Peri-Operative Kinetics of Plasma Mitochondrial DNA Levels during Living Donor Kidney Transplantation

During ischemia and reperfusion injury (IRI), mitochondria may release mitochondrial DNA (mtDNA). mtDNA can serve as a propagator of further injury but in specific settings has anti-inflammatory capacities as well. Therefore, the aim of this study was to study the perioperative dynamics of plasma mtDNA during living donor kidney transplantation (LDKT) and its potential as a marker of graft outcome. Fifty-six donor-recipient couples from the Volatile Anesthetic Protection of Renal Transplants-1 (VAPOR-1) trial were included. Systemic venous, systemic arterial, and renal venous samples were taken at multiple timepoints during and after LDKT. Levels of mtDNA genes changed over time and between vascular compartments. Several donor, recipient, and transplantation-related variables significantly explained the course of mtDNA genes over time. mtDNA genes predicted 1-month and 24-month estimated glomerular filtration rate (eGFR) and acute rejection episodes in the two-year follow-up period. To conclude, mtDNA is released in plasma during the process of LDKT, either from the kidney or from the whole body in response to transplantation. While circulating mtDNA levels positively and negatively predict post-transplantation outcomes, the exact mechanisms and difference between mtDNA genes are not yet understood and need further exploration.

[1]  R. Pol,et al.  Urinary Biomarkers in a Living Donor Kidney Transplantation Cohort—Predictive Value on Graft Function , 2023, International journal of molecular sciences.

[2]  R. Stratta,et al.  Influence of donor and recipient sex on outcomes following simultaneous pancreas–kidney transplantation in the new millennium: Single‐center experience and review of the literature , 2022, Clinical transplantation.

[3]  M. van Meurs,et al.  Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis. , 2021, Free radical biology & medicine.

[4]  M. van Meurs,et al.  Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI , 2021, Critical Care.

[5]  Regina F. Sultanova,et al.  Sex differences in renal mitochondrial function: a hormone-gous opportunity for research. , 2020, American journal of physiology. Renal physiology.

[6]  S. Tait,et al.  Mitochondrial DNA in inflammation and immunity , 2020, EMBO reports.

[7]  A. Kleiman,et al.  Perioperative Considerations Regarding Sex in Solid Organ Transplantation. , 2020, Anesthesiology clinics.

[8]  M. Struys,et al.  Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair , 2020, Journal of clinical medicine.

[9]  Y. H. Lee,et al.  Clinical relevance of cell-free mitochondrial DNA during the early postoperative period in kidney transplant recipients , 2019, Scientific Reports.

[10]  S. Wan,et al.  Donor Plasma Mitochondrial DNA is Correlated with Posttransplant Renal Allograft Function. , 2019, Transplantation.

[11]  D. Gjertson,et al.  Equally interchangeable? - How sex and gender affect transplantation. , 2019, Transplantation.

[12]  J. Pantel,et al.  Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain , 2018, Biology of Sex Differences.

[13]  Z. Balogh,et al.  The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies , 2018, European Journal of Trauma and Emergency Surgery.

[14]  J. Shults,et al.  Kidney allograft offers: Predictors of turndown and the impact of late organ acceptance on allograft survival , 2018, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  Lijun Wang,et al.  Exogenous administration of mitochondrial DNA promotes ischemia reperfusion injury via TLR9‐p38 MAPK pathway , 2017, Regulatory toxicology and pharmacology : RTP.

[16]  Jie-shou Li,et al.  Urinary Mitochondrial DNA Levels Identify Acute Kidney Injury in Surgical Critical Illness Patients , 2017, Shock.

[17]  M. Salvadori,et al.  Biomarkers in renal transplantation: An updated review , 2017, World journal of transplantation.

[18]  S. Berger,et al.  Propofol‐based anaesthesia versus sevoflurane‐based anaesthesia for living donor kidney transplantation: results of the VAPOR‐1 randomized controlled trial , 2017, British journal of anaesthesia.

[19]  R. Swerdlow,et al.  Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration , 2017, Front. Immunol..

[20]  P. Agostinis,et al.  Transplantation and Damage‐Associated Molecular Patterns (DAMPs) , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  L. Lerman,et al.  Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients , 2016, Hypertension.

[22]  R. Schnellmann,et al.  Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury , 2015, Kidney international.

[23]  M. Salvadori,et al.  Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. , 2015, World journal of transplantation.

[24]  M. Minczuk,et al.  In D-loop: 40years of mitochondrial 7S DNA , 2014, Experimental Gerontology.

[25]  U. Heemann,et al.  The effect of ischemia/reperfusion on the kidney graft , 2014, Current opinion in organ transplantation.

[26]  C. Ponticelli.  Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[27]  J. López-Sendón,et al.  Mitochondrial DAMPs Induce Endotoxin Tolerance in Human Monocytes: An Observation in Patients with Myocardial Infarction , 2014, PloS one.

[28]  J. Nunnari,et al.  Mitochondrial form and function , 2014, Nature.

[29]  R. Bueno,et al.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation , 2013, PLoS medicine.

[30]  W. van Biesen,et al.  Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[31]  V. Mootha,et al.  Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease , 2013, Nature Genetics.

[32]  A. Bello,et al.  Systematic Review: Kidney Transplantation Compared With Dialysis in Clinically Relevant Outcomes , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[33]  E. Siew,et al.  Biological markers of acute kidney injury. , 2011, Journal of the American Society of Nephrology : JASN.

[34]  W. Junger,et al.  Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury , 2009, Nature.

[35]  Alan B Leichtman,et al.  Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[36]  J. Schold,et al.  The Broad Spectrum of Quality in Deceased Donor Kidneys , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[37]  L. Rasmussen,et al.  Nuclear and mitochondrial DNA repair: similar pathways? , 2005, Mitochondrion.

[38]  Rinaldo Bellomo,et al.  Defining acute renal failure: physiological principles , 2004, Intensive Care Medicine.

[39]  B. Van Houten,et al.  Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. M. James,et al.  How mitochondrial damage affects cell function. , 2002, Journal of biomedical science.

[41]  M. Suthanthiran,et al.  Renal transplantation. , 1994, The New England journal of medicine.