Mycophenolate sodium-induced hepatotoxicity: first report.
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Acute Disease↗
Biomedical subjects
Eric Thervet
Publications and source records attributed to Eric Thervet.
[New diagnostic tools in renal transplantation].
Renal transplantation is the best treatment available for end stage renal disease. The determination of human genome has profoundly modified the possible approaches of renal transplant recipient by allowing tailoring of immunosuppressive drugs and immunologic diagnosis. The aim of this review article is to determine the role of these various techniques during the different step before and after transplantation. Genotyping, transcriptome analysis, proteomic as well as the specific immune response are analyzed in this article.
Biopsy↗
[Nephrotoxicity of sirolimus: experimental and clinical data].
Sirolimus (SRL, rapamycin) is a potent immunosuppressive drug that binds to and inhibits mammalian Target Of Rapamycine (mTOR) kinase activity, a central controller of cell growth. In response to amino acids, hormones and growth factors, mTOR activates the translational machinery. By inhibiting mTOR, SRL reduces the translational process and T-cell proliferation in the mid-to-late G1 phase of the cell cycle. The antiproliferative effects of SRL are not limited to activated T cells. SRL has also been shown to block the cell cycle in various cell types such as epithelial renal cells, and many types of tumor cell lines. Since the approval by the US Food and Drug Administration and by the European agency, SRL has provoked great interest, as evidenced by the exponential increase in clinical studies. However, whereas preclinical studies failed to show any nephrotoxic effect on animal models, many clinical trials raised the possibility that SRL might be associated with renal adverse events. The evidence for SRL-associated early graft nephrotoxicity emerged from these results, and subsequent experimental data gave some explanations about the involved mechanisms. The aim of this review is to summarize the various renal adverse events reported in clinical studies and to present the experimental evidence for putative mechanisms of action for this SRL-induced nephrotoxicity.
Cell Proliferation↗
Comparison of sequential protocol using basiliximab versus antithymocyte globulin with high-dose mycophenolate mofetil in recipients of a kidney graft from an expanded-criteria donor.
This retrospective pilot study investigated use of high-dose mycophenolate mofetil with biological induction and sequential introduction of low-dose cyclosporine in recipients of expanded criteria donor (ECD) kidneys. Fifty-four patients received mycophenolate mofetil 3 g/day for 45 days, cyclosporine 4 mg/kg/day, prednisolone, and rabbit antithymocyte globulin (rATG, n=14) or basiliximab (n=40). Acute rejection incidence was 11.3% (7.1% with rATG, 12.6% with basiliximab). Delayed graft function was observed in 31 patients (54%). At one year, measured glomerular filtration rate was 54+/-4 ml/min, with no significant differences between induction therapies. Thirty patients (55%) required > or =1 MMF dose reduction within month 1 due to adverse events (gastrointestinal symptoms, 67%; leucopenia 33%). Leucopenia was more frequent with rATG, while gastrointestinal symptoms were more frequent with basiliximab. Cytomegalovirus replication occurred in three patients (23%) with rATG and 3 (8%) with basiliximab. In conclusion, high-dose MMF, corticosteroids, delayed low-dose cyclosporine and induction therapy offers an excellent risk-to-benefit ratio in patients receiving an ECD allograft.
Antibodies, Monoclonal↗
[mTOR inhibitors: pleiotropic antiproliferative drugs].
Studies of rapamycin properties in yeast led to the discovery of TOR (target of rapamycin) and its mammalian analogue, mTOR. mTOR is a central regulator of cell growth and proliferation in response to environmental stimuli such as growth factors and nutrients. mTOR regulates several pathways, particularly translation process by controlling the activity of two proteins in response to a broad range of mitogenic stimuli, S6K1 and 4E-BP1. Inhibition of cell growth by rapamycine and analogues have been demonstrated in numerous cell types, explaining the broad development of these drugs in clinical practice. Rapamycine is a potent immunosuppressive drug used in solid organ transplantation for the prevention of allograft rejection. In oncology, mTOR inhibitors are currently evaluated in several types of cancers. They are now widely used for coating stents to reduce post-stenting restenosis after coronary angioplasty. Finally, rapamycine is now evaluated in various diseases characterized by cell growth disorders such as phacomatosis and autosomal dominant polycystic kidney disease.
Animals↗
Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients.
BACKGROUND: Immunosuppressive drugs given to solid organ transplant recipients may be responsible for cosmetic side effects which can endanger patient compliance. Cyclosporine is associated with hirsutism whereas tacrolimus has been associated with rare cases of alopecia. Since 1998, we have included tacrolimus within the immunosuppressive regimen following kidney-pancreas transplantation. The aim of this study was to evaluate the incidence of alopecia in this population and possible risk factors. METHODS: Between January 1, 1995 and October 31, 2003, 59 consecutive simultaneous kidney-pancreas (SPK) transplants were performed in 58 recipients (27 females and 31 males). The immunosuppressive regimen comprised corticosteroids, calcineurin inhibitor (cyclosporine, n=11; or tacrolimus, n=40) and a purine inhibitor (azathioprine or mycophenolate mofetil). RESULTS: Clinically significant alopecia occurred in 13 patients (28.9%) receiving tacrolimus versus none receiving cyclosporine (P<0.001). Of those who experienced alopecia, 11 were female and two were male (P=0.02). The mean delay between transplantation and alopecia was 422 days (range 100-1,567). Other causes of alopecia were excluded. Treatment of alopecia with topic minoxidil was successful in all cases but one, which required conversion from tacrolimus to cyclosporine. CONCLUSIONS: Alopecia is a frequent complication in women receiving tacrolimus therapy following SPK transplantation. Its pathogenesis is unknown. This cosmetic complication must be discussed with patients before transplantation to minimize the risk of noncompliance.
Alopecia↗
Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases.
BACKGROUND: Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients. METHODS: Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0. RESULTS: C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33+/-15 to 53+/-24 (ng/ml)/(mg/kg) and C2/ND from 161+/-64 to 248+/-80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42+/-20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2+/-1.9 to 6.5+/-2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01). CONCLUSIONS: CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.
Aged↗
Efficacy and safety outcomes among de novo renal transplant recipients managed by C2 monitoring of cyclosporine a microemulsion: results of a 12-month, randomized, multicenter study.
BACKGROUND: The clinical benefits of C2 monitoring of cyclosporine microemulsion have been demonstrated, but C2 targets in renal transplant recipients during the first year require validation. METHODS: MO2ART was a prospective, multicenter study of renal transplant recipients managed by C2 monitoring of cyclosporine microemulsion with steroids and mycophenolate mofetil or azathioprine. Patients were randomized on day 3 to two groups, which were managed from month 3 with higher or lower C2 target ranges (months 4-6, 1,000-1,200 ng/mL vs. 800-1,000 ng/mL; months 7-12, 800-1,000 ng/mL vs. 600-800 ng/mL, respectively). The primary endpoint was the glomerular filtration rate (GFR) at month 12. RESULTS: A total of 296 patients were recruited, of whom 250 remained in the study at 3 months (higher-C2, n=131; lower-C2, n=119). GFR at 12 months did not differ between the higher- and lower-C2 groups (65+/-17 mL/min vs. 66+/-14 mL/min). When patients were regrouped according to C2 achieved by months 8 to 12, those with the lowest C2 (<700 ng/mL) showed the lowest GFR at month 3 and the most pronounced increase in GFR between month 3 and month 12 (P=0.04). Five episodes of biopsy-proven acute rejection occurred after month 3 (higher-C2 group, n=2; lower-C2 group, n=3). The overall 12-month Kaplan-Meier incidence of biopsy-proven acute rejection was 13.7%. Patient and graft survival were 93% and 89%, respectively, at 12 months. CONCLUSION: Both C2 target ranges investigated showed excellent and nearly equivalent outcomes at 12 months. The decision to target the higher or lower end of these C2 ranges should be made on an individual basis, taking into account patient and graft characteristics, and co-medication.
Adult↗
Replacement kidney lipomatosis after renal transplantation.
Renal sinus lipomatosis consists of abnormal fatty proliferation of the renal sinus, hilus, and perirenal spaces. Its pathogenesis is unknown, although it is generally associated with aging, renal atrophy, and long-standing chronic inflammation or urinary tract infection. Although this condition is rare, it may be important to recognize it in renal transplant recipients. We describe three cases of replacement kidney lipomatosis that occurred after cadaveric renal transplantation and discuss the possible differential diagnosis of this condition.
Adult↗
Use of Neoral C monitoring: a European consensus.
Large-scale clinical trials using C(2) monitoring of cyclosporine (CsA) microemulsion (Neoral) in renal transplant recipients have demonstrated low acute rejection rates and good tolerability with a low adverse event profile in a variety of settings: with or without routine induction therapy; in combination with mycophenolate mofetil; with standard-exposure or low-exposure Neoral; and in patients with immediate or delayed graft function. In liver transplantation, C(2) monitoring significantly reduces the severity and incidence of acute rejection compared with C(0) monitoring, without adverse consequences in terms of renal function or tolerability. Different C(2) targets are appropriate depending on adjunctive immune suppression, level of immunologic risk, CsA tolerability, risk of renal toxicity and time since transplantation. CsA absorption may increase substantially in most patients during the first 1-2 weeks post-transplant, and this should be taken into account to avoid overshooting C(2) target range. A patient with a low C(2) value may be either a low or a delayed absorber of CsA, or be a normal absorber who is receiving too low a dose of Neoral. C(2) monitoring alone is insufficient to differentiate between these types of patients, and measurement of additional timepoints is recommended. Adopting C(2) monitoring in maintenance transplant patients identifies those who are overexposed to CsA. In summary, randomized, prospective, multicenter studies and single-center trials have evaluated Neoral C(2) monitoring within a range of regimens in different organ types, providing a robust evidence base for the benefits of this sensitive monitoring technique.
Absorption↗
Rapamycin inhibits human renal epithelial cell proliferation: effect on cyclin D3 mRNA expression and stability.
BACKGROUND: Recent data have suggested that rapamycin use during the initial period after transplantation is associated with prolonged delayed graft function (DGF). Because of the known effects of rapamycin in other cell types, we speculated that this action may be secondary to human renal epithelial cells (HRECs) inhibition of proliferation. METHODS: Primary cultures of HRECs were incubated with various concentrations of rapamycin. Cell proliferation was evaluated by cytotoxicity assays. The cell cycle was analyzed by flow cytometry. Protein expression levels were assessed by Western blot. Cyclin D3 mRNA levels were measured by quantitative real-time polymerase chain reaction (PCR). The transcriptional activity of the cyclin D3 gene was evaluated using transient transfection. RESULTS: Rapamycin exerted a significant concentration-dependent antiproliferative effect on growing HRECs by inhibiting the G(1) to S transition. The p70(S6) kinase pathway leading to cell cycle progression was found to be active, and low concentrations of rapamycin dramatically reduced p70(S6) kinase phosphorylation. Rapamycin completely inhibited the increase in cyclin D3 protein expression and mRNA accumulation induced by fetal calf serum, but did not affect cyclin E or cdk-inhibitor expression levels. This regulation of cyclin D3 protein expression is mainly due to a destabilization of its mRNA. Rapamycin reduced the mRNA half-life by 26% (4.8 +/- 1.3 hours vs. 6.5 +/- 1.0 hours, P < 0.001). CONCLUSION: Rapamycin inhibits the proliferative response of HRECs to mitogenic stimuli, and causes cell cycle arrest in the early G(1) phase, not only by a nonspecific process due to inhibition of the p70(S6k) pathway, but also by a direct effect on cyclin D3 mRNA stability.
Cell Proliferation↗
Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy.
Sirolimus (SRL) is a substrate for cytochromes P-450 3A and P-glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter-individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B, CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non-genetic factors including pharmacokinetic interactions. In patients with SRL-based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Kidney transplant in black recipients: are African Europeans different from African Americans?
Despite recent improvement, significant racial disparities in outcome still persist after renal transplantation among African American patients in the United States. This study evaluated the association of race and ethnicity with allograft outcomes in a French population of 952 Caucasian (Cauc) patients and 140 African European (AE) patients who underwent renal transplantation in our center between 1987 and 2003. Demographic characteristics were similar for the two cohorts other than cause of end-stage renal failure (more hypertension among AE and more polycystic kidney disease among Cauc) and cold ischemia time (significantly longer for AE). Immunosuppressive treatment was comparable between groups. There were no significant differences between AE and Cauc in the incidence of acute rejection (31% vs. 30%). At 5 years post-transplant, patient survival (93% vs. 92%), graft survival (83% in both groups) and graft function (creatinine clearance 48 mL/min vs. 45 mL/min) were also similar among the AE and Cauc patients. We demonstrate that ethnic origin does not affect outcome after renal transplantation in France. Therefore, differences observed in the United States cannot be only related to immunologic or pharmacologic factors. The results of renal transplantation in patients of African origin could be improved with universal immunosuppressive drug coverage.
Adult↗
Cytochrome P450 3A polymorphisms and immunosuppressive drugs.
With the use of powerful immunosuppressive drugs, organ transplantation has become the treatment of choice for many cases of end-stage chronic organ failure. The calcineurin inhibitors, cyclosporine and tacrolimus, which are the backbone of current immunosuppressive regimens, may be difficult to use because of the large interindividual variability of their pharmacokinetic characteristics and a narrow therapeutic index. Since cytochrome P450 (CYP) 3A4 and CYP3A5 are both involved in their metabolism, the consequences of the polymorphism of these enzymes were studied. It has been recently shown that the CYP3A5*3 polymorphism is associated with both the pharmacokinetics and pharmacodynamic consequences of tacrolimus. The association between the CYP3A4 and CYP3A5 polymorphisms and cyclosporine pharmacokinetics is more questionable. It is important to test these initial results prospectively to improve the individualized use of these drugs.
Animals↗
Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids.
BACKGROUND: Sequential anti-thymocyte globulins (ATG)/cyclosporine immunosuppression has two main advantages: delayed introduction of the nephrotoxic drug cyclosporine and prevention of acute rejection. Basiliximab, a recently developed chimeric monoclonal antibody that selectively depletes the minor subpopulation of activated T lymphocytes, has been shown to reduce the incidence of acute rejection when used with cyclosporine introduced on day 1. METHODS: This open, randomized, multicenter study was undertaken to compare the safety and efficacy of ATG versus basiliximab induction therapy (IT) with delayed introduction of cyclosporine for microemulsion (Neoral) in 105 low immunologic risk renal-transplant patients receiving mycophenolate mofetil and steroids. RESULTS: One-year patient and graft survival rates were 98.1% and 94.2%, respectively, in the basiliximab group (n = 52), and 98.1% and 96.2% in the ATG group (n = 53). The incidence of biopsy-confirmed acute rejection was comparable (basiliximab 9.6%, ATG 9.4%), as were key parameters of renal function, notably serum creatinine levels, time-to-nadir serum creatinine, and the number of patients requiring posttransplantation dialysis (basiliximab 28.8%, ATG 30.2%). However, significantly fewer patients in the basiliximab group experienced cytomegalovirus (CMV) infection, leukopenia, and thrombocytopenia, and this without any significant difference in any other key safety parameters (including the incidences of serum sickness, fever, lymphoma, and infections in general). CONCLUSIONS: Both ATG and basiliximab, when used for IT in a sequential protocol, are equally effective in terms of graft and patient survival as well as at preventing acute rejection. However, basiliximab is associated with a lower incidence of certain key adverse events, namely CMV infection, leukopenia, and thrombocytopenia.
Adolescent↗
Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives.
The promise of pharmacogenetics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. Genetic polymorphisms are implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs. The first pharmacogenetic trait identified was monogenic, and concerned the prototypic example of thiopurine methyltransferase (TPMT) implicated in azathioprine metabolism. Individuals with low TPMT activity, inherited in an autosomal codominant fashion, are at risk of drug-induced myelosuppression. TPMT activity determination and DNA-based tests are now used in clinical practice. It has been also demonstrated that there is a link between the polymorphisms of the cytochrome P450 3A5, 3A4 and the multidrug resistance-1 (MDR1) genes, and the daily dose necessary to achieve adequate blood tacrolimus levels. Analysis of MDR1 haplotypes or using the association of the different genes might further improve predictions. Since genotyping methods improve rapidly, it will soon be easy to test for thousands of single nucleotide polymorphisms in one assay. Present challenges are to determine the genes of interest and to validate such determination prospectively in clinical practice.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Complications of protocol renal biopsy.
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Acute Kidney Injury↗
Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature.
BACKGROUND: Hemophagocytic syndrome (HPS) combines febrile hepatosplenomegaly, pancytopenia, hypofibrinemia, and liver dysfunction. It is defined by bone marrow and organ infiltration by activated, nonmalignant macrophages phagocytizing blood cells. HPS is often caused by an infectious or neoplastic disease and has rarely been described in renal transplant recipients. METHODS: We retrospectively analyzed 17 cases of HPS after cadaveric renal transplantation (13 men and 4 women, age 41+/-8 years). The median time between transplantation and hemophagocytosis was 52 days. Eleven patients (64%) had received antilymphocyte globulins during the 3 months before presentation. RESULTS: Fever was present in all patients, and hepatosplenomegaly was present in 9 of 17 patients. Other nonspecific clinical findings included abdominal, neurologic, and respiratory symptoms. Laboratory tests showed anemia (hemoglobin 6.1+/-1.3 g/dL), thrombocytopenia (34,000+/-32,000/mm3), and leukopenia (1,700+/-1,400/mm3). Elevated liver enzymes were present in 12 of 17 patients, and cholestasis was present in 10 of 17 patients. Elevated triglycerides and ferritin were noted in 75% and 86% of cases, respectively. HPS was related to viral infection in nine patients (cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8), bacterial infection in three patients (tuberculosis and Bartonella henselae), and other infections in two patients (toxoplasmosis and Pneumocystis carinii pneumoniae). Posttransplant lymphoproliferative disease was present in two patients. Despite large-spectrum anti-infectious treatment and dramatic tapering of immunosuppression, death occurred in eight patients (47%). Graft nephrectomy was performed in four of the nine surviving patients. CONCLUSIONS: We report here the largest series of HPS after renal transplantation. This rare disease is usually secondary to herpes viridae infections, mostly cytomegalovirus and Epstein-Barr virus in severely immunocompromised patients. Despite aggressive treatment, the prognosis remains poor.
Adult↗