Acute Kidney Injury, Microvascular Rarefaction, and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients.
acute kidney injury
acute renal failure
chronic kidney failure
delayed graft function
kidney transplantation
microvascular rarefaction
pathophysiology of renal disease and progression
Journal
Clinical journal of the American Society of Nephrology : CJASN
ISSN: 1555-905X
Titre abrégé: Clin J Am Soc Nephrol
Pays: United States
ID NLM: 101271570
Informations de publication
Date de publication:
08 03 2021
08 03 2021
Historique:
received:
12
05
2020
accepted:
14
01
2021
pubmed:
3
3
2021
medline:
4
1
2022
entrez:
2
3
2021
Statut:
ppublish
Résumé
Animal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function. This observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes. Post-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation. Perioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.
Sections du résumé
BACKGROUND AND OBJECTIVES
Animal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes.
RESULTS
Post-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation.
CONCLUSIONS
Perioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.
Identifiants
pubmed: 33648972
pii: 01277230-202103000-00013
doi: 10.2215/CJN.07270520
pmc: PMC8011007
doi:
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
415-426Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Références
Coca SG, Singanamala S, Parikh CR: Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis. Kidney Int 81: 442–448, 2012 22113526
Basile DP, Yoder MC: Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc Hematol Disord Drug Targets 14: 3–14, 2014 25088124
Bábíčková J, Klinkhammer BM, Buhl EM, Djudjaj S, Hoss M, Heymann F, Tacke F, Floege J, Becker JU, Boor P: Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries. Kidney Int 91: 70–85, 2017 27678159
Basile DP, Friedrich JL, Spahic J, Knipe N, Mang H, Leonard EC, Changizi-Ashtiyani S, Bacallao RL, Molitoris BA, Sutton TA: Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol 300: F721–F733, 2011 21123492
Kwon O, Hong S-M, Sutton TA, Temm CJ: Preservation of peritubular capillary endothelial integrity and increasing pericytes may be critical to recovery from postischemic acute kidney injury. Am J Physiol Renal Physiol 295: F351–F359, 2008 18562634
Basile DP, Donohoe D, Roethe K, Osborn JL: Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 281: F887–F899, 2001 11592947
Basile DP: The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int 72: 151–156, 2007 17495858
Ehling J, Bábíčková J, Gremse F, Klinkhammer BM, Baetke S, Knuechel R, Kiessling F, Floege J, Lammers T, Boor P: Quantitative micro-computed tomography imaging of vascular dysfunction in progressive kidney diseases. J Am Soc Nephrol 27: 520–532, 2016 26195818
Kang D-H, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13: 806–816, 2002 11856789
Matsumoto M, Tanaka T, Yamamoto T, Noiri E, Miyata T, Inagi R, Fujita T, Nangaku M: Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc Nephrol 15: 1574–1581, 2004 15153568
Ohashi R, Kitamura H, Yamanaka N: Peritubular capillary injury during the progression of experimental glomerulonephritis in rats. J Am Soc Nephrol 11: 47–56, 2000 10616839
Ohashi R, Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Sugisaki Y, Yamanaka N: Peritubular capillary regression during the progression of experimental obstructive nephropathy. J Am Soc Nephrol 13: 1795–1805, 2002 12089375
Yang B, Lan S, Dieudé M, Sabo-Vatasescu JP, Karakeussian-Rimbaud A, Turgeon J, Qi S, Gunaratnam L, Patey N, Hébert MJ: Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol 29: 1900–1916, 2018 29925521
Menshikh A, Scarfe L, Delgado R, Finney C, Zhu Y, Yang H, de Caestecker MP: Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis. Am J Physiol Renal Physiol 317: F1383–F1397, 2019 31509009
Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlöndorff D, Cohen CD: Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J Am Soc Nephrol 18: 1765–1776, 2007 17475821
Bohle A, Mackensen-Haen S, Wehrmann M: Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res 19: 191–195, 1996 8887259
Kaukinen A, Lautenschlager I, Helin H, Karikoski R, Jalanko H: Peritubular capillaries are rarefied in congenital nephrotic syndrome of the Finnish type. Kidney Int 75: 1099–1108, 2009 19225555
Namikoshi T, Satoh M, Horike H, Fujimoto S, Arakawa S, Sasaki T, Kashihara N: Implication of peritubular capillary loss and altered expression of vascular endothelial growth factor in IgA nephropathy. Nephron, Physiol 102: 9–16, 2006 16179809
Basile DP: The case for capillary rarefaction in the AKI to CKD progression: Insights from multiple injury models. Am J Physiol Renal Physiol 317: F1253–F1254, 2019 31630545
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 24: 1039–1047, 2009
Cavaillé-Coll M, Bala S, Velidedeoglu E, Hernandez A, Archdeacon P, Gonzalez G, Neuland C, Meyer J, Albrecht R: Summary of FDA workshop on ischemia reperfusion injury in kidney transplantation. Am J Transplant 13: 1134–1148, 2013 23566221
Lapointe I, Lachance J-G, Noël R, Côté I, Caumartin Y, Agharazii M, Houde I, Rousseau-Gagnon M, Kim SJ, De Serres SA: Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up. Transpl Int 26: 162–169, 2013 23199029
Ishii Y, Sawada T, Kubota K, Fuchinoue S, Teraoka S, Shimizu A: Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy. Kidney Int 67: 321–332, 2005 15610258
Steegh FMEG, Gelens MACJ, Nieman FHM, van Hooff JP, Cleutjens JP, van Suylen RJ, Daemen MJ, van Heurn EL, Christiaans MH, Peutz-Kootstra CJ: Early loss of peritubular capillaries after kidney transplantation. J Am Soc Nephrol 22: 1024–1029, 2011 21566051
Stuart LN: CD Markers. CD34, 2002. Available at: http://www.pathologyoutlines.com/topic/cdmarkerscd34.html . Accessed June 19, 2018
Shaffi K, Uhlig K, Perrone RD, Ruthazer R, Rule A, Lieske JC, Navis G, Poggio ED, Inker LA, Levey AS: Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients. Am J Kidney Dis 63: 1007–1018, 2014 24703720
Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, Matas AJ: Risk factors for slow graft function after kidney transplants: A multivariate analysis. Clin Transplant 16: 425–429, 2002 12437622
Yang B, Dieudé M, Hamelin K, Hénault-Rondeau M, Patey N, Turgeon J, Lan S, Pomerleau L, Quesnel M, Peng J, Tremblay J, Shi Y, Chan JS, Hébert MJ, Cardinal H: Anti-LG3 antibodies aggravate renal ischemia-reperfusion injury and long-term renal allograft dysfunction. Am J Transplant 16: 3416–3429, 2016 27172087
Yarlagadda SG, Coca SG, Garg AX, Doshi M, Poggio E, Marcus RJ, Parikh CR: Marked variation in the definition and diagnosis of delayed graft function: A systematic review. Nephrol Dial Transplant 23: 2995–3003, 2008
Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M: The Banff 2015 kidney meeting report: Current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant 17: 28–41, 2017 27862883
Legendre C, Canaud G, Martinez F: Factors influencing long-term outcome after kidney transplantation. Transpl Int 27: 19–27, 2014 24138291
Boom H, Mallat MJ, de Fijter JW, Zwinderman AH, Paul LC: Delayed graft function influences renal function, but not survival. Kidney Int 58: 859–866, 2000 10916111
Lipták P, Kemény E, Morvay Z, Szederkényi E, Szenohradszky P, Marofka F, Toldi J, Exner M, Iványi B: Peritubular capillary damage in acute humoral rejection: An ultrastructural study on human renal allografts. Am J Transplant 5: 2870–2876, 2005 16302999
Regele H, Böhmig GA, Habicht A, Gollowitzer D, Schillinger M, Rockenschaub S, Watschinger B, Kerjaschki D, Exner M: Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: A contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol 13: 2371–2380, 2002 12191982
Rosenson RS, Tangney CC: Antiatherothrombotic properties of statins: Implications for cardiovascular event reduction. JAMA 279: 1643–1650, 1998 9613915
Wolfrum S, Jensen KS, Liao JK: Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 23: 729–736, 2003 12615672
Lewicki M, Ng I, Schneider AG: HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass. Cochrane Database Syst Rev 3: CD010480, 2015 25758322
Layton JB, Hansen MK, Jakobsen C-J, Kshirsagar AV, Andreasen JJ, Hjortdal VE, Rasmussen BS, Simpson RJ, Brookhart MA, Christiansen CF: Statin initiation and acute kidney injury following elective cardiovascular surgery: A population cohort study in Denmark. Eur J Cardiothorac Surg 49: 995–1000, 2016 26188012
Tuuminen R, Nykänen AI, Saharinen P, Gautam P, Keränen MA, Arnaudova R, Rouvinen E, Helin H, Tammi R, Rilla K, Krebs R, Lemström KB: Donor simvastatin treatment prevents ischemia-reperfusion and acute kidney injury by preserving microvascular barrier function. Am J Transplant 13: 2019–2034, 2013 23773358
Reiling J, Johnson DW, Kruger PS, Pillans P, Wall DR: Association of pre-transplant statin use with delayed graft function in kidney transplant recipients. BMC Nephrol 13: 111, 2012 22985048
Singh RP, Farney AC, Rogers J, Zuckerman J, Reeves-Daniel A, Hartmann E, Iskandar S, Adams P, Stratta RJ: Kidney transplantation from donation after cardiac death donors: Lack of impact of delayed graft function on post-transplant outcomes. Clin Transplant 25: 255–264, 2011 20331689
Bouma HR, Ploeg RJ, Schuurs TA: Signal transduction pathways involved in brain death-induced renal injury. Am J Transplant 9: 989–997, 2009 19422328
Brandes RP: Endothelial dysfunction and hypertension. Hypertension 64: 924–928, 2014
Dinh QN, Drummond GR, Sobey CG, Chrissobolis S: Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. BioMed Res Int 2014: 406960, 2014 25136585