Jennifer Garcia

MicroRNA Signature of Intestinal Acute Cellular Rejection in Formalin-Fixed Paraffin-Embedded Mucosal Biopsies

Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR‐142‐3p, miR‐886‐3p and miR‐132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents.

Citrulline level is a potent indicator of acute rejection in the long term following pediatric intestinal/multivisceral transplantation.

Citrulline has been advocated as a marker for acute cellular rejection (ACR) in intestinal transplantation; however, its significance as a forewarning in the long‐term follow‐up remains unknown. This study aimed to investigate the association between citrulline levels and the grading of ACR to establish a cutoff point that accurately predicts ACR beyond 3 months posttransplant in the pediatric patient population. During a 16‐year period (1995–2011), a total of 13 499 citrulline samples were prospectively collected from 111 consecutive pediatric intestinal/multivisceral transplant recipients: 2155 were obtained concurrently with intestinal biopsies. There were 185 ACR episodes observed among 74/111 (67%) patients (median follow‐up: 4.4 years). Citrulline levels were inversely proportional to the severity of ACR. Negative predictive values for any type of ACR (cutoff, 20 μmol/L) and moderate/severe ACR (cutoff, 10 μmol/L) were 95% and 99%, respectively. When patients were divided according to graft size, diagnostic accuracy using the same cutoff was identical. Similarly, subgroup analysis by the timing of citrulline measurement prior to biopsy varying from 1 to 7 days demonstrated comparable results. Citrulline is a potent indicator as a danger signal for ACR, being an exclusionary, noninvasive biomarker with excellent negative predictive values in the long term after pediatric intestinal/multivisceral transplant.

Prevalence of multiple sclerosis in Lanzarote (Canary Islands)

In the island of Lanzarote of the Province of Las Palmas, which is part of the Spanish archipelago of the Canary Islands, the prevalence of multiple sclerosis is 15 per 100,000. The prevalence of MS in Lanzarote seems related more to ethnic conditions than to geography.

Characteristic immune, apoptosis and inflammatory gene profiles associated with intestinal acute cellular rejection in formalin‐fixed paraffin‐embedded mucosal biopsies

Small bowel transplantation (SBT) is becoming a preferred treatment for patients with irreversible intestinal failure. Despite continuous improvement of immunosuppression, SBT is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need for reliable detection markers and novel immunosuppressive strategies that can achieve better control of ACR. We hypothesized that particular transcriptomes provide critical regulation of the intragraft immune response. The aim of our study was to detect potential molecular biomarkers for identifying ACR in minute mucosal biopsies. We examined 30 intestinal mucosal biopsies (AR/NR; 17/13) obtained from recipients after SBT or multivisceral transplantation. We utilized TaqMan® Gene Signature Arrays (immune, inflammation and apoptosis) and investigated the expression of 280 genes. As one of our validations, we performed immunohistochemistry for selected targets. We detected 252 mRNAs in total, 92 of which were found with significantly different expression levels between the AR and NR groups. Immunohistochemistry showed significantly increased staining for IL1R2, ICAM1, GZMB, and CCL3 (P < 0.05) during ACR. For the first time, we characterize the potential molecular changes that are associated with modulation of histological appearances of intestinal ACR. These differences in transcriptome patterns can be used to identify robust biomarkers and potential novel therapeutic targets for immunosuppressive agents.

Liver, Pancreas and Kidney Transplantation for the Treatment of Wolcott–Rallison Syndrome

We present the case of a child who underwent a combined liver, pancreas and double kidney transplant following complications of Wolcott–Rallison syndrome (WRS) a rare genetic disorder that causes infantile insulin‐dependent diabetes mellitus (IDDM) and often death in childhood from fulminant liver and concomitant kidney failure. WRS is characterized clinically through infantile IDDM, propensity for liver failure following viral infections, bone dysplasia and growth failure and developmental delay. Fewer than 60 cases with WRS are reported in the literature, mostly from consanguineous parents. Future episodes of liver failure, the main contributor to the increased mortality in WRS, may be prevented through timely liver transplantation. To the best of our knowledge, transplantation has not been utilized to manage complications of WRS prior to this report.

Clinical significance of intragraft miR-122 and -155 expression after liver transplantation.

Recurrent hepatitis C (RHC) and acute cellular rejection (AR) remain critical problems following liver transplantation (LT) in hepatitis C virus (HCV) positive recipients because of the similar clinical features. Discrimination between these conditions can be problematic, and adjunctive biomarkers would be useful to discriminate these processes. The aim of our study was to investigate the possibility of the intragraft miR‐122 and ‐155 expression as new biomarkers after LT.

Pediatric patient with end-stage kidney disease secondary to Eagle-Barrett syndrome and metastatic unresectable hepatoblastoma treated successfully with chemotherapy and liver-kidney transplant

HBL is the most common malignant liver neoplasm in children. The etiology of HBL is largely unknown but there are certain syndromes, such as Beckwith‐Wiedemann syndrome, that have been clearly associated with an increased incidence of this malignancy. EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions. Despite an improvement on the survival rates of patients with advanced‐stage HBL, the presence of concomitant end‐stage renal disease that occurs in patients with EBS constitutes a therapeutic challenge for the clinician not only due to the use of nephrotoxic chemotherapy but also due to the potential need for multi‐organ transplant. We report case of a 2‐year‐old male patient with EBS diagnosed with stage IV, metastatic HBL successfully treated with multi‐agent chemotherapy while on dialysis whom then underwent a simultaneous liver‐kidney transplant followed by adjuvant chemotherapy. Ultimately, the patient achieved cancer remission with normalization of his renal function. Our report emphasizes that patients with HBL in the setting of EBS will not only require careful kidney function monitoring while receiving chemotherapy, but they might also need to undergo multi‐organ transplantation in order to achieve adequate cancer control and also normalization of their kidney function. Awareness of this unusual association calls for further investigation to potentially establish a genetic association between these two disease processes.

Comparison in outcome with tailored antibiotic prophylaxis postoperatively in pediatric intestinal transplant population

BIs are ubiquitous among the pediatric intestinal transplant patient population. Personalizing postoperative prophylaxis antibiotic regimens may improve outcomes in this population. A retrospective analysis of all pediatric patients who underwent intestinal transplantation was evaluated to compare standardized and tailored regimens of antibiotics provided as prophylaxis postoperatively. Patients in the standard group have both shorter time to and higher rate of BIs, which was statistically significant (P < 0.001). Of the children who developed a BI, there was no statistical difference in average times to the development of a second BI (293 vs 119 days, P = 0.211). The tailored group had prolonged times until the development of a MDRO (52.6 vs 63.9 days, P = 0.677). Although not statistically significant, the tailored group had a propensity to present with gram‐negative pathogens after transplant as compared to the standard regimen group, which presented with gram‐positive pathogens (P = 0.103). Children with a history of an MDRO held a 7.3 (P < 0.01) times more likelihood of death within a year of transplant. A tailored prophylactic antibiotic regimen in the post‐transplant period appears to prolong the time to the first BI. Although the data do not show differences in mortality, further study may prove the impact of a tailored antibiotic regimen on morbidity and mortality rates.