Case report: Crohn's-like mycophenolate-induced colitis, a fallout in steroid-free regimens.

BACKGROUND: Diarrhea is considered to be a common side effect after renal transplantation, due to a number of infective or drug-related causes. Over the past decade the etiology has perhaps changed with the evolution of immunosuppression. In an attempt to minimize early acute rejection and potential steroid use, the recent introduction of mycophenolic acid-based therapies has increased the incidence of diarrheal symptoms. Histologic and macroscopic appearance of mycophenolate-induced colitis is not well documented. CASE REPORT: Three patients with immunosuppression-induced colitis had received deceased-donor renal transplantations and presented with diarrhea and/or abdominal pain. All patients made a full recovery after decreasing the dose or withdrawing mycophenolate mofetil or myfortic with corticosteroid-free regimens. CONCLUSIONS: Patients with immunosuppression-induced colitis require prompt intervention by dose reduction or withdrawal. Both myocophenolate mofetil and myfortic can induce a Crohn's-like colitis even after a long period of exposure. The symptoms may require 6 months to resolve, suggesting that surgery should be considered only as a last resort after a significant period off therapy.

Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans.

AIMS/HYPOTHESIS: TNF-alpha levels are increased in obesity and type 2 diabetes. The regulation of TNF-alpha converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. METHODS: We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-alpha, TNF-alpha-receptor 1 (TNFR1), TNF-alpha-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. RESULTS: TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-alpha, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. CONCLUSIONS/INTERPRETATION: TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-alpha and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.

Acute rejection after renal transplantation is reduced by approximately 50% by prior therapeutic blood transfusions, even in tacrolimus-treated patients.

BACKGROUND: The authors investigated the relationship between therapeutic blood transfusion before renal transplantation and rejection rates in cyclosporine- and tacrolimus-treated patients. METHODS: In one center, 265 consecutive recipients were studied. Protocol induction was with azathioprine, prednisolone, and cyclosporine or tacrolimus; 37% had biopsy-proven acute rejection in the first 6 months and 46% had received zero to two units of blood before transplantation. RESULTS: Lower risk of rejection was associated with tacrolimus induction (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.29-0.95; P=0.049), prior transfusion of three or more units of blood (OR, 0.54; 95% CI, 0.33-0.90; P=0.024), and older age at transplantation (mean, 44.23 +/- 12.56 [+/- SD] years vs. 38.96 +/- 12.37 years; P=0.001). Multiple logistic regression modeling showed the effect of three or more prior transfusions on acute rejection was as follows: OR, 0.49; 95% CI, 0.29 to 0.83; P=0.008. CONCLUSIONS: Induction immunosuppression should take account of the higher risk of rejection in patients coming to transplantation who have previously received zero to two units of blood.