Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study.

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

[Side effects of proliferation signal inhibitors and their management]. / Effets secondaires des inhibiteurs du signal de prolifération et leur gestion.

Proliferation signal inhibitors (PSI) could help to lower the calcineurine inhibitors level to minimize their toxicity and improve long-term graft survival. Side effects of this drugs are specific and must been known. Hyperlipidemia and cutaneous side-effects are the most frequent, angioedema and interstital pneumonitis the most serious. In majority of cases, early and adapted management could limit the impact of these side effects.

C4d: a marker for hepatic transplant rejection.

BACKGROUND: Acute rejection is still a common complication of hepatic transplantation. The diagnosis, based on the histological examination of the graft, may be difficult to confirm in the setting of combined hepatitis C virus infection. The presence of C4d in the portal capillaries could facilitate differentiation between acute rejection and relapsed hepatitis C. The deposit of C4d provides evidence of activation of humoral immunity. To attempt to confirm this hypothesis, we searched for the presence of C4d in posttransplant hepatic biopsies. METHODS: Thirty-six biopsies from 34 patients were analyzed retrospectively. The samples had been requested for one of the following reasons: suspected rejection, relapsed hepatitis C infection, or systematic check-up 1 year after the transplant. RESULTS: C4d expression was common in biopsies classified as acute rejection (33%) and chronic rejection (100%). C4d was never detected in the event of recurrent hepatitis C infection without rejection. CONCLUSION: These results, which are comparable to recently published data, give credence to the theory that C4d could be used as a marker for rejection following hepatic transplantation.

Improved liver function and decreased hepatitis C viral load after tacrolimus was replaced by cyclosporine.

Potential antiviral properties of cyclosporine against hepatitis C virus have been highlighted in several publications. Therefore, we investigated the effect of a switch from tacrolimus to cyclosporine in a liver transplant recipient with recurrent hepatitis C who did not respond to antiviral therapy. The patient received a liver transplant for hepatitis C cirrhosis. Initial immunosuppressive treatment was based on tacrolimus. Because of viral activity, a combined therapy was initiated 20 months later including interferon and ribavirine. Then, due to a lack of virological and biochemical response, tacrolimus was replaced by cyclosporine (Neoral), while maintaining the same antiviral therapy. Decreases in the viral load and transaminases levels were observed.

[HFE hemochromatosis: pathogenic and diagnostic approach]. / Hémochromatose HFE: approche pathogénique et diagnostique.

HFE hemochromatosis is the most frequent genetic iron overload disease. It is linked to the C282Y mutation of the HFE protein, protein encoded by the HFE gene, which is located on chromosome 6. The mechanisms accounting for iron excess are not only digestive hyperabsorption of iron but also excessive recycling of macrophagic iron coming from erythrophagocytosis and secreted into the blood. Both mechanisms are linked to an HFE-related hepatic failure in producing hepcidin, a key hormone of body iron regulation. The marked phenotypic variability of C282Y homozygosity expression is likely related to both genetic and environmental factors. The HFE gene discovery has rendered non invasive the positive diagnostic of HFE hemochromatosis, which is now based first on an increased level of plasma transferrin saturation leading to the request of the HFE mutation. Then, hepatic MRI is a reliable method to quantify iron overload. The HFE gene discovery has also paved the road of an enlarged field of differential diagnoses corresponding to novel entities of non-HFE related genetic iron overload syndromes.

Necrotic skin lesions in a dialysis patient: a multifactorial entity.

A female dialysis patient with a consistently high serum calcium phosphate product presented with large necrotic skin lesions with ulcers. The clinical course was highly suggestive of calciphylaxis. Parathyroidectomy was followed by the healing of the lesions. New skin lesions appeared following relapse of hyperparathyroidism. Her clinical records included a long past of hypertension, which was the cause of her renal failure. She had a limited walking range and previously had presented bilateral ulcers of vascular origin. This case presents a type of lesion which bears a serious prognosis in dialysis patients. The clinical context and the presentation of the lesions are compatible with multiple etiology: vascular lesions and calciphylaxis. The documented longitudinal follow-up illustrates the importance of treating the different factors known to participate in the appearance of skin lesions in dialysis patients. Particularly, it stresses the benefit of performing parathyroidectomy, even if the parathyroid hormone level is not in the range normally accepted as requiring surgical removal of parathyroid glands.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Genetic hemochromatosis update.

Hereditary Hemochromatosis is an autosomal recessive disease, characterized by chronic iron overload. It is mainly due to mutations of the HFE-1 gene. In the large majority of patients, the substitution of tyrosine for cysteine at amino acid 282 (C282Y) is found at the homozygous state. Since the HFE-1 hemochromatosis identification, several other entities of iron overload have been individualized. In the present article, the frequency, penetrance and pathophysiology of HFE-1 hemochromatosis as well as various clinical presentations resulting from different mutations affecting different proteins involved in iron metabolism are described.

[Post-transfusional anti-HLA hyperimmunization: importance of erythropoietin]. / Hyperimmunisation anti-HLA post-transfusionnelle: intérêt de l'érythropoïétine.

The use of erythropoietin (Epo) in chronic renal failure patients improves anemia and avoids iterative transfusions. As a consequence, a significant decrease of anti-HLA antibodies might be observed. From 31.12.1985 to 30.07.1991, among the 61 highly sensitized patients (pts) waiting for renal transplantation at our institution, 23 (7 men, 16 women, mean age 43.3 +/- 2.3 years) were treated with Epo during 21.4 +/- 1.7 months. After introduction of Epo, the mean number of transfusions significantly decreased from 35 +/- 8 to 0.5 +/- 0.4 (p < 0.0001) and the Panel Reactive Antibodies decreased from 88.1 +/- 1.7 to 18.8 +/- 5.6% (p < 0.0001). HLA antibodies totally disappeared in 12 patients, decreased more than 30% in 9 patients and remained stable in the 3 others. Renal transplantation was performed in 9 patients; 4 with a negative cross-match in both historical and current sera and 5 with a negative current cross-match but with a positive historical cross-match. 6/9 patients are doing well with a good graft function; 2 patients returned to hemodialysis for rejection and 1 patient died with a functioning kidney. Since Epo permits the transfusion withdrawal, its introduction in chronic renal failure treatment suppresses both the main factor of immunisation and one of the most important mechanisms of persistence of antibodies.

Antilymphocyte globulins versus OKT3 as prophylactic treatment in highly sensitized renal transplant recipients.

Monoclonal antibodies were proposed as an effective prophylactic immunosuppressive treatment in highly sensitized patients (HSP). In this study we compared the results obtained in HSP treated with OKT3 or antilymphocyte globulins (ALG). From January 1989 to January 1993, 38 transplantations were performed in patients with high panel reactive antibodies (PRA > 50%). The group comprised 22 women and 16 men, mean age 45 +/- 2 (23-67) years; ten were second grafts and two were third grafts. Peak PRA was > or = 80% in 24 sensitized patients and 50-80% in 14 sensitized patients. Patients were randomly assigned to either prophylactic OKT3 (n = 15) or ALG (n = 23). Oral cyclosporin A (10 mg/kg) was started at day 8 in the OKT3 group and when the serum creatinine level decreased to 200 micromol/l in the ALG group. OKT3 was systematically withdrawn on day 10 but ALG was stopped only when total blood cyclosporin A concentration reached 150-200 ng/ml. In both groups, azathioprine (150 mg/day) and prednisolone were given. During the first months, 6/15 grafts were lost in the OKT3 group (three hyperacute rejections, one renal vein thrombosis, one steroid-resistant rejection, one death); in the ALG group 4/23 grafts were lost (one hyperacute rejection, two steroid-resistant rejections, one death). Side effects were significantly more frequent in the OKT3 group than in the ALG group. After 12 months of follow up, the graft survival was 71% (27/38) and did not significantly differ (log-rank test, NS) between the OKT3 (60%, 9/15) and the ALG group (78%, 18/23). We conclude that the use of the monoclonal antibody OKT3 as a prophylactic agent in HSP does not improve the early graft survival when compared with prophylactic ALG. Polyclonal antibodies, which react with many epitopes and are much better tolerated seem to offer a good strategy for induction therapy in this population.

Precise quantification of dialysis using continuous sampling of spent dialysate and total dialysate volume measurement.

The "gold standard" method to evaluate the mass balances achieved during dialysis for a given solute remains total dialysate collection (TDC). However, since handling over 100 liter volumes is unfeasible in our current dialysis units, alternative methods have been proposed, including urea kinetic modeling, partial dialysate collection (PDC) and more recently, monitoring of dialysate urea by on-line devices. Concerned by the complexity and costs generated by these devices, we aimed to adapt the simple "gold standard" TDC method to clinical practice by diminishing the total volumes to be handled. We describe a new system based on partial dialysate collection, the continuous spent sampling of dialysate (CSSD), and present its technical validation. Further, and for the first time, we report a long-term assessment of dialysis dosage in a dialysis clinic using both the classical PDC and the new CSSD system in a group of six stable dialysis patients who were followed for a period of three years. For the CSSD technique, spent dialysate was continuously sampled by a reversed automatic infusion pump at a rate of 10 ml/hr. The piston was automatically driven by the dialysis machine: switched on when dialysis started, off when dialysis terminated and held during the by pass periods. At the same time the number of production cycles of dialysate was monitored and the total volume of dialysate was calculated by multiplying the volume of the production chamber by the number of cycles. Urea and creatinine concentrations were measured in the syringe and the masses were obtained by multiplying this concentration by the total volume. CSSD and TDC were simultaneously performed in 20 dialysis sessions. The total mass of urea removed was calculated as 58038 and 60442 mmol/session (CSSD and TDC respectively; 3.1 +/- 1.2% variation; r = 0.99; y = 0.92x -28.9; P < 0.001). The total mass of creatinine removed was 146,941,143 and 150,071,195 mumol/session (2.2 +/- 0.9% variation; r = 0.99; y = 0.99x + 263; P < 0.001). To determine the long-term clinical use of PDC and CSSD, all the dialysis sessions monitored during three consecutive summers with PDC (during 1993 and 1994) and with CSSD (1995) in six stable dialysis patients were included. The clinical study comparing PDC and CSSD showed similar urea removal: 510 +/- 59 during the first year with PDC and 516 +/- 46 mmol/dialysis session during the third year, using CSSD. Protein catabolic rate (PCR) could be calculated from total urea removal and was 1.05 +/- 0.11 and 1.05 +/- 0.09 g/kg/day with PDC and CSSD for the same periods. PCR values were clearly more stable when calculated from the daily dialysate collections than when obtained with urea kinetic modeling performed once monthly. We found that CSSD is a simple and accurate method to monitor mass balances of urea or any other solute of clinical interest. With CSSD, dialysis efficacy can be monitored at every dialysis session without the need for bleeding a patient. As it is external to the dialysis machine, it can be attached to any type of machine with a very low cost. The sample of dialysate is easy to handle, since it is already taken in a syringe that is sent directly to the laboratory. The CSSD system is currently in routine use in our unit and has demonstrated its feasibility, low cost and high clinical interest in monitoring dialysis patients.