Endocan as a marker of microvascular inflammation in kidney transplant recipients

Abstract

Endocan is a water-soluble proteoglycan exclusively secreted by vascular endothelium. Endocan levels may be elevated in kidney transplant recipients experiencing antibody-mediated rejection (ABMR), which is characterized by vascular inflammation in transplanted kidney. We evaluated the clinical relevance of endocan as markers of microvascular inflammation in patients who underwent kidney transplantation. Plasma and urinary endocan levels were measured in 203 kidney transplant recipients and were compared across different etiologies of allograft dysfunction and various pathologic scores. Both plasma and urinary endocan levels were significantly higher in patients with acute ABMR than those in patients with normal pathology, acute tubular necrosis (ATN), acute pyelonephritis, BK virus associated nephropathy (BKVN), and T-cell mediated rejection (TCMR). Patients with chronic active ABMR also exhibited significantly higher plasma and urinary endocan levels than patients with long-term graft survival. Scores of glomerulitis and peritubular capillaritis, which are typical features of microvascular inflammation, were significantly elevated in patients with higher plasma and/or urinary endocan levels. Furthermore, plasma and urinary endocan levels could effectively discriminate ABMR from ATN, BKVN, and TCMR. Finally, patients exhibiting high urinary and plasma endocan levels in acute ABMR group showed significantly worse renal survival. Altogether, plasma and urinary endocan levels may serve as potential markers of microvascular inflammation in kidney transplant recipients.

Figure 1

Endocan levels according to renal allograft status. (A) Plasma endocan levels were significantly higher in patients with acute ABMR than those in patients with NP, ATN, APN, BKVN, and TCMR. Patients with chronic active ABMR exhibited significantly higher plasma endocan levels than patients with LTGS. (B) Similar to plasma endocan levels, urinary endocan levels were significantly increased in patients with acute ABMR compared to those in the other groups in the short transplant vintage set. Patients with TCMR exhibited higher urinary endocan levels than patients with NP, and the levels were also higher in patients with chronic active ABMR than in patients with LTGS. *p < 0.05, **p < 0.005. Abbreviations: NP, normal pathology; ATN, acute tubular necrosis; APN, acute pyelonephritis; BKVN, BK virus associated nephropathy; TCMR, T-cell mediated rejection; aABMR, acute antibody-mediated rejection; LTGS, long-term graft survival; cABMR, chronic active antibody-mediated rejection.

Figure 2

Association between plasma, urinary endocan levels and various Banff pathologic scores. Patients were divided into quartiles according to levels of (A) plasma and (B) urinary endocan, and various Banff pathologic scores were compared according to quartiles. Glomerulitis, peritubular capillaritis, and microvascular inflammation scores were elevated in the patients both in high plasma and/or urinary endocan quartiles, while tubulitis and interstitial inflammation scores were not.

Figure 3

Immunohistochemistry with endocan antibody. (A) Tissues obtained from patients with clear cell renal cell carcinoma were selected as positive controls and stained with endocan. Diffuse immunoreactivity with endocan was found in vascular structures within tumors. (B,C) No immunoreactivity was observed in renal tissues obtained from patients with normal pathology and T-cell mediated rejection. (D) Positive immunostaining with endocan was observed in proximal tubular cells of tissues obtained from patients with acute antibody-mediated rejection. Other regions, including glomerulus, peritubular capillaries, and interstitium, were negative for endocan staining.

Figure 4

Receiver operating characteristics curves to evaluate the discriminative power of plasma and urinary endocan levels in distinguishing acute antibody-mediated rejection from acute tubular necrosis, BK virus associated nephropathy and T-cell mediated rejection. (A) Plasma endocan, (B) urinary endocan, and (C) the combination of plasma and urinary endocan levels.

Figure 5

Renal allograft survival of enrolled patients. (A) Renal survival according to the diagnosis. (B–D) Renal survival according to plasma and urinary endocan levels in (B) acute T-cell mediated rejection, (C) acute antibody-mediated rejection, and (D) chronic active antibody-mediated rejection group. Plasma and urinary endocan levels were integrated by binary regression analysis.