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Keywords:
Endostatin, Graft loss, All-cause mortality, Kidney transplant recipient

Background: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown. Methods: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA. Results: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71–0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19–31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality. Conclusion: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.

Keywords:
Endostatin, Graft loss, All-cause mortality, Kidney transplant recipient
1.
Xie Y, Bowe B, Mokdad AH, Xian H, Yan Y, Li T, et al. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.
Kidney Int
. 2018 Sep;94(3):567–81.
2.
Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients.
JAMA
. 1993 Sep;270(11):1339–43.
3.
Ojo AO, Port FK, Wolfe RA, Mauger EA, Williams L, Berling DP. Comparative mortality risks of chronic dialysis and cadaveric transplantation in black end-stage renal disease patients.
Am J Kidney Dis
. 1994 Jul;24(1):59–64.
4.
Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up.
J Am Soc Nephrol
. 1998 Nov;9(11):2135–41.
5.
Outcomes. KDIG. KDIGO clinical practice guideline on the evaluation and management of candidates for kidney transplantation (Draft). 2018.
6.
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996.
N Engl J Med
. 2000 Mar;342(9):605–12.
7.
Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.
Am J Transplant
. 2004 Mar;4(3):378–83.
8.
Thiel G, Bock A, Spöndlin M, Brunner FP, Mihatsch M, Rufli T, et al. Long-term benefits and risks of cyclosporin A (sandimmun)—an analysis at 10 years.
Transplant Proc
. 1994 Oct;26(5):2493–8.
9.
Almond PS, Matas A, Gillingham K, Dunn DL, Payne WD, Gores P, et al. Risk factors for chronic rejection in renal allograft recipients.
Transplantation
. 1993 Apr;55(4):752–6.
10.
Basadonna GP, Matas AJ, Gillingham KJ, Payne WD, Dunn DL, Sutherland DE, et al. Early versus late acute renal allograft rejection: impact on chronic rejection.
Transplantation
. 1993 May;55(5):993–5.
11.
Escofet X, Osman H, Griffiths DF, Woydag S, Adam Jurewicz W. The presence of glomerular sclerosis at time zero has a significant impact on function after cadaveric renal transplantation.
Transplantation
. 2003 Feb;75(3):344–6.
12.
Li C, Yang CW. The pathogenesis and treatment of chronic allograft nephropathy.
Nat Rev Nephrol
. 2009 Sep;5(9):513–9.
13.
O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
Cell
. 1997 Jan;88(2):277–85.
14.
Ding YH, Javaherian K, Lo KM, Chopra R, Boehm T, Lanciotti J, et al. Zinc-dependent dimers observed in crystals of human endostatin.
Proc Natl Acad Sci USA
. 1998 Sep;95(18):10443–8.
15.
Jung DH, Moon SH, Park SJ, Kim EJ, Jang IH, Park CS, et al. Angiogenesis in the Transplanted Donor Graft after Living-Donor Liver Transplantation.
Transplantation
. 2018 Jan;102(1):e26–9.
16.
Uda Y, Hirano T, Son G, Iimuro Y, Uyama N, Yamanaka J, et al. Angiogenesis is crucial for liver regeneration after partial hepatectomy.
Surgery
. 2013 Jan;153(1):70–7.
17.
Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, et al. Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart.
J Exp Med
. 2007 Dec;204(13):3257–69.
18.
Tanaka T, Nangaku M. Angiogenesis and hypoxia in the kidney.
Nat Rev Nephrol
. 2013 Apr;9(4):211–22.
19.
Maeshima Y, Makino H. Angiogenesis and chronic kidney disease.
Fibrogenesis Tissue Repair
. 2010 Aug;3(1):13.
20.
Lerman LO, Chade AR. Angiogenesis in the kidney: a new therapeutic target?
Curr Opin Nephrol Hypertens
. 2009 Mar;18(2):160–5.
21.
Lin CH, Chen J, Zhang Z, Johnson GV, Cooper AJ, Feola J, et al. Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney.
Kidney Int
. 2016 Jun;89(6):1281–92.
22.
Carlsson AC, Östgren CJ, Länne T, Larsson A, Nystrom FH, Ärnlöv J. The association between endostatin and kidney disease and mortality in patients with type 2 diabetes.
Diabetes Metab
. 2016 Nov;42(5):351–7.
23.
Carlsson AC, Ruge T, Sundström J, Ingelsson E, Larsson A, Lind L, et al. Association between circulating endostatin, hypertension duration, and hypertensive target-organ damage.
Hypertension
. 2013 Dec;62(6):1146–51.
24.
Chen J, Hamm LL, Kleinpeter MA, Husserl F, Khan IE, Chen CS, et al. Elevated plasma levels of endostatin are associated with chronic kidney disease.
Am J Nephrol
. 2012;35(4):335–40.
25.
Kato Y, Furusyo N, Tanaka Y, Yamasaki S, Ueyama T, Takayama K, et al. Association of the Serum Endostatin Level, Renal Function, and Carotid Atherosclerosis of Healthy Residents of Japan: Results from the Kyushu and Okinawa Population Study (KOPS).
J Atheroscler Thromb
. 2018 Sep;25(9):829–35.
26.
Ruge T, Carlsson AC, Larsson TE, Carrero JJ, Larsson A, Lind L, et al. Endostatin level is associated with kidney injury in the elderly: findings from two community-based cohorts.
Am J Nephrol
. 2014;40(5):417–24.
27.
Kanbay M, Afsar B, Siriopol D, Unal HU, Karaman M, Saglam M, et al. Endostatin in chronic kidney disease: associations with inflammation, vascular abnormalities, cardiovascular events and survival.
Eur J Intern Med
. 2016 Sep;33:81–7.
28.
Chauhan K, Verghese DA, Rao V, Chan L, Parikh CR, Coca SG, et al. Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes.
Kidney Int
. 2019 Feb;95(2):439–46.
29.
Wiessner R, Hannemann-Pohl K, Ziebig R, Grubitzsch H, Hocher B, Vargas-Hein O, et al. Impact of kidney function on plasma troponin concentrations after coronary artery bypass grafting.
Nephrol Dial Transplant
. 2008 Jan;23(1):231–8.
30.
Iqbal CW, Dean PG, Ishitani MB. Early-onset coronary artery disease after pediatric kidney transplantation: implicating the angiogenesis inhibitor, endostatin.
Am Surg
. 2011 Jun;77(6):731–5.
31.
Gurlek Demirci B, Sezer S, Uyanik Yildirim S, Kaynar Erdoğan M, Tutal E, Özdemir Ö, et al. FGF23, NGAL, and Endostatin: the Predictors of Allograft Function in Renal Transplant Recipients.
Exp Clin Transplant
. 2018;16(Suppl 1):136–9.
32.
Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions.
Transplantation
. 2006 Mar;81(5):643–54.
33.
Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction.
J Am Soc Nephrol
. 2005 Oct;16(10):3015–26.
34.
Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease.
Matrix Biol
. 2011 Mar;30(2):83–92.
35.
Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaissé J. Generation and degradation of human endostatin proteins by various proteinases.
FEBS Lett
. 2000 Dec;486(3):247–51.
36.
Folkman J. The role of angiogenesis in tumor growth.
Semin Cancer Biol
. 1992 Apr;3(2):65–71.
37.
Lähteenvuo J, Rosenzweig A. Effects of aging on angiogenesis.
Circ Res
. 2012 Apr;110(9):1252–64.
38.
Folkman J, Kalluri R. Cancer without disease.
Nature
. 2004 Feb;427(6977):787.
39.
Lin CH, Chen J, Ziman B, Marshall S, Maizel J, Goligorsky MS. Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy?
Am J Physiol Heart Circ Physiol
. 2014 Jun;306(12):H1692–9.
40.
Gigante A, Navarini L, Margiotta D, Barbano B, Afeltra A, Rosato E. In systemic sclerosis, microvascular and hands digital arteries damage correlates with serum levels of endostatin.
Microcirculation
. 2018 May;25(4):e12449.
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2020
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