ABO-incompatible Pediatric Liver Transplantation With Antibody and B-cell Depletion-free Immunosuppressive Protocol in High Consanguinity Communities.

The success of orthotopic liver transplantation as a life-saving treatment has led to new indications and a greater competition for organ grafts. Pediatric patients with acute liver-related crises can benefit from orthotopic liver transplantation, but organ availability in the limited time can be a major obstacle. Crossing ABO blood group barriers could increase the organs available to such patients. Methods: From November 2010 to June 2015, 176 children aged 0.2-to18 y were transplanted in the King Faisal Specialist Hospital and Research Center. Out of those, 19 children were transplanted across blood group barriers (ABO incompatible). The underlying diseases were biliary atresia (n = 6); progressive familial intrahepatic cholestasis type 2 (n = 4); Crigler-Najjar syndrome (n = 3); hepatoblastoma (n = 2); and urea cycle disorder, Caroli disease, cryptogenic cirrhosis, and neonatal sclerosing cholangitis (n = 1 each). Immunosuppression consisted of basiliximab, mycophenolate, tacrolimus, and steroids. Pretransplant prophylactic plasmapheresis, high-dose immunoglobulins, and rituximab were not administered. Results: The grafts were from living donors (n = 17) and deceased donors (n = 2). Living donor morbidity was nil. The recipient median age was 21 mo (5-70 mo). After a median follow-up of 44 mo, 2 recipients (10%) died because of sepsis, 1 because of uncontrolled acute myeloid leukemia. The overall rejection rate was 7%, and no grafts were lost because of antibody-mediated rejection (AMR). HLA matching was 3.8 of 6 (A, B, DR), and there were 2 patients presented with acute cellular rejection, 1 patient with AMR, and 1 patient with biliary strictures. Conclusions: ABO incompatible liver transplantation is a feasible and life-saving option even with antibody and B-cell depletion-free protocol without increasing the risks for AMR. We speculate that this excellent result is most likely because of presence of relatively low titer ABO isoagglutinins and the high HLA match compatibility caused by habit of longstanding interfamilial marriages as typical of Saudi Arabia.

Protocol Duodenal Graft Biopsies Aid Pancreas Graft Surveillance.

BACKGROUND: Histological evaluation of the pancreas graft is usually done on demand resulting in significant delays. This analysis reports on endoscopic protocol duodenal graft biopsies at regular intervals to determine feasibility, safety, and monitoring benefits. METHODS: Protocol duodenal graft biopsies in 27 consecutive pancreas transplants (10 simultaneous pancreas kidney [SPK], 17 pancreas after kidney [PAK]) with a follow-up of a minimum of 12 months were performed at days 14, 30, 90, 180, 360, 430. University of Pittsburgh Medical Center classification for intestinal rejection was used. C4d staining was performed when antibody-mediated rejection was suspected. RESULTS: Overall patient and pancreas graft survival was 100% and 93% at a mean follow-up of 2.8 years. One hundred sixty-seven endoscopic biopsy procedures were performed in 27 grafts without any complication. Biopsies revealed rejection in 3 (30%) SPK recipients and in 15 (82%) of PAK recipients as early as 14 days posttransplant. Two patients underwent PAK retransplantation diagnosed with acute rejection at day 180. All except 1 recipient being treated for rejection, showed histological improvement following antirejection treatment. Following transient treatment success, a total of 3 pancreas grafts were lost for immunological reason. One loss was immediate despite antirejection treatment, 1 secondary to nonresolving rejection at 7 months and the third due to recurrent rejection 15 months posttransplantation. Additionally, biopsies detected vascular (venous thrombosis) and overimmunosuppression (cytomegalovirus infection) complications. CONCLUSIONS: Protocol graft duodenal biopsies detect complications after whole-organ pancreas transplantation, are useful in guiding therapy, and carry potential for improving outcome.

Spectrum of the KIT Gene Mutations in Gastrointestinal Stromal Tumors in Arab Patients

Background: Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract, which originate from the interstitial cells of Cajal. These tumors are characterized by expression of CD117 and CD34 antigens and activating mutations in the KIT and PDGFRA genes. While KIT and PDGFRA mutations have been extensively studied in other populations, the spectrum of mutations in Arab patients remains unknown. The study aimed at determining the distribution of KIT and PDGFRA mutations and phenotypic characterization of the gastrointestinal stromal tumors in Arab patients. Methods: Sanger sequencing was used to analyze 52 archived gastrointestinal stromal tumors for mutations in the KIT and the PDGFRA genes. Tumor descriptions were obtained from the clinical reports of patients. Results: In these patients, most tumors occur in the stomach, followed by the rest of the digestive tract. A vast majority of tumors express the CD117 and CD34 antigens. Sequencing of the KIT and PDGFRA genes identified five non-synonymous mutations and 26 deletions (25 novel) in exon 11 of the KIT gene. All non-synonymous mutations and deletions affect the juxta-membrane domain, which is known to inhibit ligand-independent activation of the KIT receptor. No mutations were found in the PDGFRA gene. Conclusions: Molecular profiling of the gastrointestinal stromal tumors in Arab patients identified a unique spectrum of mutations in exon 11 of the KIT gene. These data are important for the diagnosis and management of patients of Arab ethnic origin.

Hepatic fibrinogen storage disease due to the fibrinogen γ375 Arg → Trp mutation "fibrinogen Aguadilla" is present in Arabs.

The mutation γ375Arg → Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.

Aspirin induced leukocytoclastic vasculitis, lower gastrointestinal hemorrhage and acute renal failure (mimicking systemic vasculitis).

This is a case of a 60-year-old gentleman who presented with an extensive cutaneous vasculitic rash (leukocytoclastic) with lower gastrointestinal bleeding following a small dose of aspirin (81 mg). The aspirin was stopped immediately. Three weeks later, he had acute renal failure, which was initially thought to be secondary to systemic vasculitis, but proved to be acute renal tubular necrosis as a delayed reaction to aspirin.