Emerging Issues in Hepatitis C Virus-Positive Liver and Kidney Transplant Recipients

Hepatitis C virus (HCV) infection is a major health care issue in liver and kidney transplantation. Besides negatively affecting both patient and graft survival, HCV is associated with a heightened risk for new onset diabetes mellitus (NODM). The mechanisms underlying the diabetogenicity of HCV are complex but are likely to involve insulin resistance caused by inhibitory actions of the virus on insulin regulatory pathways in the liver. The resultant glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients. This review highlights the concerns for outcomes in HCV-positive liver and kidney transplant patients with particular focus on the interrelationship between hepatitis C and diabetes. Data about the potential role of calcineurin inhibitors, corticosteroids and mycophenolate mofetil in HCV infection and HCV-associated NODM will also be discussed.     

Preservation of Bile Ductules Mitigates Bile Duct Loss

The finer branches of the biliary tree (FBBT) contain a regenerative compartment. We hypothesized that preservation of the FBBT together with its microvasculature will lead to recovery of biliary damage and prolonged preservation of bile ductules during the development of chronic liver allograft rejection. The interlobular bile ducts, portal bile ductules and extraportal biliary cells with and without microvessels were studied in sequential biopsies in five patients who fulfilled the Banff criteria of early chronic rejection (CR) (imminence group). Biopsies of CR patients (n = 12) served as controls. Biopsies were double immunostained with CD34 (microvessels) and cytokeratin 7 (biliary structures). Proliferation and proangiogenic activity were assessed with Ki67 and VEGF-A immunostaining. Severe damage of bile ducts in the imminence group did not progress to significant bile duct loss. This was associated with a high proliferative activity in all biliary structures and preservation of the microvascular compartment. VEGF-A expression was increased in all but the reperfusion biopsies. In conclusion, both regenerative activity of the FBBT and an intact microvascular compartment are associated with less damage of the biliary tree and could therefore be prerequisites for biliary regeneration.     

Tacrolimus Combined with Two Different Dosages of Sirolimus in Kidney Transplantation: Results of a Multicenter Study

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.     

A clinical approach to the management of a patient with suspected renovascular disease who presents with leg ischemia.

Atherosclerotic renal artery stenosis (ARAS) may cause hypertension, progressive renal failure, and recurrent pulmonary edema. It typically occurs in high risk patients with coexistent vascular disease elsewhere. Most patients with ARAS are likely to die from coronary heart disease or stroke before end-stage renal failure occurs. Recent controlled trials have shown that most patients undergoing angioplasty to treat renovascular hypertension still need antihypertensive agents 6 or 12 months after the procedure. Nevertheless, the number of antihypertensive agents required to control blood pressure adequately is lower following angioplasty than for medication alone. Trials assessing the value of revascularization for preserving renal function or preventing clinical events are only in the early recruitment phase. Revascularization should be undertaken in patients with ARAS and resistant hypertension or heart failure, and probably in those with rapidly deteriorating renal function or with an increase in plasma creatinine levels during angiotensin-converting enzyme inhibition. With or without revascularization, medical therapy using antihypertensive, hypolipidemic and antiplatelet agents is necessary in almost all cases.