Mannose binding lectin (mbl2) haplotype frequencies in solid organ transplant patients and correlation with MBL protein levels--evaluation of complement-mediated effector pathway deficiency.

Mannose-binding lectin (MBL) is a protein critical in activating complement. Patients with wild-type and variant mbl2 genotypes have high or low concentrations of MBL protein, which is known to increase susceptibility to transplant rejection or infection, respectively. Our objective was to determine mbl2 genotype frequencies in future solid organ transplant recipients in order to optimize their induction and maintenance immunosuppressive therapies, and to provide MBL reference data for this unique population. We genotyped 1687 patients, and concurrently measured protein in 807 of them, during 2010-2011. Frequencies of the structural allele SNPs in our population were similar to those of other studied populations; however, Black patients with the same intermediate and deficient mbl2 genotypes as Caucasians produced significantly lower levels of MBL protein; therefore, within this population more genotypes should be considered MBL-deficient. Overall, the most critical parameter in determining serum MBL protein concentration was genotype, which was independent of other factors including ethnicity, gender, or diseased native organ type.

The Pathology of full-thickness cadaver skin transplant for large abdominal defects: a proposed grading system for skin allograft acute rejection.

Closure of large abdominal defects after extensive abdominal surgery is a major technical surgical problem. Failure to close the abdomen leaves the patient at risk for grave complications. Full-thickness abdominal wall skin transplantation appears to solve this problem. This is the first time that detailed histopathologic features of skin abdominal wall transplantation from cadaver donors are described. Five adults and four children underwent 10 transplants because of large abdominal wall defects. Twenty-two posttransplantation skin specimens were evaluated during a mean follow-up of 23.5 weeks, and the findings were compared with the clinical appearance of the skin. Rejection was manifested as a maculopapular rash. The histologic features were categorized as perivascular infiltrates, epidermal changes, and stromal changes. A grading system is proposed based on the number of cases encountered: No rejection, grade 0 (n = 9): No perivascular infiltrates. Indeterminate for rejection, grade 1 (n = 2): Up to 10% of vessels show infiltrates of small lymphocytes. No eosinophils, large lymphocytes, spongiosis, epidermal, or stromal inflammation are seen. Mild rejection, grade 2 (n = 5): 11% to 50% of vessels are infiltrated by small lymphocytes. Eosinophils and mild spongiosis may or may not be present. No epidermal infiltrates, stromal infiltrates, or large lymphocytes are seen. Moderate rejection, grade 3 (n = 4): Greater than 50% of vessels show lymphocytic infiltrates that may be accompanied by epidermal and stromal inflammation. Spongiosis is absent or mild. Endothelial plumping, eosinophils, and large lymphocytes may be seen. Severe rejection, grade 4 (n = 2): Greater than 50% of vessels show infiltrates, but different from moderate rejection, there is dyskeratosis and the epidermis shows heavier lymphocytic infiltrates and moderate to severe spongiosis. The stroma shows infiltrates extending into the base of the epidermis. Endothelial plumping, eosinophils, and large lymphocytes are present. The mean number of weeks after transplantation for the development of clearcut rejection (grades 2-4) was 8.36. Among the 9 nonrejection cases, 4 specimens from 3 patients had thrombosis of the vessels feeding the graft. A grading system serves to better assess skin allograft rejection.

Acute cellular rejection grading scheme for human gastric allografts.

The control of acute cellular rejection (ACR) in multivisceral transplantation improves long-term survival, but monitoring this process can be challenging because different allografts can display varying forms and degrees of rejection. Criteria for ACR of small bowel and liver have been established, but a systematic analysis for ACR in stomach is lacking. For this reason we have developed a comprehensive grading scheme for the evaluation of gastric allograft rejection. The grading scheme was designed to individually grade a variety of changes in the surface epithelium, lamina propria, and glandular structures. The individual values are cumulated, and the final score determines assignment of the rejection grade. The ACR grades range from no evidence of acute cellular rejection to severe rejection. We performed a retrospective study based on 70 gastric allograft biopsies from 20 patients who received multivisceral transplantation from 1995 to 2001. We found that the scoring system showed no significant interobserver variability and allowed for an accurate designation of the ACR grade to the gastric allografts. We found with this grading system that neither clinical symptoms nor gastric endoscopic findings could serve as specific indicators of gastric ACR. Our results also showed that there were differences in the occurrence and intensity of acute rejection between the stomach and other transplanted organs, suggesting that ACR can occur independently among different allografts of the same host. In conclusion, we find that this scheme for grading ACR in gastric transplants is objective and reproducible. This grading system will likely allow for improved correlation between gastric ACR grade and clinical symptoms, as well as improve interobserver uniformity within and between institutions.

Use of liver grafts from donors positive for antihepatitis B-core antibody (anti-HBc) in the era of prophylaxis with hepatitis-B immunoglobulin and lamivudine.

BACKGROUND: The increasing demand for transplantation has resulted in a trend toward using virologically compromised donors. We reviewed our experience with liver grafts from hepatitis-B surface antigen (HBsAg)(-), antibody to core antigen (anti-HBc)(+) donors. METHODS: Sixty-two liver transplants using HBsAg(-), anti-HBc(+) donors were studied. The decision to use prophylaxis was based on the presence or absence of donor and recipient risk factors for posttransplant hepatitis-B virus (HBV) transmission or reinfection. If the donor or recipient showed positive HBVDNA, hepatitis-B immunoglobulin (HBIg) and lamivudine were used. If both donor and recipient HBVDNA were negative, a choice between lamivudine and no prophylaxis was made on the basis of presence or absence of HBsAg and antibody to the surface antigen (anti-HBs) in the recipient. RESULTS: No death or graft loss could be ascribed to HBV. Mild HBV infection occurred in two patients who were not taking the recommended prophylaxis. Among the other 60 patients, 1 showed positive e antigen (HBeAg) early after transplantation, and 2 (1 with recurrent cancer, 1 with HIV infection) showed HBsAg(+). None of the three patients had any other evidence of HBV infection. Forty-seven patients underwent liver biopsies. Changes consistent with hepatitis were observed in 26, and 24 had HCV infection; immunostains for HBV antigens were negative in all cases, and 7 showed positive HBVDNA. CONCLUSIONS: A selective protocol based on donor and recipient risk factors for post-liver transplant HBV infection can prevent hepatitis-B infection and avoid unnecessary administration of antiviral prophylaxis in recipients of HBsAg(-), anti-HBc(+) liver allografts.

Mucosal vascular alterations in isolated small-bowel allografts: relationship to humoral sensitization.

Acute vascular rejection (AVR) in human small-bowel transplantation is an inadequately characterized entity whose frequency and severity is not well understood. As compared to severe AVR, changes identifying early, mild or evolving AVR are not known. We created a scoring system to evaluate subtle mucosal vascular changes and examined 188 biopsies from 21 patients obtained in the first 3 months post transplant. A majority of patients had a transient rise in vascular injury, often within 30 days of transplant. Small-vessel congestion and erythrocyte extravasation were the most common alterations. The vascular injury score was not related to acute cellular rejection, HLA type or HLA antigen disparities. However, the patients with the vascular changes had significantly higher peak panel reactive antibodies (PRA) and a higher incidence of positive T-cell and B-cell crossmatch. Finally, graft survival was significantly lower in the patients demonstrating the early vascular lesions. These data suggest that the vascular injury is partially associated with humoral presensitization of the recipient and may be a form of acute vascular rejection. Since these vascular changes are frequent, we advocate early post-transplant monitoring to identify and manage potentially high-risk patients.

Liver and gastrointestinal transplantation at the University of Miami.

The field of liver and intestinal transplantation is continuously evolving. At present, we cannot escape the need for long-term immunosuppression. Management of side effects and complications of immunosuppression is difficult, as well as recurrence of viral disease after transplantation. Similar challenges are present in virally induced diseases such as PTLD. The clinical applicability of tolerance inducing protocols in the future will rely more and more on the ability to decrease the total amount of immunosuppression given around the time of transplant. The introduction of induction protocols using Campath 1-H has allowed us to decrease the average dose of calcineurin inhibitors and virtually avoid the use of steroids. We have been able to achieve, at least in the short run, patient and graft survivals similar to historical controls, without any added infectious complication. It has still to be proven whether these short-term results will translate in longterm avoidance of calcineurin inhibitors nephrotoxicity and steroid-related diabetes, osteoporosis and so forth. We continue to pursue an active program of intestinal and combined liver-intestinal or multivisceral transplantation, with survival rates constantly improving. The monitoring of graft function and rejection represents the major challenge in intestinal transplantation. The development of laboratory tests such as citrulline levels, combined with the use of advanced endoscopic techniques such as the use of the zoom video endoscope has allowed us to integrate the clinical and histopathological information in an effort to diagnose early and treat appropriately intestinal rejection.

Intestinal and multivisceral transplantation.

Intestinal transplantation has been gradually instituted in the management of intestinal failure. More than 200 cases including isolated intestinal transplant, liver/intestinal transplant, and multivisceral transplant have been performed worldwide,with 1-year graft and patient survival rates of 66% and 54%,respectively. Indications for the procedure include short bowel syndrome and functional abnormalities secondary to a variety of diseases or conditions. Tacrolimus-based immunosuppression regimens have been used universally with improved outcomes. The major contributors to the morbidity and mortality include rejection,infection, and technical complications. Of those, control of rejection remains the most difficult dilemma and it will be the key to improved patient and graft survival.