Upfront use of eculizumab to treat early acute antibody-mediated rejection after kidney allotransplantation and relevance for xenotransplantation

Acute antibody-mediated rejection (AMR) early after transplant remains a challenge, both in allotransplantation and in xenotransplantation. We report the case of an early and severe acute AMR episode in a kidney transplant recipient that was successfully treated with upfront eculizumab. A 58-year-old woman had been on dialysis since 2014. She underwent a first kidney transplant in 2018 with primary non-function and received several blood transfusions. Postoperatively, she developed anti-HLA antibodies. One year later, she received a second allograft from a deceased donor. At day 0, there was only one preformed low-level donor-specific antibody (DSA) anti-DQ7. After initial excellent allograft function, serum creatinine increased on days 7-9, and this was associated with oligo-anuria. On day 7, there was an increase in her DSA anti-DQ7 and 4 de novo DSA had developed at high MFI values. Allograft biopsy showed severe active AMR with diffuse C4d deposits in peritubular capillaries. The early acute AMR episode was treated with upfront eculizumab administration (2 doses) with efficient CH50 blockade (< 10% CH50). Rituximab was also administered on day 12, and intravenous immunoglobulin (IVIG) was given over the following days. There was an excellent clinical response to eculizumab administration. Eculizumab administration rapidly reversed the acute AMR episode without the need for plasmapheresis. Rituximab and IVIG were also used as B-cell immunomodulators to decrease DSA. Blocking efficiently the terminal complement pathway may become a useful strategy to treat acute AMR in sensitized recipients of allografts, and possibly in recipients of discordant xenografts.     

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.     

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady- state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Humoral immune function in pediatric patients treated with autologous bone marrow transplantation for B cell non-Hodgkin's lymphoma. The influence of ex vivo marrow decontamination with anti-Y 29/55 monoclonal antibody and complement

Elimination of neoplastic B cell populations from autologous bone marrow grafts also removes normal B lymphocytes. This is potentially hazardous for the reconstitution of the immune system in patients undergoing high-dose chemotherapy and total body irradiation followed by autologous marrow rescue. Five pediatric patients with B cell non- Hodgkin's lymphoma in first remission undergoing such a regimen were studied. They received bone marrow pretreated with anti-Y 29/55 monoclonal antibody and complement. B and T lymphocyte subpopulations reached normal levels within 6 months after autologous bone marrow transplantation (ABMT), and serum immunoglobulin levels became normal within 4 to 9 months. Vaccination with diphtheria and tetanus toxoid, trivalent poliomyelitis vaccine of the Salk type, and pneumococcal capsular antigens (38 to 54 months after transplantation) gave rise to specific antibody production. ABO isoagglutinins could be demonstrated in all patients. The response pattern was similar to that of patients who received unmanipulated autologous bone marrow. It is concluded that ex vivo anti-Y 29/55 depletion of the marrow graft does not induce relevant disturbances of humoral immune functions.     

From the Cover: In situ carbonation of peridotite for CO2 storage

The rate of natural carbonation of tectonically exposed mantle peridotite during weathering and low-temperature alteration can be enhanced to develop a significant sink for atmospheric CO₂. Natural carbonation of peridotite in the Samail ophiolite, an uplifted slice of oceanic crust and upper mantle in the Sultanate of Oman, is surprisingly rapid. Carbonate veins in mantle peridotite in Oman have an average ¹⁴C age of ≈26,000 years, and are not 30–95 million years old as previously believed. These data and reconnaissance mapping show that ≈10⁴ to 10⁵ tons per year of atmospheric CO₂ are converted to solid carbonate minerals via peridotite weathering in Oman. Peridotite carbonation can be accelerated via drilling, hydraulic fracture, input of purified CO₂ at elevated pressure, and, in particular, increased temperature at depth. After an initial heating step, CO₂ pumped at 25 or 30 °C can be heated by exothermic carbonation reactions that sustain high temperature and rapid reaction rates at depth with little expenditure of energy. In situ carbonation of peridotite could consume >1 billion tons of CO₂ per year in Oman alone, affording a low-cost, safe, and permanent method to capture and store atmospheric CO₂.     

Lifestyle Modification Parallels to Sleeve Success

Background

The role of laparoscopic sleeve gastrectomy (LSG) has increased over the past 10 years. We present our results of patients who were 5 years out from surgery with regard to safety and long-term efficacy.

Methods

Retrospective analysis was carried out from prospectively collected data of patients who underwent LSG for morbid obesity. Bariatric Analysis and Reporting Outcome System (BAROS) and Food Tolerance Scores (FTS) were assessed. At 5 years, two lifestyle modification questions (regarding nutrition habits and physical fitness) were separately assessed.

Results

One hundred fourteen patients underwent LSG and were available for postoperative visits. Mean excess weight loss (EWL) was >65 % during the initial 3 years and declined to 45.3 % in 5 years. Of the patients, 71.92 % did not reach 50 % EWL at 60 months and were considered objective failures. BAROS and FTS scores were 7.15 and 4.32, and 23.5 and 22.5 at 30 and 60 months, respectively. Analyzing the 32 patients with EWL >50 % in the 5-year group, 26 (81.25 %) of them had scored ≥0.5 on the two lifestyle modification questions compared with 6 (18.75 %) that scored <0.5 (P?<?0.001).

Conclusion

LSG is an effective bariatric surgical procedure with significant long-term (5 year) weight loss, resolution of comorbid medical conditions and significant improvement in the quality of life. The basis for this success, which must be always emphasized preoperatively by the bariatric team, is knowledge and implementation of better nutritional habits and increasing physical fitness or, in other words, in significant lifestyle modification.