Mannitol and renal graft injury in patients undergoing deceased donor renal transplantation - a randomized controlled clinical trial

Christian Reiterer, Karin Hu, Samir Sljivic, Markus Falkner von Sonnenburg, Edith Fleischmann, Alexander Kainz, Barbara Kabon, Christian Reiterer, Karin Hu, Samir Sljivic, Markus Falkner von Sonnenburg, Edith Fleischmann, Alexander Kainz, Barbara Kabon

Abstract

Background: Ischaemia/reperfusion (I/R) injury is associated with renal tissue damage during deceased donor renal transplantation. The effect of mannitol to reduce I/R injury during graft reperfusion in renal transplant recipients is based on weak evidence. We evaluated the effect of mannitol to reduce renal graft injury represented by 16 serum biomarkers, which are indicators for different important pathophysiological pathways. Our primary outcome were differences in biomarker concentrations between the mannitol and the placebo group 24 h after graft reperfusion. Additionally, we performed a linear mixed linear model to account biomarker concentrations before renal transplantation.

Methods: Thirty-four patients undergoing deceased donor renal transplantation were randomly assigned to receive either 20% mannitol or 0.9% NaCl placebo solution before, during, and after graft reperfusion. Sixteen serum biomarkers (MMP1, CHI3L1, CCL2, MMP8, HGF, GH, FGF23, Tie2, VCAM1, TNFR1, IGFBP7, IL18, NGAL, Endostatin, CystC, KIM1) were measured preoperatively and 24 h after graft reperfusion using Luminex assays and ELISA.

Results: Sixteen patients in each group were analysed. Tie2 differed 24 h after graft reperfusion between both groups (p = 0.011). Change of log2 transformed concentration levels over time differed significantly in four biomarkers (VCAM1,Endostatin, KIM1, GH; p = 0.007; p = 0.013; p = 0.004; p = 0.033; respectively) out of 16 between both groups.

Conclusion: This study showed no effect of mannitol on I/R injury in patients undergoing deceased renal transplantation. Thus, we do not support the routinely use of mannitol to attenuate I/R injury.

Trial registration: NCT02705573 . Registered on 10th March 2016.

Keywords: Biology-derived biomarker; I/R injury; Mannitol; Renal transplantation; Renoprotection.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
CONSORT 2010 patients flow chart
Fig. 2
Fig. 2
Concentration levels (log2 transformed) for all 16 biomarkers before transplantation and 24 h after graft reperfusion grouped by treatment. All concentrations are given in pg/mL. The quantifiable range of assays is indicated by areas shaded in blue

References

    1. Kaballo MA, Canney M, O’Kelly P, Williams Y, O’Seaghdha CM, Conlon PJ. A comparative analysis of survival of patients on dialysis and after kidney transplantation. Clin Kidney J. 2018;11:389–393. doi: 10.1093/ckj/sfx117.
    1. Rabbat CG, Thorpe KE, Russell JD, Churchill DN. Comparison of mortality risk for dialysis patients and cadaveric first renal transplant recipients in Ontario, Canada. J Am Soc Nephrol. 2000;11:917–922.
    1. Ponticelli C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol Dial Transplant. 2014;29:1134–1140. doi: 10.1093/ndt/gft488.
    1. Kezić A, Stajic N, Thaiss F. Innate immune response in kidney ischemia/reperfusion injury: potential target for therapy. J Immunol Res. 2017.
    1. Cosentino M, Breda A, Sanguedolce F, et al. The use of mannitol in partial and live donor nephrectomy: an international survey. World J Urol. 2013;31:977–982. doi: 10.1007/s00345-012-1003-1.
    1. Lugo-Baruqui JA, Ayyathurai R, Sriram A, Pragatheeshwar KD. Use of Mannitol for ischemia reperfusion injury in kidney transplant and partial nephrectomies—review of literature. Curr Urol Rep. 2019;20.
    1. Bragadottir G, Redfors B, Ricksten SE. Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study. Crit Care. 2012;17.
    1. Thomas ME, Blaine C, Dawnay A, et al. The definition of acute kidney injury and its use in practice. Kidney Int Elsevier Masson SAS. 2015;87:62–73. doi: 10.1038/ki.2014.328.
    1. Parikh CR, Jani A, Mishra J, et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant. 2006;6:1639–1645. doi: 10.1111/j.1600-6143.2006.01352.x.
    1. Mayer P, Mayer B, Mayer G. Systems biology building a useful model from multiple markers and profiles. Nephrol Dial Transplant. 2012;27:3995–4002. doi: 10.1093/ndt/gfs489.
    1. Mayer G, Heerspink HJL, Aschauer C, et al. Systems biology-derived biomarkers to predict progression of renal function decline in type 2 diabetes. Diabetes Care. 2017;40:391–397. doi: 10.2337/dc16-2202.
    1. Van Timmeren MM, Vaidya VS, Van Ree RM, et al. High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation. 2007;84:1625–1630. doi: 10.1097/01.tp.0000295982.78039.ef.
    1. Einecke G, Sis B, Reeve J, et al. Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant. 2009;9:2520–2531. doi: 10.1111/j.1600-6143.2009.02799.x.
    1. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62:237–244. doi: 10.1046/j.1523-1755.2002.00433.x.
    1. Lohkamp LN, Öllinger R, Chatzigeorgiou A, Illigens BMW, Siepmann T. Intraoperative biomarkers in renal transplantation. Nephrology. 2016;21:188–199. doi: 10.1111/nep.12556.
    1. Malhotra R, Siew ED. Biomarkers for the early detection and prognosis of acute kidney injury. Clin J Am Soc Nephrol. 2017;6:149–173. doi: 10.2215/CJN.01300216.
    1. Feldheiser A, Conroy P, Bonomo T, Cox B, Ruiz Garces T, Spies C. Development and feasibility study of an algorithm for intraoperative goaldirected haemodynamic management in noncardiac surgery. J Int Med Res. 2012;40:1227–1241. doi: 10.1177/147323001204000402.
    1. Moledina DG, Hall IE, Thiessen-Philbrook H, et al. Performance of serum Creatinine and kidney injury biomarkers for diagnosing histologic acute tubular injury. Am J Kidney Dis. 2017;70.
    1. Lugo-Baruqui JA, Ayyathurai R, Sriram A, Pragatheeshwar KD. Use of Mannitol for ischemia reperfusion injury in kidney transplant and partial nephrectomies—review of literature. Curr Urol Rep. 2019;26.
    1. Green RD, Boyer DA, Halasz N, Collins GM. Pharmacological protection of rabbit kidneys from normothermic ischemia. Transplantation. 1979;28:131–134. doi: 10.1097/00007890-197908000-00012.
    1. Van Valenberg PLJ, Hoitsma AJ, Tiggeler RGWL, Berden JHM, Van Lier HJJ, Koene RAP. Mannitol as an indispensable constituent of an intraoperative hydration protocol for the prevention of acute renal failure after renal cadaveric transplantation. Transplantation. 1987;44:784–788. doi: 10.1097/00007890-198712000-00012.
    1. Weimar W, Geerlings W, Bijnen A, et al. A controlled study on the effect of mannitol on immediate renal function after cadaver donor kidney transplantation. Transplantation. 1983;35:99–101.
    1. Tiggeler RGWL, Berden JHM, Hoitsma AJ, Koene RAP. Prevention of acute tubular necrosis in cadaveric kidney transplantation by the combined use of mannitol and moderate hydration. Ann Surg. 1985;201:246–251. doi: 10.1097/00000658-198502000-00020.
    1. Hanif F, Macrae AN, Littlejohn MG, Clancy MJ, Murio E. Outcome of renal transplantation with and without intra-operative diuretics. Int J Surg. 2011;9:460–463. doi: 10.1016/j.ijsu.2011.04.010.
    1. Raju DL, Grover VK, Shoker A. Limitations of glomerular filtration rate equations in the renal transplant patient. Clin Transpl. 2005;19:259–268. doi: 10.1111/j.1399-0012.2005.00335.x.
    1. Singh H, Hansen TM, Patel N, Brindle NPJ. The molecular balance between receptor tyrosine kinases Tie1 and Tie2 is dynamically controlled by VEGF and TNFα and regulates angiopoietin signalling. PLoS One. 2012;7.
    1. Chung NAY, Makin AJ, Lip GYH. Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay. Eur J Clin Investig. 2003;33:529–535. doi: 10.1046/j.1365-2362.2003.01173.x.
    1. Koutroubakis IE, Xidakis C, Karmiris K, Sfiridaki A, Kandidaki E, Kouroumalis EA. Potential role of soluble angiopoietin-2 and Tie-2 in patients with inflammatory bowel disease. Eur J Clin Investig. 2006;36:127–132. doi: 10.1111/j.1365-2362.2006.01602.x.
    1. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - In control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–371d. doi: 10.1038/nrm1911.
    1. Bolignano D, Donato V, Coppolino G, et al. Neutrophil Gelatinase-associated Lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis. 2008;52:595–605. doi: 10.1053/j.ajkd.2008.01.020.
    1. Fan W, Ankawi G, Zhang J, et al. Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice. Clin Chem Lab Med. 2019;57:567–576. doi: 10.1515/cclm-2018-0776.
    1. Cassie S, Masterson MF, Polukoshko A, Viskovic MM, Tibbles LA. Ischemia/reperfusion induces the recruitment of leukocytes from whole blood under flow conditions. Free Radic Biol Med. 2004;36:1102–1111. doi: 10.1016/j.freeradbiomed.2004.02.007.
    1. Mrowka C, Sieberth HG. Circulating adhesion molecules ICAM-1, VCAM-1 and E-selectin in systemic vasculitis : marked differences between Wegener’s granulomatosis and systemic lupus erythematosus. Clin Investig. 1994;72:762–768. doi: 10.1007/BF00180543.
    1. Tomono Y, Naito I, Ando K, et al. Epitope-defined monoclonal antibodies against Multiplexin collagens demonstrate that type XV and XVIII collagens are expressed in specialized basement membranes. Cell Struct Funct. 2002;27:9–20. doi: 10.1247/csf.27.9.
    1. Marneros AG, Olsen BR. Physiological role of collagen XVIII and endostatin. FASEB J. 2005.
    1. Jia HM, Zheng Y, Huang LF, et al. Derivation and validation of plasma endostatin for predicting renal recovery from acute kidney injury: a prospective validation study. Critical Care. 2018;22:305. doi: 10.1186/s13054-018-2232-5.
    1. Malyszko J, Lukaszyk E, Glowinska I, Durlik M. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep. 2015;15.
    1. Wasung ME, Chawla LS, Madero M. Biomarkers of renal function, which and when? Clin Chim Acta [Internet] Elsevier B.V. 2015;438:350–357. doi: 10.1016/j.cca.2014.08.039.
    1. Yong Z, Pei X, Zhu B, Yuan H, Zhao W. Predictive value of serum cystatin C for acute kidney injury in adults: a meta-analysis of prospective cohort trials. Sci Rep [Internet] Nature Publishing Group. 2017;7:1–11.
    1. Rygasiewicz K, Hryszko T, Siemiatkowski A, Brzosko S, Rydzewska-Rosolowska A, Naumnik B. C-terminal and intact FGF23 in critical illness and their associations with acute kidney injury and in-hospital mortality. Cytokine. 2018;103:15–19. doi: 10.1016/j.cyto.2017.12.024.
    1. Christov M, Waikar SS, Pereira RC, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013;84:776–785. doi: 10.1038/ki.2013.150.
    1. Collange O, Jazaerli L, Lejay A, et al. Intraoperative Pleth variability index is linked to delayed graft function after kidney transplantation. Transplant Proc. 2016;48:2615–2621. doi: 10.1016/j.transproceed.2016.06.046.
    1. Othman MM, Ismael AZ, Hammouda GE. The impact of timing of maximal crystalloid hydration on early graft function during kidney transplantation. Anesth Analg. 2010;110:1440–1446. doi: 10.1213/ANE.0b013e3181d82ca8.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться