Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation

Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow-up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety.     

Recognition and operative management of patients with arteriosclerotic coronary artery aneurysms.

Arteriosclerotic aneurysms of the coronary arteries have been noted in 38 patients undergoing cardiac surgical procedures. Age, sex, and risk factors are similar to those in other patients with coronary artery disease. A high incidence of previous myocardial infarction (24 of 38) is related to the frequency of clot formation and embolism associated with such aneurysms. There is also an increased risk of perioperative infarction following coronary artery bypass grafting if the suture line involves the aneurysm wall (6 of 6), but not when sutures are placed away from it. The importance of recognition and proper operative management is stressed.     

Ileorectal anastomosis for ulcerative and Crohn's colitis

Except in the presence of severe perineal suppuration or sphincter damage by previous surgery for fistulas, the rectum was preserved in all patients considered candidates for surgery for inflammatory disease of the bowel. A primary anastomosis with a single-layer 5-0 monofilament stainless steel wire was carried out when a relatively healthy rectum with erythema and granularity presented. For patients with more severe disease of the rectum, a two-stage operation with intensive interval treatment of the rectum stump with topical corticosteroids was carried out. Of a total of eighty-six patients with involvement of the colon and rectum with either Crohn's disease or chronic ulcerative colitis, fifty-six patients were treated by local abdominal colectomy and ileorectal anastomosis. Twenty-four had primary anastomosis and thiry-two had a two-stage operation. One anastomotic dehiscence developed. A mean follow-up of 8.4 years (6 months to 20 years) has been satisfactory. Only three anastomoses have been taken down for unsatisfactory results. With the proper selection of patients and with appropriate treatment of the diseased rectal segment, a large majority of patients with inflammatory disease of the bowel can have long-term salutory results after colectomy and ileorectal anastomosis.     

Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom,October to November 2020

Two new SARS-CoV-2 lineages with the N501Y mutation in the receptor-binding domain of the spike protein spread rapidly in the United Kingdom. We estimated that the earlier 501Y lineage without amino acid deletion Δ69/Δ70, circulating mainly between early September and mid-November, was 10% (6–13%) more transmissible than the 501N lineage, and the 501Y lineage with amino acid deletion Δ69/Δ70, circulating since late September, was 75% (70–80%) more transmissible than the 501N lineage.     

AKR‐501 (YM477) a novel orally‐active thrombopoietin receptor agonist

Thrombopoietin (TPO) is the principal physiologic regulator of platelet production. We have searched for small molecule compounds that mimic the action of TPO by using human TPO receptor‐expressed in Ba/F3 cells, resulting in the discovery of AKR‐501 (YM477). AKR‐501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. AKR‐501, however, was shown to be effective only in humans and chimpanzees with high species specificity. Therefore, we examined the in vivo platelet‐increasing effect of AKR‐501 in human platelet producing non‐obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver CD34⁺ cells. Daily oral administration of AKR‐501 dose‐dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR‐501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. These results suggest that AKR‐501 is an orally‐active TPO receptor agonist that may be useful in the treatment of patients with thrombocytopenia.