Monitoring of calcineurin inhibitors induced-nephrotoxicity

Chronic allograft nephropathy is characterized by an increase over time of interstitial fibrosis, tubular atrophy, fibrointimal thickening, arteriolar hyalinosis and glomerulosclerosis, resulting in progressive renal dysfunction. It is mainly caused by calcineurin inhibitors-induced nephrotoxicity, which is related to an imbalance between vasoconstrictor and vasodilator factors. Cyclosporine A-induced nephrotoxicity is particularly due to the activation of pro-apoptotic genes leading to tubular atrophy with tubular cell apoptosis and to hemodynamic changes inducing interstitial fibrosis by the activation of factors stimulating the fibroblast proliferation (TGFbeta, Endothelin-A and Plasminogen activator inhibitor-1). Calcineurin inhibitors (CNI) treatment monitoring is essentially based on histology, but a better follow-up of drug exposure post-transplantation leading to a regular and rapid adjustment of the doses to avoid extended periods of overexposure, could enable to decrease their nephrotoxicity and improve graft survival in treated patients. CNIs dose reduction or conversion to proliferating signal inhibitors may be a therapeutic alternative.     

Hepatitis C virus viral load after conversion from tacrolimus to cyclosporine in liver transplant patients: a pilot study

We assessed whether conversion from tacrolimus (TAC) to cyclosporine (CsA) was associated with a reduction in hepatitis C virus (HCV) viral load among HCV-positive liver transplant (OLT) patients. PATIENTS AND METHODS: Nine OLT patients with recurrent HCV have TAC and prednisone immunosuppression. None received any HCV antiviral therapy. After the last intake of TAC, the patients underwent a 12-hour area under the curve (AUC(12)) measurement of both TAC and HCV viral loads. The next morning (D(0)) patients were given CsA (4 mg/kg bid). At the first intake of CsA and at 1 month (M(1)) later, the patients underwent AUC(12) for CsA and HCV viral loads. Biological data, including aspartate (AST) and alanine (ALT) aminotransferase, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), and bilirubin levels, were collected during AUC(12), and at M(1) and M(3). RESULTS: With respect to liver enzymes (AST, ALT, GGT), there was no significant difference between D(0), M(1), and M(3). Conversely, there was a significant decrease in AP between D(0) and M(3) (P = .02), and a significant increase in total bilirubin between D(0) and M(1) (P = .04), and between D(0) and M(3) (P = .01). HCV viral load significantly increased by M(3) (P = .01). At no time (D(0), M(1)) was there any correlation between the AUC(12) of TAC or CsA, and between AUC(12) HCV viral load. CONCLUSION: This pilot study found no acute or chronic anti-HCV effects from CsA that were evident within 12 hours after CsA administrations or beyond 1 month of CsA therapy, respectively.     

Effect of FTY720 on apoptosis of smooth muscle cells

BACKGROUND: Hyperproliferation of smooth muscle cells (SMCs) plays a key role in allograft arteriosclerosis. This prompted us to investigate the effect of the novel immune modulator and synthetic sphingolipid FTY720 on apoptosis of SMCs. METHODS: Rabbit SMC cultures were treated with FTY720 and apoptosis and necrosis were detected by fluorescence microscopy. RESULTS: We investigated dose- and time-dependent effects of FTY720 and found that clinically relevant low doses of FTY720 (<1 micromol/L) did not induce apoptosis, whereas 10 micromol/L FTY720 induced apoptosis after 48 hours incubation. CONCLUSION: At doses of FTY720 used in clinics for treatment of renal allografts and multiple sclerosis. FTY720 did not induce SMC apoptosis.     

Negative impact of one-year anemia on long-term patient and graft survival in kidney transplant patients receiving calcineurin inhibitors and mycophenolate mofetil

BACKGROUND: The impact of posttransplant anemia (PTA) upon patient and graft survival remains controversial. The aim of this study was to assess the incidence of PTA 1 year after transplantation in patients treated with calcineurin inhibitors and mycophenolate mofetil, and to determine the impact of 1-year PTA upon long-term patient and graft survival. METHODS: Between January 1, 1999, and December 31, 2003, all patients with a functioning graft at 1 year, and who were receiving an immunosuppressive regimen based on calcineurin inhibitors and mycophenolate mofetil, were included in the study (n=339). Anemia was defined according to the World Health Organization criteria, that is, hemoglobin levels less than 13 g/dL for men and less than 12 g/dL for women. RESULTS: One hundred and eight of 339 were anemic at 1 year after transplantation (31.85%; group I). Independent predictors for 1-year anemia are donor's age and serum creatinine at 6 months. At last follow-up, that is, 69.4+/-17.7 months after transplantation, there had been a significant number of deaths in group I (n=7; 6.9%) compared with nonanemic patients (group II) (n=4; 1.73%; P=0.04). Mean allograft survival was significantly better in group II (70.7+/-17.1 months) compared with group I (66.4+/-18.7 months; P=0.03). Also, 12 graft losses (11.1%) were observed in group I and seven occurred in group II (3%; P=0.004). Independent predictors for allograft loss included delayed graft function and serum creatinine at 1 year. CONCLUSION: After kidney transplantation, the occurrence of PTA at 1 year is harmful, in the long term, to patient survival.     

HEV and transfusion-recipient risk

HEV infections are mainly food- and water-borne but transfusion-transmission has occurred in both developing and developed countries. The infection is usually asymptomatic but it can lead to fulminant hepatitis in patients with underlying liver disease and pregnant women living in developing countries. It also causes chronic hepatitis E, with progressive fibrosis and cirrhosis, in approximately 60% of immunocompromised patients infected with HEV genotype 3. The risk of a transfusion-transmitted HEV infection is linked to the frequency of viremia in blood donors, the donor virus load and the volume of plasma in the final transfused blood component. Several developed countries have adopted measures to improve blood safety based on the epidemiology of HEV.