Renal Dysfunction After Liver Transplantation: Effect of Donor Type.

Recipients of donation after circulatory death (DCD) grafts are reportedly at higher risk of developing renal dysfunction after liver transplantation (LT). We compared the development of acute kidney injury (AKI) and chronic kidney disease (CKD) after LT in recipients of DCD versus donation after brain death (DBD) or living donor liver transplantation (LDLT) livers. Adult recipients of DBD, LDLT, and DCD between 2012 and 2016 at Toronto General Hospital were included. AKI was defined as a post-LT increase of serum creatinine (sCr) ≥26.5 µmol/L within 48 hours or a ≥50% increase from baseline, and CKD was defined as an estimated glomerular filtration rate <60 mL/minute for >3 months. A total of 681 patients (DCD, n = 57; DBD, n = 446; and LDLT, n = 178) with similar baseline comorbidities were included. Perioperative AKI (within the first 7 postoperative days) was observed more frequently in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak AST levels (P < 0.001). Additionally, patients in the DCD group had a significantly higher peak sCr (P < 0.001) and a trend toward higher rates of AKI stage 3 (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). The proportions of recovery from AKI (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and patients developing CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar. Nevertheless, patients who received DCD or DBD LT and required perioperative renal replacement therapy showed significantly lower patient survival in multivariate analysis (hazard ratio, 7.90; 95% confidence interval, 4.51-13.83; P < 0.001). In conclusion, recipients of DCD liver grafts experience higher rates of short-term post-LT renal dysfunction compared with DBD or LDLT. Additional risk factors for the development of severe kidney injury, such as high Model for End-Stage Liver Disease score, massive transfusions, or donor age ≥60 years should be avoided.

Regulation of contact sensitivity in non-obese diabetic (NOD) mice by innate immunity.

BACKGROUND: Genetic background influences allergic immune responses to environmental stimuli. Non-obese diabetic (NOD) mice are highly susceptible to environmental stimuli. Little is known about the interaction of autoimmune genetic factors with innate immunity in allergies, especially skin hypersensitivity. OBJECTIVES: To study the interplay of innate immunity and autoimmune genetic factors in contact hypersensitivity (CHS) by using various innate immunity-deficient NOD mice. METHODS: Toll-like receptor (TLR) 2-deficient, TLR9-deficient and MyD88-deficient NOD mice were used to investigate CHS. The cellular mechanism was determined by flow cytometry in vitro and adoptive cell transfer in vivo. To investigate the role of MyD88 in dendritic cells (DCs) in CHS, we also used CD11cMyD88+ MyD88-/- NOD mice, in which MyD88 is expressed only in CD11c+ cells. RESULTS: We found that innate immunity negatively regulates CHS, as innate immunity-deficient NOD mice developed exacerbated CHS accompanied by increased numbers of skin-migrating CD11c+ DCs expressing higher levels of major histocompatibility complex II and CD80. Moreover, MyD88-/- NOD mice had increased numbers of CD11c+ CD207- CD103+ DCs and activated T effector cells in the skin-draining lymph nodes. Strikingly, re-expression of MyD88 in CD11c+ DCs (CD11cMyD88+ MyD88-/- NOD mice) restored hyper-CHS to a normal level in MyD88-/- NOD mice. CONCLUSION: Our results suggest that the autoimmune-prone NOD genetic background aggravates CHS regulated by innate immunity, through DCs and T effector cells.

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated ß cell-specific CD8 T cells, and favorable ß cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in ß cell function, and is associated with antigen-specific and nonspecific immune modulation.

Hepatitis B virus genotypes, precore and core promoter variants among predominantly Asian patients with chronic HBV infection in a Canadian center.

BACKGROUND AND AIMS: The epidemiology of hepatitis B virus (HBV) infection in North America may be changing as a result of immigration from endemic countries. The purpose of this study was to determine the prevalence of HBV genotypes, precore (PC) and core promoter (CP) variants, and the proportion of patients meeting treatment criteria for HBV. METHODS: A cross-sectional study of consecutive HBV patients attending a Canadian tertiary liver center was conducted. HBV DNA was quantified by polymerase chain reaction assay. HBV genotypes and variants were determined using a line probe assay. RESULTS: Two hundred and seventy-two patients were enrolled; 200 were not receiving treatment at enrollment, of whom 116 were men and 84 women with a mean age 42+/-14 years. Among this group, 177 (88%) patients were Asian and 19 (10%) were Caucasian and 69 (35%) patients were hepatitis B e antigen (HBeAg) positive. Genotypes B and C were found in 42% and 50% untreated patients, respectively; while CP and PC were detected in 52% and 43% patients, respectively. Approximately 20% patients not receiving treatment (29% HBeAg positive, 14% HBeAg negative) met AASLD guidelines for antiviral therapy. If lower cutoff values for alanine aminotransferase and HBV DNA levels were used, 49% patients would qualify for treatment. CONCLUSIONS: The vast majority of patients at a Canadian tertiary referral center were Asian. Virological and clinical characteristics of these patients reflect their country of origin. Our findings highlight the need to monitor the changing patterns of HBV infection in countries with large immigrant populations.

Ramipril-associated hepatotoxicity.

CONTEXT: Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported. OBJECTIVE: To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril. DESIGN: Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature. RESULTS: The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously. CONCLUSION: Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.