embryo Today. 2012 Mar;96(1):1–29.|||Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013 Jan 17;493(7432):433–6.|||Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003 Sep 19;114(6):763–76.|||Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001 Apr 5;410(6829):701–5.|||Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009 Apr 3;324(5923):98–102.|||Ballard VL, Edelberg JM. Stem cells for cardiovascular repair - the challenges of the aging heart. J Mol Cell Cardiol. 2008 Oct;45(4):582–92.|||Bonventre JV. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol. 2003 Jun;14( Suppl 1):S55–61.|||Schmitt R, Marlier A, Cantley LG. Zag expression during aging suppresses proliferation after kidney injury. J Am Soc Nephrol. 2008 Dec;19(12):2375–83.|||Westhoff JH, Schildhorn C, Jacobi C, Homme M, Hartner A, Braun H, et al. Telomere shortening reduces regenerative capacity after acute kidney injury. J Am Soc Nephrol. 2010 Feb;21(2):327–36.|||Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008 Mar 6;2(3):284–91.|||Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, et al. Proliferation and migration of label-retaining cells of the kidney papilla. J Am Soc Nephrol. 2009 Nov;20(11):2315–27.|||Miya M, Maeshima A, Mishima K, Sakurai N, Ikeuchi H, Kuroiwa T, et al. Age-related decline in label-retaining tubular cells: Implication for reduced regenerative capacity after injury in the aging kidney. Am J Physiol Renal Physiol. 2012 Mar 15;302(6):F694–702.|||Schmitt R, Cantley LG. The impact of aging on kidney repair. Am J Physiol Renal Physiol. 2008 Jun;294(6):F1265–72.|||Lahteenvuo J, Rosenzweig A. Effects of aging on angiogenesis. Circ Res. 2012 Apr 27;110(9):1252–64.|||Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011 Apr 14;364(15):1431–40.|||Taylor MJ, Baicu S, Leman B, Greene E, Vazquez A, Brassil J. Twenty-four hour hypothermic machine perfusion preservation of porcine pancreas facilitates processing for islet isolation. Transplant Proc. 2008 Mar;40(2):480–2.|||Guarrera JV, Henry SD, Samstein B, Odeh-Ramadan R, Kinkhabwala M, Goldstein MJ, et al. Hypothermic machine preservation in human liver transplantation: The first clinical series. Am J Transplant. 2010 Feb;10(2):372–81.|||Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2009 Jan 1;360(1):7–19.|||Moers C, Pirenne J, Paul A, Ploeg RJ Machine Preservation Trial Study Group. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2012 Feb 23;366(8):770–1.|||Treckmann J, Moers C, Smits JM, Gallinat A, Maathuis MH, van Kasterop-Kutz M, et al. Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death. Transpl Int. 2011 Jun;24(6):548–54.|||Gallinat A, Moers C, Smits JM, Strelniece A, Pirenne J, Ploeg RJ, et al. Machine perfusion versus static cold storage in expanded criteria donor kidney transplantation: 3-year follow-up data. Transpl Int. 2013 Jun;26(6):E52–3.|||Gallinat A, Moers C, Treckmann J, Smits JM, Leuvenink HG, Lefering R, et al. Machine perfusion versus cold storage for the preservation of kidneys from donors >/= 65 years allocated in the eurotransplant senior programme. Nephrol Dial Transplant. 2012 Dec;27(12):4458–63.|||Guarrera JV. Assist devices: Machine preservation of extended criteria donors. Liver Transpl. 2012 Nov;18( Suppl 2):S31–3.|||St Peter SD, Imber CJ, Friend PJ. Liver and kidney preservation by perfusion. Lancet. 2002 Feb 16;359(9306):604–13.|||Gracia-Sancho J, Villarreal G, Jr, Zhang Y, Yu JX, Liu Y, Tullius SG, et al. Flow cessation triggers endothelial dysfunction during organ cold storage conditions: Strategies for pharmacologic intervention. Transplantation. 2010 Jul 27;90(2):142–9.|||Gallinat A, Fox M, Luer B, Efferz P, Paul A, Minor T. Role of pulsatility in hypothermic reconditioning of porcine kidney grafts by machine perfusion after cold storage. Transplantation. 2013 Jul 2;|||Matas AJ, Smith JM, Skeans MA, Lamb KE, Gustafson SK, Samana CJ, et al. OPTN/SRTR 2011 annual data report: Kidney. Am J Transplant. 2013 Jan;13( Suppl 1):11–46.|||Giessing M, Fuller TF, Friedersdorff F, Deger S, Wille A, Neumayer HH, et al. Outcomes of transplanting deceased-donor kidneys between elderly donors and recipients. J Am Soc Nephrol. 2009 Jan;20(1):37–40.|||Koppelstaetter C, Schratzberger G, Perco P, Hofer J, Mark W, Ollinger R, et al. Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation. Aging Cell. 2008 Aug;7(4):491–7.|||Gingell-Littlejohn M, McGuinness D, McGlynn LM, Kingsmore D, Stevenson KS, Koppelstaetter C, et al. Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria. PLoS One. 2013 Jul 4;8(7):e68133.