Research Spotlight

Schinstock, C. A., R. B. Mannon, K. Budde, A. S. Chong, M. Haas, S. Knechtle, C. Lefaucheur, R. A. Montgomery, P. Nickerson, S. G. Tullius, C. Ahn, M. Askar, M. Crespo, S. J. Chadban, S. Feng, S. C. Jordan, K. Man, M. Mengel, R. E. Morris, I. O’Doherty, B. H. Ozdemir, D. Seron, A. R. Tambur, K. Tanabe, J. L. Taupin and P. J. O’Connell (2019). “Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: the 2019 Expert Consensus From the Transplant Society Working Group.” Transplantation Dec 27. [Epub ahead of print].

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With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low level evidence. The number of prospective randomized trials for the treatment of AMR is small and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated.At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes and outcomes were discussed. The evidence for different treatments was reviewed and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented.Whilst it was agreed that the aims of treatment are to preserve renal function, reduce histological injury and reduce the titer of donor specific antibody (DSA), there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

Schiller, L. R. (2020). “Good News about BAD.” Clin Gastroenterol Hepatol 18(1): 45-47.

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In this issue the Canadian Association of Gastroenterology (CAG) presents its official guidelines for the management of bile acid diarrhea (BAD). The American Gastroenterological Association (AGA) recently published its clinical guidelines for the laboratory diagnosis of chronic diarrhea, and the British Society of Gastroenterology (BSG) published its guidelines for investigation of chronic diarrhea in 2018. All 3 guidelines and the reviews that present the underlying evidence highlight the importance of bile acid malabsorption (BAM) as a potential mechanism for chronic diarrhea. The concept that bile acid entering the colon might cause secretory diarrhea goes back more than 50 years. In 1967 Alan F. Hofmann, then at the Mayo Clinic, synthesized what was known about the physiology of bile acids with several clinical reports of diarrhea occurring in patients who had evidence of BAM into the concept of “cholegenic diarrhea” or “cholerheic enteropathy.” These patients had several features in common, including ileal disease or resection, diarrhea, steatorrhea, and evidence of accelerated bile acid turnover. Bile acids were known to be cathartic, and Hofmann postulated that the excess bile acid in the colon inhibited water transport and caused diarrhea through that mechanism . . . [R]esearch during the last 50 years has established that BAD is a real mechanism for chronic diarrhea, not just with ileal disease or resection but in patients with functional diarrhea or IBS-D. It is incumbent on physicians now to consider this diagnosis in patients with chronic diarrhea. Whether one tests and then treats or just empirically treats, we will do a great service for many of our patients with chronic diarrhea by addressing this mechanism of disease. (Excerpts from text, p. 45-46, summarizing Sadowski D.C. et al: Canadian Association of Gastroenterology clinical practice guideline on the management of bile acid diarrhea; no abstract available.)

Roberts, W. C., S. Siddiquiz, A. E. Rafael-Yarihuaman and C. S. Roberts (2020). “Management of Adults With Normally Functioning Congenitally Bicuspid Aortic Valves and Dilated Ascending Aortas.” Am J Cardiol 125(1): 157-160.

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We describe herein a 65-year-old woman who underwent resection of a dilated (5.1 cm) ascending aorta associated with a normally functioning congenitally bicuspid aortic valve. The patient provided the framework to discuss proper management-operative versus nonoperative-of the dilated ascending aorta associated with a normally functioning bicuspid aortic valve. Unfortunately, there is inadequate data to provide an unequivocal answer to this dilemma. Operative intervention requires that the short-term risk of the prophylactic procedure be considerably lower than the long-term risk of aortic dissection/rupture without operative intervention. Because there is no proof that operative intervention provides less morbidity and lower mortality, nonoperative management at this time seems to be the better approach.

Roberts, C. S., Y. M. Salam, A. J. Moore and W. C. Roberts (2019). “Pseudoaneurysm of the Ascending Aorta at the Cannulation Site Diagnosed More Than Four Decades After Repair of Ventricular Septal Defect.” Am J Cardiol 124(12): 1962-1965.

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Described herein is a 69-year-old woman who developed a large saccular aortic aneurysm at a previous cannulation site for repair of a ventricular septal defect at age 25 years. The aneurysm was resected and proved histologically to be a false one. The long interval between operations (44 years) exceeds those reported previously.

Patel, S. S., L. A. Rybicki, M. Yurch, D. Thomas, H. Liu, R. Dean, D. Jagadeesh, B. Hill, B. Pohlman, B. Bolwell, R. Hanna, B. K. Hamilton, M. Kalaycio, A. T. Gerds, E. Cober, S. Mossad, A. Zhang, N. S. Majhail, M. Askar and R. Sobecks (2019). “Influence of major histocompatibility complex class I chain-related gene a polymorphisms on cytomegalovirus disease after allogeneic hematopoietic cell transplantation.” Hematol Oncol Stem Cell Ther Dec 24. [Epub ahead of print].

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OBJECTIVE/BACKGROUND: Cytomegalovirus (CMV) infection and disease are common infectious complications after allogeneic hematopoietic cell transplantation (alloHCT). Major histocompatibility complex (MHC) class I chain-related gene A (MICA) is a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity. We hypothesized that MICA polymorphisms may influence CMV infection and disease incidence after alloHCT. METHODS: We conducted a retrospective analysis of 423 adults at the Cleveland Clinic with hematologic malignancies treated with a matched related or unrelated donor alloHCT. CMV cases analyzed included a compositive of instances of viral copy replication above detection limits as well as any biopsy-proven tissue invasive disease episodes. Genotypes at the MICA-129 position have been categorized as weak (valine/valine; V/V), intermediate (methionine/valine; M/V), or strong (methionine/methionine; M/M) receptor affinity. RESULTS: In multivariable analysis, V/V donor MICA-129 genotype was associated with CMV infection and disease (hazard ratio [HR]=1.40; 95% confidence interval [CI], 1.00-1.96; p=.05), but not MICA mismatch (HR=1.38; 95% CI, 0.83-2.29; p=.22). There was no association of acute or chronic GVHD with MICA donor-recipient mismatch (HR=1.05; 95% 95% CI, 0.66-1.68; p=.83 and HR=0.94; 95% CI, 0.51-1.76; p=.85, respectively) or V/V donor MICA-129 genotypes (HR=1.02; 95% CI, 0.79-1.31; p=.89 and HR=0.89; 95% CI, 0.65-1.22; p=.47, respectively). CONCLUSION: These findings suggest that the donor MICA-129V/V genotype with weak NKG2D receptor binding affinity is associated with an increased risk of CMV infection and disease after alloHCT.