Mucosal Fibrosis in Intestinal Transplant Biopsies Correlates Positively With the Development of Chronic Rejection

Mucosal Fibrosis in Intestinal Transplant Biopsies Correlates Positively With the Development of Chronic Rejection P. Tryphonopoulos, D. Weppler, S. Nishida, T. Kato, D. Levi, G. Selvaggi, J. Moon, J.R. Madariaga, J. DelaGarza, A. Tzakis, and P. Ruiz ABSTRACT Endoscopic biopsies of intestinal allografts are limited to the superficial layers of the bowel. We investigated whether the presence of mucosal fibrosis in graft biopsies was indicative of chronic allograft rejection. We examined graft biopsies of 182 intestinal transplant recipients for the presence of mucosal fibrosis. Kaplan-Meier analysis showed that within 5 years posttransplantation 33% of intestinal transplant patients had graft biopsies positive for mucosal fibrosis. Although the presence of mucosal fibrosis did not affect patient or graft survival, patients with this lesion were at higher risk of developing chronic allograft enteropathy.

E

NDOSCOPIC BIOPSIES of intestinal allografts are limited to the superficial layers of the bowel, thus limiting evaluation for chronic injury.1 The aim of our study was to investigate whether the presence of mucosal fibrosis in the graft biopsy was indicative of chronic rejection.

MATERIALS AND METHODS Endoscopic graft biopsies of patients who had received an intestinal graft from October 1994 to October 2004 were reviewed for the presence of mucosal fibrosis. Follow-up was until the end of February 2005. Mucosal fibrosis was detected by microscopic examination of the graft biopsy. Its presence was confirmed by a positive Trichrome stain.

RESULTS Patients with Mucosal Fibrosis

Table 1. Patient Demographics

n Male/female Adult/pediatric Type of graft Intestine Liver-intestine Modified multivisceral Multivisceral Cold ischemia time (min) Warm ischemia time (min) Donor age (y) Recipient age (y)

Fig 1. Kaplan-Meier curve of percentage of patients without mucosal fibrosis at their graft biopsies.

Group A (mucosal fibrosis)

Group B (no fibrosis)

39 23/16 18/22

143 74/69 52/91

.4 .3

15 4 6 14 421 ⫾ 14 39 ⫾ 1 13.25 ⫾ 2.52 17.84 ⫾ 2.67

42 28 8 65 425 ⫾ 8 41 ⫾ 2 10.41 ⫾ 1.12 15.08 ⫾ 1.45

.3 .2 .04 .3 .8 .6 .3 .4

P

Among 182 intestinal transplant patients, 39 (group A) showed mucosal fibrosis in their graft biopsies versus 143 (group B) who did not display this lesion. In group A, the patients including 22 pediatric and 18 adult recipients and 16 female and 23 male subjects received isolated intestinal (n ⫽ 15), liver-intestinal (n ⫽ 4), multivisceral (n ⫽ 14), or From the Department of Surgery and Pathology, University of Miami, Miami, Florida, USA. Address reprint requests to Phillip Ruiz, University of Miami, Department of Surgery and Pathology, 1611 NW 12th Avenue, JMH-Holtz Center #2101, Miami, FL, 33136, USA. E-mail: Pruiz@ med.miami.edu

© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.05.019

Transplantation Proceedings, 38, 1685–1686 (2006)

1685

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TRYPHONOPOULOS, WEPPLER, NISHIDA ET AL

Fig 2. Patient (A) and graft (B) survival. Group A: patients with presence of mucosal fibrosis at their graft biopsies; group B: patients without mucosal fibrosis.

modified multivisceral grafts (n ⫽ 6). There were no significant differences in the distribution of the types of transplants between the two groups (Table 1). Four recipients were transplanted from 1996 to 1997 under immunosuppression with tacrolimus and steroids. The rest of the patients, who were transplanted from 1998 until 2004, additionally received Zenapax (n ⫽ 25) or Campath-1H (n ⫽ 10) induction immunosuppression. Twelve patients transplanted between 1996 and 2000 also received donor bone marrow infusions. Mucosal fibrosis was observed for the first time at 0.7 to 90 (mean: 7.3 ⫾ 1.2) months posttransplantation. The fibrosis lesion was mild in the majority of the cases (n ⫽ 35) and moderate in a few (n ⫽ 4). Kaplan-Meier analysis showed that 33% of our intestinal transplant patients had graft biopsies positive for mucosal fibrosis within 5 years posttransplantation (Fig 1). There was no significant difference in patient or graft survival when the patient displayed mucosal fibrosis (Fig 2). At the end of the follow-up period, 18 of the 39 patients in group A are still alive with functioning grafts at 0.02 to 6 years (median 2.7 ⫾ 0.63) after the initial graft biopsy was positive for mucosal fibrosis. The causes of death included chronic rejection (n ⫽ 2); acute rejection (n ⫽ 8); sepsis (n ⫽ 6); graft-versus-host disease (n ⫽ 1); portal vein thrombosis (n ⫽ 1); hemolysis (n ⫽ 2); and viral pneumonia (n ⫽ 1).

Presence of Chronic Rejection in the Explanted Grafts

In group A 13 full-thickness grafts were available for pathological examination after total (n ⫽ 11) or partial (n ⫽ 2) graft resection. Nine grafts (69.2%) showed changes consistent with chronic rejection that were mild (n ⫽ 5) or moderate (n ⫽ 2), or severe (n ⫽ 2). Among group B, out of the 14 explanted grafts available for pathologic examination, none had changes consistent with chronic rejection.

DISCUSSION

Mucosal fibrosis was present in graft biopsies of about one third of intestinal transplant patients at 5 years posttransplantation. The presence of mucosal fibrosis did not significantly affect patient or graft survival. Mucosal fibrosis identified a group of recipients at higher risk for developing chronic allograft enteropathy.1

REFERENCE 1. Perez MT, Garcia M, Weppler D, et al: Temporal relationships between acute cellular rejection features and increased mucosal fibrosis in the early post-transplant period of human small bowel allografts. Transplantation 73:555, 2002