Medical director of pancreas and living-donor kidney transplant program
Department of transplantation
Impact of duodenal cuff inflammation on outcome after clinical pancreas transplantation – A survey of a comprehensive follow-up strategy including serial protocol biopsy of the duodenal cuff
Ali-Reza Biglarnia1, Shinji Yamamoto1, Amir Sedigh1, Cinthia Drachenberg4, Michael Wagner2, Fredrick Sund3, David Berglund5, Bengt von Zur-Mühlen1, Erik Larsson6.
1Department of transplantation, Uppsala university, Uppsala, Sweden; 2Department of gastroenterology, Uppsala university, Uppsala, Sweden; 3Department of infectious disease, Uppsala university, Uppsala, Sweden; 4Department of pathology, University of Maryland Hospital , Baltimore, MD, United States; 5Department of immunology, Uppsala university, Uppsala, Sweden; 6Department of pathology, Uppsala university, Uppsala, Sweden
Background: The true incidence of duodenal cuff inflammation (caused by rejection/viral infection) as well as its impact on pancreas graft outcome is unknown. Here we present data on the first systematic pathomorphological evaluation of a large biopsy (px) material that was prospectively obtained during a comprehensive surveillance including serial protocol px of the duodenal cuff after pancreas transplantation (PT).
Methods: Between 2010 and 2013, 72 patients underwent simultaneous pancreas and kidney (n= 55), pancreas after kidney (n= 12) and PT alone (n= 5). Three patients with technical failure were excluded. In 3 patients (not excluded), no biopsy was obtained due to death, refusal and graft inaccessibility. Sixty-six patients underwent serial protocol biopsy (px) of the duodenal cuff and native duodenum (for comparative analysis) at 0-3, 6,12 months and thereafter yearly/on-demand. Biopsies were obtained by double balloon enteroscopy (n= 61), cystoscopy (n= 4) and open surgery (n= 1). Protocol surveillance included also Luminex for HLA-DSA and PCR for cytomegalovirus (CMV). Thorough morphological and immunohistological analysis, including immunostaining for CMV antigens was implemented. CMV-prophylaxis included valaciclovir (n= 53) and valganciclovor (n= 12). Four patients received no prophylaxis.
Results: Six patients died with normal renal and pancreas graft function as a result of neck trauma (day 199), traffic accident (day 1029), self-inflicted intoxication (day 234), myocardial infarction (day 53), metastatic sarcoma (1413) and severe graft-versus-host-disease (day 496). At the median follow-up of 988 days (50-1704), the median creatinine and Hb1Ac for the study population was 92 μmol/L (ref. 45-90) and 36.5 mmol/mol (ref. 31-46), respectively. Overall, 2052 duodenal cuff px and 732 native duodenal px were obtained from 280 biopsy occasions during 4-years follow-up. No biopsy-related morbidity was observed. In 21/69 patients (30%), significant duodenal inflammation was presented. In 8/21 cases, only rejection was evident at a median of 209 days (11-428). In 13/21 cases, intra-graft CMV-infection (IG-CMV) of the duodenal cuff occurred at a median of 121 days (16-589). Seven patients with IG-CMV (54%) also developed rejection at a median of 433 days (65-1234). In 15/21 patients (71%), duodenal inflammation was resolved (biopsy verified) post rejection/antiviral treatment. In Six patients (with consistent inflammation), pancreas graft lost occurred at a median of 625 days (242-925). In 5/6 cases, graft loss was preceded by IG-CMV. Cox hazard-ratio on time dependent effect of IG-CMV on graft loss was 22 (p< 0.05). Donor CMV(+) serostatus was associated with IG-CMV (logrank p= 0.01). The majority of cases with IG-CMV occurred with no CMV-viremia and no attributable symptoms. There was no correlation between IG-CMV and de novo DSA.
Conclusion: Duodenal cuff inflammation clearly impacts outcome post-PT. IG-CMV infection seems to be a so far underestimated entity of CMV-infection, which is strongly associated with sustained duodenal cuff inflammation and graft failure. Furthermore, IG-CMV is challenging to diagnose, since most cases occurred with no CMV-DNAemia and/or attributable symptoms. These data emphasize the importance of better understanding and classification of duodenal cuff pathomorphology in context of rejection and IG-CMV to improve outcome post-PT.
11:00 - 12:30
|Progress and clinical outcomes in pancreas transplantation||Impact of duodenal cuff inflammation on outcome after clinical pancreas transplantation – A survey of a comprehensive follow-up strategy including serial protocol biopsy of the duodenal cuff||Room 110|