(Pro)renin, Erythropoietin, Vitamin D and Urodilatin Release From Human Donor Kidneys During Normothermic Machine Perfusion: Predictors of Early Post-Transplant Outcome?

Abstract

Background: Human donor kidneys release (pro)renin, erythropoietin (EPO), active vitamin D, and urodilatin during normothermic machine perfusion (NMP). However, whether the endocrine function of donor kidneys is associated with post-transplant kidney function is unclear.

Methods: We studied 28 donor kidneys, including seven from donation after brain death (DBD) donors and 21 from donation after circulatory death (DCD) donors. Prior to transplantation, we measured levels of (pro)renin, EPO, 1,25(OH)₂D in the perfusate, and urodilatin in urine during NMP. Hormone release rates were compared between kidneys with and without delayed graft function (DGF), and correlations were assessed between hormone release rates and donor characteristics and transplant outcome, including DGF duration, serum creatinine levels at 1-week post-transplant, and estimated glomerular filtration rate at 1-month post-transplant.

Results: DBD kidneys secreted significantly less EPO and more active vitamin D than DCD kidneys. Kidneys with DGF exhibited significantly higher release rates of active vitamin D and lower release rates of urodilatin compared to those without DGF. In addition, EPO release rate was positively correlated with serum creatinine levels at 1-week post-transplant. Finally, urodilatin release rates were negatively correlated with DGF duration and positively correlated with urine output.

Conclusions: Urodilatin release in urine and EPO and active vitamin D release in perfusate during NMP may serve as potential biomarkers for predicting early post-transplant outcomes.

Trial registration: ClinicalTrials.gov identifier: NCT04882254.

Keywords: donor kidney; early post‐transplant outcome; endocrine function; hormone release; normothermic machine perfusion.

FIGURE 1

Levels of different hormones secreted by the kidneys during 2 h of NMP. (A–D) Prorenin, renin, EPO, and 1,25(OH)₂D in the perfusate at timepoints 0, 1, and 2 h of NMP. Black, orange, and red lines respectively represent kidneys that exhibited non‐DGF, DGF, and PNF after transplantation. Open circles and open triangles display DCD and DBD kidneys, respectively. DGF, delayed graft function; PNF, primary non‐function; DCD, donation after circulatory death; DBD, donation after brain death.

FIGURE 2

Urodilatin levels in the urine at timepoints 1 and 2 h of NMP. Each line represents a kidney, as shown in the legend. Three samples were missing for urodilatin measurements. Black, orange, and red lines respectively represent kidneys that exhibited non‐DGF, DGF, and PNF after transplantation. Open circles and open triangles display DCD and DBD kidneys, respectively. DGF, delayed graft function; PNF, primary non‐function; DCD, donation after circulatory death; DBD, donation after brain death.

FIGURE 3

Release rates of different hormones during 2 h of NMP between DCD and DBD kidneys. (A–D) Prorenin, renin, EPO, and 1,25(OH)₂D release rates in the perfusate during 2 h of NMP. (E and F) Urodilatin release rates in the urine during the first hour and the second hour of NMP. Values are shown as median with interquartile range. *p < 0.05; ***p < 0.001; ns, non‐significant p > 0.05; DBD, donation after brain death; DCD, donation after circulatory death.

FIGURE 4

Comparison of hormone release capacity during NMP between DGF and non‐DGF kidneys. (A–H) Prorenin, renin, EPO, and 1,25(OH)₂D release rates in the perfusate during the first hour and the complete 2 h of NMP. (I and J) Urodilatin release rates in the urine during the first and second hour of NMP. The two primary non‐function kidneys were included in the DGF group. Values are shown as median with interquartile range. *p < 0.05; **p < 0.01; ns, non‐significant p > 0.05; DGF, delayed graft function.

FIGURE 5

Negative correlation between the duration of DGF and the urodilatin release rate during the second hour of NMP. The release rate and DGF duration were log‐transformed before plotting. A DGF duration of 1 day was set for non‐DGF kidneys to include those in the figure. Each dot represents a machine‐perfused kidney. DGF, delayed graft function.

FIGURE 6

Positive correlation between the serum creatinine levels at 1‐week post‐transplant and EPO release rate during 2 h of NMP. Each dot represents a machine‐perfused kidney. EPO, erythropoietin.