Carolyn Smullin is a general surgery resident at UCLA. She graduated magna cum laude from UC Berkeley in 2017 and was a David Geffen Scholar at the David Geffen School of Medicine at UCLA in 2022. During her medical school education, while under the mentorship of Dr. Douglas Farmer, she developed an interest in the field of transplant surgery, particularly abdominal organ and intestinal. Her current research focuses on identifying early biomarkers of acute rejection after intestinal transplantation, understanding mechanisms of immunity and tolerance, and describing interactions between the intestinal microbiome and solid organ transplant outcomes.Carolyn Smullin is a general surgery resident at UCLA. She graduated magna cum laude from UC Berkeley in 2017 and was a David Geffen Scholar at the David Geffen School of Medicine at UCLA in 2022. During her medical school education, while under the mentorship of Dr. Douglas Farmer, she developed an interest in the field of transplant surgery, particularly abdominal organ and intestinal. Her current research focuses on identifying early biomarkers of acute rejection after intestinal transplantation, understanding mechanisms of immunity and tolerance, and describing interactions between the intestinal microbiome and solid organ transplant outcomes.
Noninvasive biomarkers for allograft monitoring after intestinal transplantation: promising early results from a novel peptide, REG3α
Carolyn P. Smullin1, Robert S. Venick2, Elizabeth A. Marcus2, Bita V. Naini3, Douglas G. Farmer1.
1Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; 2Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; 3Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Background: The field of intestinal transplantation (ITx) lacks a specific biomarker for diagnosing acute rejection. Currently, calprotectin and citrulline, biomarkers used in monitoring disease activity in inflammatory bowel disease (IBD) and short-bowel syndrome, are employed for detection of allograft rejection. However, neither have proved their utility in distinguishing rejection from other non-specific causes of intestinal inflammation, giving these tests high sensitivity but low specificity and predictive value. The regenerating islet-derived (REG) proteins, a family of C-type lectin anti-inflammatory/anti-bacterial proteins expressed in Paneth cells within the epithelium of the small intestine, are emerging as a potential biomarker for intestinal pathology. Initially discovered in connection with pancreas islet regeneration in rats, REG proteins are known to be highly expressed in several human intestinal pathologies related to epithelial injury and inflammation. REG3α specifically has been correlated with disease severity in IBD and intestinal graft vs host disease (GVHD). While it shows potential as a biomarker for intestinal pathology, it has not been extensively studied in ITx.
Methods: Our center has maintained a detailed prospective database on all ITx recipients since 1991. A protocol of weekly allograft monitoring with stool calprotectin, serum citrulline and endoscopy with biopsy is followed. In 2015, REG3α was added to this protocol. Biopsy-confirmed acute rejection (BCAR) is graded according to international standards. Biomarkers are correlated to BCAR by post-operative week (POW). We compared biomarkers by severity of rejection (grade 0-2 vs 3-4) using standard statistical tests.
Results: Five adults underwent isolated ITx and one child underwent multivisceral transplantation. Median time to first BCAR was 3 weeks; all experienced at least 1 episode of BCAR. One-year patient and graft survival was 100%. Calprotectin, citrulline and REG3α were significantly associated with grade 3-4 BCAR (p=0.00). The median REG3α level was 5.5 times the upper limit of normal during grade 3-4 BCAR. Calprotectin had the highest positive predictive value (PPV) (76%); REG3α had the highest negative predictive value (NPV) (89%). Together, they demonstrate a high PPV and NPV (100% and 93%, respectively).
Conclusions: This is the first case series to describe a protocol of allograft monitoring after ITx using invasive and noninvasive testing including REG3α. Calprotectin, citrulline and REG3α are individually associated with moderate-severe BCAR and together demonstrate a high PPV and NPV. REG3α demonstrates a superior NPV for detecting rejection. This preliminary experience indicates that REG3α may be useful for ITx allograft monitoring. Ongoing efforts are aimed at conducting a prospective multicenter investigation to further determine the association of REGα with BCAR.
right-click to download
