Systemic Changes in Endocannabinoids and Endocannabinoid-like Molecules in Response to Partial Nephrectomy-Induced Ischemia in Humans

Abstract

Renal ischemia-reperfusion (IR), a routine feature of partial nephrectomy (PN), can contribute to the development of acute kidney injury (AKI). Rodent studies show that the endocannabinoid system (ECS) is a major regulator of renal hemodynamics and IR injury; however, its clinical relevance remains to be established. Here, we assessed the clinical changes in systemic endocannabinoid (eCB) levels induced by surgical renal IR. Sixteen patients undergoing on-clamp PN were included, with blood samples taken before renal ischemia, after 10 min of ischemia time, and 10 min following blood reperfusion. Kidney function parameters (serum creatinine (sCr), blood urea nitrogen (BUN), and serum glucose) and eCB levels were measured. Baseline levels and individual changes in response to IR were analyzed and correlation analyses were performed. The baseline levels of eCB 2-arachidonoylglycerol (2-AG) were positively correlated with kidney dysfunction biomarkers. Unilateral renal ischemia increased BUN, sCr, and glucose, which remained elevated following renal reperfusion. Renal ischemia did not induce changes in eCB levels for all patients pooled together. Nevertheless, stratifying patients according to their body mass index (BMI) revealed a significant increase in N-acylethanolamines (anandamide, AEA; N-oleoylethanolamine, OEA; and N-palmitoylethanolamine, PEA) in the non-obese patients. No significant changes were found in obese patients who had higher N-acylethanolamines baseline levels, positively correlated with BMI, and more cases of post-surgery AKI. With the inefficiency of 'traditional' IR-injury 'preventive drugs', our data support future research on the role of the ECS and its manipulation in renal IR.

Keywords: N-acylethanolamines; endocannabinoids; partial nephrectomy; renal ischemia reperfusion.

Figure 1

Univariate linear regression analysis and the Pearson correlation coefficient of baseline 2-AG levels with intra-operative pre-renal artery clamping levels of (a) sCr and (b) BUN and pre-operative levels of (c) sCr, (d) eGFR, and (e) tumor size. 2-AG = 2-arachidonoylglycerol; sCr = serum creatinine; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate.

Figure 2

Effect of renal ischemia and reperfusion during partial nephrectomy on the circulating kidney dysfunction markers, (a) BUN, (b) glucose, and (c) sCr. BUN = blood urea nitrogen; sCr = serum creatinine. **** p < 0.0001; *** p < 0.001; ** p < 0.01.

Figure 3

Changes in the systemic levels of endocannabinoids, ((a) 2-AG and (b) AEA), endocannabinoid-like compounds, ((c) OEA and (d) PEA), and a degradative product ((e) AA) as a result of renal ischemia and reperfusion during partial nephrectomy. 2-AG = 2-arachidonoylglycerol; AEA = anandamide; OEA = N-oleoylethanolamine; PEA = N-palmitoylethanolamine; AA = arachidonic acid.

Figure 4

Univariate linear regression analysis and the Pearson correlation coefficient of BMI with baseline N-acylethanolamine levels, (a) AEA, (b) OEA, and (c) PEA. BMI = body mass index; AEA = anandamide; OEA = N-oleoylethanolamine; PEA = N-palmitoylethanolamine.

Figure 5

Patient stratification by BMI displaying changes in the systemic levels of endocannabinoids, ((a) 2-AG and (b) AEA), endocannabinoid-like compounds, ((c) OEA and (d) PEA), and a degradative product ((e) AA) as a result of renal ischemia–reperfusion during partial nephrectomy. Results are stratified for non-obese (BMI < 30; left panels) versus obese (BMI > 30; right panels) patients. BMI = body mass index; 2-AG = 2-arachidonoylglycerol; AEA = anandamide; OEA = N-oleoylethanolamine; PEA = N-palmitoylethanolamine; AA = arachidonic acid. * p < 0.05.