L. Olson

High-dose donor bone marrow infusions to enhance allograft survival: The effect of timing

BACKGROUND The development of strategies to enhance survival of transplanted organs and to potentially lower or even discontinue immunosuppressive therapy would represent a significant advance in posttransplant patient care. The aim of this clinical trial was to determine the effect of timing and dose of peripheral donor bone marrow cell (DBMC) infusion on graft and patient survival after liver transplantation. METHODS DBMC, obtained from vertebral bodies, were administered in 101 recipients of liver allografts (OLTX). There were 107 patients for whom DBMC could not be obtained; they received OLTX alone (controls). A total of 5 x 10(8)/kg DBMC were infused at day 0 (group 1; n=9); at days 0 and 11 (group 2; n=26); or at days 5 and 11 (group 3; n=26). In group 4 (n=40), patients received up to five infusions of 2 x 10(8)/kg DBMC at days 5, 14, 21, 28, and 90 after OLTX. RESULTS When the results from patients receiving two or more DBMC infusions (groups 2, 3, and 4) are considered, both patient and graft survival were significantly improved compared with the control group (P=0.02 and P=0.01, respectively). In groups 3 and 4, 88.5% and 95% of patients were alive with mean follow-up of 536 and 265 days, respectively, compared with 77.6% of patients in the control group (average follow-up of 452 days) (P=0.02). Graft survival was also significantly improved in groups 3 (88.5%) and 4 (92.5%), compared with the controls (72%) (P=0.007). CONCLUSIONS The results suggest that dose and timing of DBMC infusions may be important variables affecting allograft survival. A randomized prospective trial is now in progress to compare group 3 DBMC infusion protocol with controls receiving OLTX alone.

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

Background—Most clinical studies have shown that &bgr;-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective &bgr;-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results—Myocardial strips (≈1 mm3) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to &bgr;-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full &bgr;-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by ≈25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64±0.25-fold and 2.00±0.27-fold over control, respectively, P <0.01 for human tissue). Conclusions—Bucindolol exhibits ≈60% of the &bgr;-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

Human islet allografts in patients with type 2 diabetes undergoing liver transplantation.

BACKGROUND Most patients with cirrhosis have insulin resistance and impaired glucose tolerance, and 20% eventually develop diabetes. Although diabetes in this setting may be reversible after orthotopic liver transplantation (OLTx), immunosuppressive agents administered after transplantation could exacerbate this disease. We report the results of the first pilot trial of islet cell transplantation (ICTx) in patients with diabetes undergoing OLTx. METHODS Five patients with diabetes and liver cirrhosis underwent OLTx and ICTx. Donor bone marrow cells were also infused to enhance the acceptance of the graft. We identified seven patients who received only OLTx and donor bone marrow cells as historical controls. RESULTS Preliminary results suggest that ICTx in conjunction with OLTx may improve glucose metabolism (insulin requirement, hemoglobin A1c) in patients with liver cirrhosis. However, there was virtually no change in pre- and posttransplant basal C-peptide levels in the recipients of OLTx + ICTx. CONCLUSIONS We are planning to further evaluate the effect of OLTx with or without ICTx in a randomized prospective trial, using euglycemic insulin clamp studies.

Use of percutaneous liver biopsies in marginal liver donors

STRATEGIES to maximize availability of scarce donor organs have included evaluation of suboptimal or marginal organ donors. This may include donors over age 60; those with positive serologic markers for hepatitis B or hepatitis C; those with hypertensive, renal, or cardiac disease; and those with high-risk behavior for HIV transmission. Under some circumstances, these donors may be considered for liver donation only. Histologic examination of marginal liver-only donors by frozen section prior to transplantation can exclude some marginal donors. The liver biopsy can be performed prior to surgical recovery, and the results can be used to decide whether surgical recovery is appropriate. This study looks at the utility and cost savings to the Organ Procurement Organization (OPO) when percutaneous liver biopsy (PLB) frozen section evaluation is performed prior to surgical recovery in a group of marginal liver-only donors.