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Presence of Cytotoxic Extracellular Histones in Machine Perfusate of Donation After Circulatory Death Kidneys

van Smaalen, Tim C. MD, MSc; Beurskens, Daniëlle M. H. MSc; Hoogland, E. R. Pieter MD, PhD; Winkens, Bjorn PhD; Christiaans, Maarten H. L. MD, PhD; Reutelingsperger, Chris P. PhD; van Heurn, L. W. Ernest MD, PhD; Nicolaes, Gerry A. F. PhD

doi: 10.1097/TP.0000000000001590
Original Basic Science—General

Background Extracellular histones are cytotoxic molecules that are related to cell stress and death. They have been shown to play a crucial role in multiple pathophysiologic processes like sepsis, inflammation, vascular dysfunction, and thrombosis. Their role in organ donation and graft function and survival is still unknown. The aim of this study was to assess whether an association exists between the presence of extracellular histones in machine perfusates and deceased donor kidney viability.

Methods Machine perfusates of 390 donations after circulatory death kidneys were analyzed for histone concentration, and corresponding graft function and survival were assessed.

Results Extracellular histone concentrations were significantly higher in perfusates of kidneys with posttransplant graft dysfunction (primary nonfunction and delayed graft function) and were an independent risk factor for delayed graft function (odds ratio, 2.152; 95% confidence interval [95% CI], 1.199-3.863) and 1 year graft failure (hazard ratio, 1.386; 95% CI, 1.037-1.853), but not for primary nonfunction (odds ratio, 1.342; 95% CI, 0.900-2.002). One year graft survival was 12% higher in the group with low histone concentrations (P = 0.008) as compared with the group that contained higher histone concentrations.

Conclusions This study warrants future studies to probe for a possible role of cytotoxic extracellular histones in organ viability and suggests that quantitation of extracellular histones might contribute to assessment of posttransplant graft function and survival.

The authors investigate the association between the histone concentration from machine perfusates and graft function in deceased donor kidney transplantation. The cytotoxic extracellular histones may contribute to graft dysfunction and poor survival.

1 Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

2 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

3 Department of Methodology and Statistics, School for Public Health and Primary Care (CAPHRI), Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands.

4 Department of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands.

5 Department of Surgery, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

Received 10 July 2016. Revision received 18 October 2016.

Accepted 22 November 2016.

This work was supported by the Cardiovascular Research Institute Maastricht (to G.A.F.N.) and the Hemker foundation (to G.A.F.N. and C.P.R.)

T.C.v.S. and D.M.H.B. contributed equally.

T.C.v.S. participated in the design of the study, sample and data collection and analysis and writing of the manuscript. D.M.H.B. participated in the design of the study, sample and data collection, and analysis and writing of the article. E.R.P.H. participated in the design of the study, sample and data collection, and analysis and writing of the article. B.W. participated in data analysis and writing of the article. M.H.L.C. participated in data collection and writing of the article. C.P.R. participated in design of the study and writing of the article. L.W.E.v.H. participated in the design of the study, sample and data collection and writing of the article. G.A.F.N. Participated in the design of the study, sample and data collection and writing of the article.

Correspondence: Tim C. van Smaalen, MD, MSc, Department of Surgery, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. (vansmaalen@gmail.com).

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