Low Pre-Transplant Caveolin-1 Serum Concentrations Are Associated with Acute Cellular Tubulointerstitial Rejection in Kidney Transplantation

Abstract

Acute and chronic transplant rejections due to alloreactivity are essential contributors to graft loss. However, the strength of alloreactivity is biased by non-immunological factors such as ischemia reperfusion injury (IRI). Accordingly, protection from IRI could be favorable in terms of limiting graft rejection. Caveolin-1 (Cav-1) is part of the cell membrane and an important regulator of intracellular signaling. Cav-1 has been demonstrated to limit IRI and to promote the survival of a variety of cell types including renal cells under stress conditions. Accordingly, Cav-1 could also play a role in limiting anti-graft immune responses. Here, we evaluated a possible association between pre-transplant serum concentrations of Cav-1 and the occurrence of rejection during follow-up in a pilot study. Therefore, Cav-1-serum concentrations were analyzed in 91 patients at the time of kidney transplantation and compared to the incidence of acute and chronic rejection. Higher Cav-1 levels were associated with lower occurrence of acute cellular tubulointerstitial rejection episodes.

Keywords: Caveolin-1; graft rejection; ischemia and reperfusion injury (IRI); kidney transplantation.

Figure 1

Bee-/Boxplots of Cav-1 serum levels in pg/mL vs. items according to the histological categories of the Banff classification. (A) Acute interstitial rejection, (B) acute tubular rejection, (C) vascular rejection, (D) acute glomerulitis, (E) acute peritubular capillaritis, (F) C4d positivity, (G) chronic transplant glomerulopathy, (H) mesangial matrix increase, (I) arteriolohyalinosis, (J) CNI-type arteriolohyalinosis, (K) transplant-vasculopathy, (L) interstitial fibrosis, (M) tubular atrophy, (N) total inflammation, (O) inflammation in scarred parenchyma.

Figure 2

Overview of Banff categories/grades compared to Cav-1 serum levels. Boxes correspond to the 25% and 75% percentile, median line inside the box, whiskers display the rest of the distribution, outliers are outside the whiskers. (A) Acute cellular rejections: NCR = no cellular rejection; BTCMR = borderline (suspicious for) T-cell mediated rejection; ATCMR = acute T-cell mediated rejection; ATCMR IA,B = acute T-cell mediated rejection of grade IA,B (tubulointerstitial rejection); ATCMR IIA,B,III = acute T-cell mediated rejection of grade IIA,B,III (cellular vascular rejection). Values were available from all 91 patients. (B) Chronic damage: CA-TCMR = chronic and active T-cell mediated rejection (values were available from 46 patients); CTxV = chronic transplantation vasculopathy (cumulative and separated by intensity of fibrointimal narrowing from low/CTxV1 to high/CTxV3; values were available from 89 patients). (C) Antibody mediated rejection: A-ABMR = acute antibody mediated rejection; CA-ABMR = chronic active antibody mediated rejection; CI-ABMR = chronic inactive antibody mediated rejection. Values were available from 62 patients.

Figure 3

Kaplan-Meier curves of time from serum draw to ATCMR IA,B in the different Cav-1 classifier (CC) groups. (A) The eight events of ATCMR IA,B only occurred in the lowest CC group (CC0), p < 0.005 (logrank test). (B) Event was defined as borderline or ATCMR IA,B. The 42 events only occurred in the lower CC groups (CC0,1), p < 0.005 (multivariate logrank test).