Abstract
Kidney transplantation is the best renal-replacement option for most patients with end-stage renal disease. Normothermic machine preservation (NMP) of the kidney has been studied extensively during the last two decades and implemented in clinical trials. Biomarker research led to success in identifying molecules with diagnostic, predictive and therapeutic properties in chronic kidney disease. However, perfusate biomarkers and potential predictive mechanisms in NMP have not been identified yet. Twelve discarded human kidneys (n = 7 DBD, n = 5 DCD) underwent NMP for up to 24 h. Eight were perfused applying urine recirculation (URC), four with replacement of urine (UR) using Ringer's lactate. The aim of our study was to investigate biomarkers (NGAL, KIM-1, and L-FABP), cells and cytokines in the perfusate in context with donor characteristics, perfusate hemodynamics and metabolic parameters. Cold ischemia time did not correlate with any of the markers. Perfusates of DBD kidneys had a significantly lower number of leukocytes after 6 h of NMP compared to DCD. Arterial flow, pH, NGAL and L-FABP correlated with donor creatinine and eGFR. Arterial flow was higher in kidneys with lower perfusate lactate. Perfusate TNF-α was higher in kidneys with lower arterial flow. The cytokines IL-1β and GM-CSF decreased during 6 h of NMP. Kidneys with more urine output had lower perfusate KIM-1 levels. Median and 6-h values of lactate, arterial flow, pH, NGAL, KIM-1, and L-FABP correlated with each other indicating a 6-h period being applicable for kidney viability assessment. The study results demonstrate a comparable cytokine and cell profile in perfusates with URC and UR. In conclusion, clinically available perfusate and hemodynamic parameters correlate well with donor characteristics and measured biomarkers in a discarded human NMP model.
Highlights
Improving the quality and duration of donor kidney preservation prior to transplant may increase utility and potentially improve outcomes
No biomarkers exist that can predict the usability or quality of a kidney during perfusion. Broad hemodynamic parameters such as arterial flow during hypothermic machine perfusion (HMP) with DGF and higher levels of Neutrophil gelatinase-associated lipocalin (NGAL) and/or liver fatty acid-binding protein (L-FABP) over time have been inversely associated with estimated glomerular filtration rate together with an increasing intrarenal resistance (IRR) [5]
Critical criteria consisting of arterial flow, macroscopic appearance of the kidney and volume of excreted urine have been incorporated into a decision-making score during normothermic machine perfusion (NMP) [6], but clearly, a prognostic marker of post-transplant function would represent a stepwise improvement to perfusion
Summary
Improving the quality and duration of donor kidney preservation prior to transplant may increase utility and potentially improve outcomes. No biomarkers exist that can predict the usability or quality of a kidney during perfusion Broad hemodynamic parameters such as arterial flow during hypothermic machine perfusion (HMP) with DGF and higher levels of NGAL and/or L-FABP over time have been inversely associated with estimated glomerular filtration rate (eGFR) together with an increasing intrarenal resistance (IRR) [5]. The kidney is equipped with a sophisticated immune compartment, hosting a plethora of non-hematopoetic cell types and a variety of both transient and resident leukocytes [7, 8]. A potent inflammatory cascade ensues involving severe cytokine activation and cellular extravasation [9,10,11] Given this inflammatory response is initiated in the donor and continues throughout preservation, evaluating leukocyte diapedesis and cytokine secretion may identify novel biomarkers during kidney perfusion
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