Combined en bloc heart and liver organ procurement.

A combined heart+liver transplant is the only option for survival in some patients with end-stage combined cardiac and hepatic disease. These patients may suffer from congenital or acquired cardiac disease. The potential aetiologies of the associated hepatic disease are heterogeneous and include systemic disease that impacts the liver as well as venous congestion in patients with functionally univentricular circulation. In the latter scenario, patients with functionally univentricular circulation often require complex cardiac reconstruction in the setting of a cardiac transplant after staged palliation. During cardiac procurement, our approach is to dissect the entire ascending aorta and aortic arch in continuity; the entire superior caval vein and innominate vein in continuity; and the pulmonary arteries from hilum to hilum if the donor is not a candidate for recovery of the lungs. The cardiac and abdominal organ procurement teams work in parallel during dissection and combined en bloc cardio-hepatectomy. This technique minimizes exposure of both organs to cold ischaemia. This video tutorial demonstrates the key steps for combined en bloc heart+liver organ procurement.

Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. METHODS: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. RESULTS: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. CONCLUSIONS: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.

Methylated ctDNA Quantification: Noninvasive Approach to Monitoring Hepatocellular Carcinoma Burden.

BACKGROUND: Noninvasive, precision monitoring of hepatocellular carcinoma (HCC) treatment efficacy would greatly facilitate personalized therapy and improve patient outcomes. We hypothesize that quantifying methylated circulating tumor DNA (ctDNA) can be used to effectively monitor HCC burden without the need for biopsy. STUDY DESIGN: Blood samples were collected from 25 patients, 21 with HCC and 4 with benign liver masses, at various timepoints throughout the course of treatment at a high-volume academic medical center. Quantification of methylated ctDNA molecules assessed CpG sites on more than 550 preselected cancer-specific amplicons. The tumor methylation score (TMS) was calculated by measuring the difference between the amount of methylation in the plasma and buffy coat with a normal cutoff value of 120 or less. RESULTS: Among 10 patients with surgical HCC (5 surgical resections and 5 liver transplants), TMS revealed a statistically significant, rapid postoperative decline in 9. One patient who had a persistently elevated TMS on postoperative day 1 was subsequently found to have had metastatic disease. Patients in the negative control cohort all had normal-range pre- and postoperative TMS. Preoperative TMS correlated moderately with tumor burden on pathology (Spearman r = 0.54) of surgical specimens. From 11 subjects undergoing systemic therapy or Y90 radioembolization, analysis of 16 time periods demonstrated that the change in TMS (ΔTMS) was better associated with tumor progression than the change in Δalpha-fetoprotein (area under the curve 0.800 and 0.783, respectively). A composite score combining ΔTMS and Δalpha-fetoprotein further improved performance for detecting tumor progression with an area under the curve of 0.892. CONCLUSIONS: These findings indicate that ctDNA methylation scores can effectively evaluate changes in tumor burden without the need for tumor biopsy.

Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial ( NCT03527238 ), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis. Lay Summary: In a study on 62 adults who underwent liver transplantation, researchers investigated whether a new dosing method called Phenotypic Personalized Medicine (PPM) would improve daily dosing of the immunosuppression drug tacrolimus. They found that PPM guided tacrolimus dosing leads to better drug level maintenance than the standard-of-care clinician-determined dosing. This means that the PPM approach leads to actionable dosing recommendations on a day-to-day basis and can help improve patient outcomes.

Ex Vivo Liver Resection and Autotransplantation: Should It be Used More Frequently?

OBJECTIVE: We herein advocate for more extensive utilization of ex vivo resection techniques for otherwise unresectable liver tumors by presenting the largest collective American experience. BACKGROUND: Advanced in situ resection and vascular reconstruction techniques have made R0 resection possible for otherwise unresectable liver tumors. Ex vivo liver resection may further expand the limits of resectability but remains underutilized due to concerns about technical complexity and vascular thrombosis. However, we believe that the skillset required for ex vivo liver resection is more widespread and the complications less severe than widely assumed, making ex vivo resection a more attractive option in selected case. METHODS: We retrospectively analyzed 35 cases performed by surgical teams experienced with ex vivo liver resections (at least 4 cases) between 1997 and 2021. RESULTS: We categorized malignancies as highly aggressive (n=18), moderately aggressive (n=14), and low grade (n=3). All patients underwent total hepatectomy, vascular reconstruction and resection in hypothermia on the backtable, and partial liver autotransplantation. Overall survival was 67%/39%/28%, at 1/3/5 years, respectively, with a median survival of 710 days (range: 22-4824). Patient survival for highly aggressive, moderately aggressive, and low-grade tumors was 61%/33%/23%, 67%/40%/22%, and 100%/100%/100% at 1/3/5 years, respectively, with median survival 577 days (range: 22-3873), 444 days (range: 22-4824), and 1825 days (range: 868-3549). CONCLUSIONS: Ex vivo resection utilizes techniques commonly practiced in partial liver transplantation, and we demonstrate relatively favorable outcomes in our large collective experience. Therefore, we propose that more liberal use of this technique may benefit selected patients in centers experienced with partial liver transplantation.

Carnitine Deficiency in an Adult With Short Bowel Syndrome After Surgical Resection.

Carnitine is an essential cofactor for fatty acid metabolism. Deficiencies can be associated with muscle weakness, fatigue, weight loss, and cardiomyopathies. A 27-year-old woman with short bowel syndrome (SBS) presented with significant weight loss, fatigue, and muscle wasting despite adequate parenteral nutrition. Her laboratory test results revealed carnitine deficiency secondary to malnutrition. Levocarnitine supplementation was initiated with normalization of her carnitine levels. Her fatigue improved, and her weight returned to baseline. Carnitine deficiencies are seldomly reported in adults, particularly those with SBS. Carnitine deficiency should be suspected and corrected in patients with SBS and malabsorptive capacity due to surgical resection.

Impact of the acuity circle model for liver allocation on multivisceral transplant candidates.

Liver allocation was updated on February 4, 2020, replacing a Donor Service Area (DSA) with acuity circles (AC). The impact on waitlist outcomes for patients listed for combined liver-intestine transplantation (multivisceral transplantation [MVT]) remains unknown. The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify all candidates listed for both liver and intestine between January 1, 2018 and March 5, 2021. Two eras were defined: pre-AC (2018-2020) and post-AC (2020-2021). Outcomes included 90-day waitlist mortality and transplant probability. A total of 127 adult and 104 pediatric MVT listings were identified. In adults, the 90-day waitlist mortality was not statistically significantly different, but transplant probability was lower post-AC. After risk-adjustment, post-AC was associated with a higher albeit not statistically significantly different mortality hazard (sub-distribution hazard ratio[sHR]: 8.45, 95% CI: 0.96-74.05; p = .054), but a significantly lower transplant probability (sHR: 0.33, 95% CI: 0.15-0.75; p = .008). For pediatric patients, waitlist mortality and transplant probability were similar between eras. The proportion of patients who underwent transplant with exception points was lower post-AC both in adult (44% to 9%; p = .04) and pediatric recipients (65% to 15%; p = .002). A lower transplant probability observed in adults listed for MVT may ultimately result in increased waitlist mortality. Efforts should be taken to ensure equitable organ allocation in this vulnerable patient population.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2021.

The American Transplant Congress 2021 was a virtual meeting and occurred between June 4 and June 9 through an online platform. We highlighted abstracts discussing machine perfusion preservation, a hot topic that may become the gold standard of organ preservation in the future. A total of 33 abstracts on organ machine preservation (3 for heart, 4 for lungs, 18 for liver, and 8 for kidneys) were presented at the meeting. We selected 23 abstracts that showed advances including new approaches to organ preservation, promising treatments and biomarkers, cellular therapy, and novel research areas. Here, we summarize the new developments concerning machine perfusion in both experimental and clinical studies.

High levels of donor-derived cell-free DNA in a case of graft-versus-host-disease following liver transplantation.

The diagnosis of graft-versus-host-disease (GVHD) after solid organ transplantation is made difficult by its variable clinical presentation and lack of sensitive and specific biomarkers to evaluate the immune state of transplant recipients. Emerging noninvasive diagnostic techniques like the quantification of donor-derived cell-free DNA (dd-cfDNA) for surveillance may improve the current standard-of-care. Herein, we report the use of this methodology in a patient with GVHD and corresponding levels of dd-cfDNA without any evidence of graft injury. Correlation of dd-cfDNA levels with the clinical course and its novel application here could lead to improvements in the rapid diagnosis of GVHD and in monitoring of response to treatment.

Intestinal Autotransplantation and In-Situ Resection of Recurrent Pancreatic Head Intraductal Tubulopapillary Neoplasm with Portal Cavernoma: A Case Report.

BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) is a new entity of a rare premalignant pancreatic neoplasia, and a radical curative resection is indicated. As with other tumors of the root of the mesentery, the proximity of the lesion to large splanchnic vessels, abdominal aorta, and inferior vena cava poses major risks of a massive hemorrhage and visceral ischemia using conventional surgical techniques. At times, these lesions are amenable for resection using novel techniques developed from organ transplantation. Multivisceral (allo-) transplantation should be considered when radical resection of a benign tumor is likely to compromise portal flow and possibly precipitate acute liver failure, but it may be associated with a long waitlist time and tumor progression. Autotransplantation offers a safe and curative resection of otherwise inoperable tumors in a bloodless field, an excellent exposure, and prevention of warm ischemic injury to the affected viscera, which are then autotransplanted. METHODS: We describe the en bloc resection of a large and recurrent ITPN of the pancreas, distal stomach, proximal duodenum, transverse colon, superior mesenteric vein, and portal cavernoma, followed by intestinal autotransplantation. RESULTS: A complete tumor resection was achieved with negative margins, adequate cold preservation of the reimplanted intestine, and without significant hemorrhage. The patient was discharged from the hospital 10 days later. The histopathologic examination revealed free-margin resection of ITPN with an associated invasive carcinoma. The patient received adjuvant chemotherapy with folinic acid, fluorouracil, and oxaliplatin and remains disease-free 20 months after surgery. CONCLUSIONS: Autotransplantation offers curative resection of otherwise unresectable lesions of the root of the mesentery.

Re-evaluating Blood Markers as Predictors of Outcome in Multivisceral and Intestinal Transplantation.

BACKGROUND: Multivisceral transplant (MVTx) and isolated intestinal transplant (ITx) are complex surgical procedures. The subsequent proinflammatory state in the immediate postoperative period makes interpretation of blood markers difficult. METHOD: We aimed to establish the course of various blood markers after MVTx/ITx, and to evaluate their use as diagnostic markers of complications. This was a single center prospective cohort. We analyzed blood markers collected preoperatively, on alternate days for the first postoperative week, and then weekly for 4 weeks. This study was in compliance with The Declaration of Helsinki. RESULTS: Over a 16-month period (July 2017-October 2018), 20 subjects aged 2 to 67 years with a median age of 24.5 years received MVTx/ITx. Twelve recipients (60%) had an infection. Neutrophil lymphocyte count ratio (NLCR) was higher than established upper limits of normal, regardless of infection status. NLCR and white blood cell count were useful to identify infected MVTx/ITx recipients, with P values <.05 for 2 and 1 of 7 time points post transplant, respectively. Higher preoperative eosinophil% predicted future acute cellular rejection (P value .023). CONCLUSIONS: This is the first study to extensively track the course of blood markers post MVTx/ITx and identified NLCR and white blood cell count as potential diagnostic blood markers of infection.

En-Bloc Simultaneous Heart-Liver Transplantation in Adult Patients.

INTRODUCTION: Complexity of combined heart-liver transplantation has resulted in low adoption rates. We report a case series of adult patients receiving en-bloc heart-liver transplantation (HLTx), describe technical aspects, and discuss benefits of the technique. METHODS: Retrospective review of patients receiving en-bloc HLTx over 18 months, with clinical follow up to 1 year. Primary outcomes included postoperative mortality and major complications. Secondary outcomes included 1-year survival, cardiac or hepatic allograft rejection, and infection. RESULTS: Five patients received en-bloc HLTx. Mean recipient age was 43 years (26-63), and 3 patients were male. Total operative time was 430 minutes (393-480), cold and warm ischemic times of 85 (32-136) and 37.5 (31-47) minutes. Hospital survival was 80%. One patient died on postoperative day 55 due to fungal sepsis. Major postoperative complications included prolonged mechanical ventilation in 2 of 5 patients (40%), and renal insufficiency requiring hemodialysis in 2 of 5 patients (40%). Among patients discharged from hospital 1-year survival was 100%, with no evidence of rejection or infectious complications. CONCLUSION: En-bloc HLTx technique is a safe and effective strategy, decreasing operative times, and allograft ischemic times, whereas offering protection of implanted allografts during early stages of reperfusion while patient is hemodynamically supported on cardiopulmonary bypass.

Multivisceral transplant as an option to transplant cirrhotic patients with severe portal vein thrombosis.

Non-tumoral portal vein thrombosis (PVT) is a critical complication in the patient with advanced cirrhosis awaiting liver transplantation (LT). With the evolution of liver transplant (LT) technique, PVT has morphed from an absolute contraindication to a relative contraindication, depending on the grade of the thrombus. The Yerdel classification is one system of grading PVT severity. Patients with Yerdel class 1-3 PVT can undergo LT at centers with experience in complex portal vein (PV) dissection, thrombectomy, and reconstruction. Class 4 PVT, however, is even more complex and may require heroic techniques such as cavoportal hemitransposition, PV arterialization or multivisceral transplant (MVT). Some centers use a MVT back-up approach for patients with Yerdel class 4 PVT. In these patients, all organs with PV outflow are procured simultaneously as a cluster graft from a deceased donor (liver, pancreas, intestine±stomach). If physiologic PV inflow is established intraoperatively, the recipient undergoes LT. Otherwise the MVT graft is transplanted. MVT establishes physiologic PV flow, but transplantation of the intestine confers significant lifelong risks including rejection, graft-versus host disease and post-transplant lymphoma. Yerdel class 1-4 PVT patients undergoing successful LT have 5-year survival similar to non-PVT patients, while patients requiring full MVT experience somewhat higher mortality because of the complexity of the surgery and medical management.

Immunosuppression in Visceral Transplantation: Current Trends and Future Perspectives.

Visceral transplant represents an immunologic challenge due to high intestinal graft immunogenicity. Over the last 20 years, significant advances in immunosuppression regimens have resulted in excellent short-term outcomes. Currently, visceral transplant is the standard of care for patients with gut failure having life-threatening complications and complex abdominal pathology. In this review, we describe immunosuppressive strategies in the visceral transplant field.

Association of More Intensive Induction With Less Acute Rejection Following Intestinal Transplantation: Results of 445 Consecutive Cases From a Single Center.

BACKGROUND: In intestinal transplantation, acute cellular rejection (ACR) remains a significant challenge to achieving long-term graft survival. It is still not clear which are the most important prognostic factors. METHODS: We performed a Cox multivariable analysis of the hazard rates of developing any ACR, severe ACR, and cause-specific graft loss during the first 60 months posttransplant among 445 consecutive intestinal transplant recipients at our institution since 1994. Of particular interest was to determine the prognostic influence of induction type: rabbit antithymocyte globulin (rATG; 2 mg/kg × 5)/rituximab (150 mg/m × 1; begun in 2013), alemtuzumab (2001-2011), and less intensive forms. RESULTS: First ACR and severe ACR occurred in 61.3% (273/445) and 22.2% (99/445) of cases. The following 3 multivariable predictors were associated with significantly lower hazard rates of developing ACR and severe ACR: transplant type modified multivisceral or full multivisceral (P = 0.0009 and P < 0.000001), rATG/rituximab induction (P < 0.000001 and P < 0.01), and alemtuzumab induction (P = 0.004 and P = 0.07). For both ACR and severe ACR, the protective effects of rATG/rituximab and alemtuzumab were highly significant (P ≤ 0.000005 for ACR; P ≤ 0.01 for severe ACR) but only during the first 24 days posttransplant (when the ACR hazard rate was at its peak). The prognostic effects of rATG/rituximab and alemtuzumab on ACR/severe ACR disappeared beyond 24 days posttransplant (ie, nonproportional hazards). While significant protective effects of both rATG/rituximab and alemtuzumab existed during the first 6 months posttransplant for the hazard rate of graft loss-due-to-rejection (P = 0.01 and P = 0.003), rATG/rituximab was additionally associated with a consistently lower hazard rate of graft loss-due-to-infection (P = 0.003). All significant effects remained after controlling for the propensity-to-be-transplanted since 2013. CONCLUSIONS: More intensive induction was associated with a significant lowering of ACR risk, particularly during the early posttransplant period.

Association of Alemtuzumab Induction With a Significantly Lower Incidence of GVHD Following Intestinal Transplantation: Results of 445 Consecutive Cases From a Single Center.

BACKGROUND: In intestinal transplantation, graft versus host disease (GVHD), while relatively rare, remains a major cause of morbidity and mortality posttransplant. Because of its rarity of occurrence, no multivariable analysis of risk factors for GVHD development has previously been reported. METHODS: We used Cox stepwise regression to determine the significant multivariable predictors of the hazard rate of developing biopsy-proven GVHD during the first 60 months posttransplant among 445 consecutive intestinal transplant cases at our center since 1994. RESULTS: GVHD was observed in 8.8% (39/445); median time-to-GVHD development (range) was 1.5 months (0.5-17.3 mo) posttransplant. Sites of GVHD included skin (N = 21), skin/gastrointestinal tract (N = 6), gastrointestinal tract/rectum (N = 4), skin/liver (N = 4), skin/lung (N = 2), skin/rectum (N = 1), and skin/bone marrow (N = 1). Three factors were selected into the Cox model offering significant protection from GVHD development (listed in order of selection): isolated intestine or liver-intestine (LI) (versus modified multivisceral [MV] or MV) allograft (P = 0.00003), alemtuzumab (versus no induction, anti-CD25, rabbit antithymocyte globulin, or rabbit antithymocyte globulin/rituximab) induction (P = 0.004), and liver inclusion (LI or MV) (P = 0.009). These results remained unchanged even after accounting for the propensity to receive alemtuzumab induction. Observed GVHD incidence was 2.4% (3/125), 0.0% (0/38), 17.9% (7/39), and 11.9% (29/243) for isolated intestine, LI, modified MV, and MV allografts, and 2.7% (3/113) versus 10.8% (36/332) for those receiving versus not receiving alemtuzumab induction, respectively. CONCLUSIONS: These results may help advance the current state of knowledge about risk factors for GVHD development following intestinal transplantation.

Use of pediatric donor en bloc kidneys along with bladder segment in pediatric liver-kidney and multivisceral-kidney transplantation.

The combination of pediatric multivisceral and kidney transplantation leads to additional recipient risks due to the number of anastomoses and to the small sizes of donor structures. The inclusion of donor kidneys, ureters, and a bladder patch en bloc with multivisceral organs decreases the number and complexity of anastomoses and has not yet been reported. Four patients were transplanted in this fashion; three underwent multivisceral-kidney and one underwent liver-kidney transplantation. The first patient was a 3-year-old male with polycystic kidney disease and congenital hepatic fibrosis. The second was a 7-year-old female with complications from necrotizing enterocolitis. The third was a 12-month-old male with megacystis microcolon intestinal hypoperistalsis syndrome and secondary hydronephrosis, and the fourth was a 3-year-old male with multiple intestinal resections secondary to incarcerated hernia. The third patient developed a right ureteral stenosis with an intact bladder patch. The fourth child expired from maintained abdominal sepsis. The first 3 patients maintained normal graft function. There were no cases of thrombosis, arterial stenosis, or urinary leakages. These reported cases demonstrate that small pediatric en bloc transplantation of the multivisceral organs and dual kidneys with a bladder patch anastomosis is a feasible and less complex alternative to the standard procedure.

Combined off-pump coronary bypass grafting without heparin and liver transplantation: A novel approach to a complex dilemma.

Cardiac disease is a leading cause of early mortality for patients undergoing liver transplantation (LT), and severe coronary artery disease (CAD) is usually considered a contraindication for LT in patients with cirrhosis. Incidence of CAD in LT candidates has increased in recent years. While stable patients might be candidates for percutaneous interventions, patients with decompensated liver failure, or critical coronary lesions present a therapeutic challenge, and are often not considered candidates for LT. We present the case of a 60 year old male patient with decompensated liver failure, and critical CAD, who received successful combined off-pump coronary bypass grafting without heparin and LT using ex vivo normothermic liver perfusion machine. This approach represents a novel strategy to offer LT to this very selective group of patients.

Clostridium difficile infection mimics intestinal acute cellular rejection in pediatric multivisceral transplant-A case series.

Clostridium difficile infection (CDI) is the most common health care-associated infection in the United States. Thirty-nine percent of intestinal transplant recipients may develop CDI. Induction of rejection has been reported as a rare event. To our knowledge, this will be the second report of an association between CDI and rejection in the literature. We describe our experience with four pediatric MVT recipients, three of whom on treatment of their CDI alone had resolution of biopsy findings of intestinal ACR. Our patients were males aged 2-5 years old who had their first CDI post-MVT occurring from 2 months to 15 months post-transplant. All first episodes of CDI were treated with a 10-14 day course of metronidazole with one additionally receiving vancomycin. All four recipients had recurrent CDI, and two recipients had septic shock as a manifestation of their CDI. Three recipients had biopsies showing mild rejection during episodes of CDI, and treatment of the CDI resulted in resolution of biopsy findings of rejection. Our case series suggests CDI may mimic ACR on intestinal biopsy. Treatment of rejection during active CDI carries the risk of over-suppression and worsening of CDI. Our experience has taught us that surveillance endoscopy for rejection may be deceiving during an active CDI, and if mild acute rejection is noted during active CDI, treatment of rejection can be safely delayed and potentially avoided.