Marc Hazzan

Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.

Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil: Results from a Prospective, Randomized Trial

The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n = 54) or MMF (CsA group, n = 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 +/- 18.7 versus 56.5 +/- 18.0 ml/min; P = 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P = 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P = 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 +/- 9 versus 58 +/- 22 mg/h per L; P = 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.

CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation

BACKGROUND The effect of potentially relevant genetic polymorphisms, CYP3A5 6986A>G and ABCB1 3435C>T, on Tacrolimus pharmacokinetics and graft clinical outcome was investigated in donor and recipient DNA samples from 209 kidney transplant patients. METHODOLOGY/PRINCIPAL FINDINGS The mean follow-up was 21.8 ± 9 months. The Tacrolimus dose, trough blood concentrations (C0) and C0/dose ratio were only statistically correlated with the recipient CYP3A5 genotype. CYP3A5 and ABCB1 genotypes appeared to have no influence on the incidence of Biopsy Proven Acute Rejection and Delayed Graft Function. Renal function was not affected by CYP3A5 and ABCB1 genotypes. Histological evaluation of biopsies revealed also no significant association between Tacrolimus toxicity features and donor or recipient CYP3A5 and ABCB1 polymorphisms. Tacrolimus sparing appeared to be independent of CYP3A5 and ABCB1 genotypes. CONCLUSIONS/SIGNIFICANCE Recipient CYP3A5 6986A>G polymorphism explains part of the interindividual variability of the pharmacokinetics of Tacrolimus. The clinical outcome at 2-year follow-up does not appear to be related to the donor or recipient CYP3A5 6986A>G and/or ABCB1 3435C>T polymorphisms.

Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (β-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (β-score greater than 3).

CONTEXT For the last 10 yr, continuous glucose monitoring (CGM) has brought up new insights into the accuracy of blood glucose analysis. OBJECTIVE Our objective was to determine how islet graft function was able to influence the various components of dysglycemia after islet transplantation (IT). DESIGN AND SETTING We conducted a single-arm open-labeled study with a 3-yr follow-up in a referral center (ClinicalTrial.gov identifiers NCT00446264 and NCT01123187). PATIENTS Twenty-three consecutive patients with type 1 diabetes (14 islet alone, nine islet after kidney) received IT within 3 months using the Edmonton protocol. INTERVENTION INTERVENTION included 72-h CGM before and 3, 6, 9, 12, 24, and 36 months after transplantation. MAIN OUTCOME MEASURE Graft function was estimated via β-score, a previously validated index (range 0-8) based on treatment requirements, C-peptide, blood glucose, and glycated hemoglobin. RESULTS At the 3-yr visit, graft function persisted in 19 patients (82%), and 10 (43%) remained insulin independent. Glycated hemoglobin decreased in the whole cohort from 8.3% (7.3-9.0%) at baseline to 6.7% (5.9-7.7%) at 3 yr [median (interquartile range), P < 0.01]. Mean glucose, glucose sd, and time spent with glycemia above 10 mmol/liter (hyperglycemia) and below 3 mmol/liter (hypoglycemia) were significantly lower after IT (P < 0.05 vs. baseline). The four CGM outcomes were related to β-score (P < 0.001). However, partial function (β-score >3) was sufficient to abrogate hypoglycemia; suboptimal function (β-score >5) was necessary to significantly improve mean glucose, glucose sd, and hyperglycemia; and optimal function (β score >7) was necessary to normalize them. CONCLUSION The four components of dysglycemia were not equally affected by the degree of islet graft function, which could have important implications for future development of β-cell replacement. A β-score above 3 dramatically reduced the occurrence of hypoglycemia.

Evolution of immunoglobulin and mannose binding protein levels after renal transplantation: association with infectious complications.

Hypogammaglobulinemia (hypo‐Ig) and low mannose binding protein (MBP) levels might be involved in the infectious risk in renal transplantation. In 152 kidney transplant recipients treated with calcineurin inhibitors (CNI) and mycophenolate mofetil (MMF), during the first year, we prospectively recorded the incidence of hypogammaglobulinemia, and low MBP levels. Their influence on infectious complications was evaluated in 92 patients at 3 and 12 months (T3 and T12). The proportion of deficiency increased significantly: hypo‐IgG: 6% (T0), 45% (T3), and 30% (T12) (P < 0.001); hypo‐MBP: 5%, 11%, and 12% (P = 0.035). Hypo‐IgG at T3 was not associated with an increased incidence of first‐year infections. A significantly higher proportion of patients with combined hypogammaglobulinemia [IgG+ (IgA and/or IgM)] at T3 and with isolated hypo‐IgG at T0 developed infections until T3 compared with patients free of these deficits (P < 0.05). Low MBP levels at T3 were associated with more sepsis and viral infections. Hypogammaglobulinemia is frequent during the first year after renal transplantation in patients treated with a CNI and MMF. Hypo‐IgG at T0 and combined Igs deficts at T3 were associated with more infections. MBP deficiency might emerge as an important determinant of the post‐transplant infectious risk.

Subtotal parathyroidectomy with thymectomy for autonomous hyperparathyroidism after renal transplantation

There is currently no consensus on the operation that should be performed in patients with tertiary hyperparathyroidism (HPT) after renal transplantation.

Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.

Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients.

AbstractBackground and Objective: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®)Patients and Methods: This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen ‘expressor’ patients (CYP3A5*1/*3 or *1/*1) were matched to 15 ‘non-expressor’ patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours [AUC24]) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49±24 months; non-expressors: 45±22 months). Results: During administration of tacrolimus as Prograf® or Advagraf®, the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC24 was significantly lower in the expressor group. Following the switch to Advagraf®, there was a significant decrease in the dose-adjusted AUC24 for both non-expressor (5910 ± 3019 vs 5334 ± 2668 ng · h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 ± 1409 vs 3273 ± 1372 ng · h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C0) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 ± 2.2 vs 6.3 ± 2.5ng/mL; p = 0.02). However, a good correlation between AUC24 and C0 was observed for both Advagraf® and Prograf® regardless of CYP3A5 genotype. Conclusion: Tacrolimus exposure significantly decreases after a switch from Prograf® to Advagraf®, on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored.

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy.

Aliment Pharmacol Ther 2011; 34: 454–461

Assessment of the risk of chronic allograft dysfunction after renal transplantation in a randomized cyclosporine withdrawal trial.

Background. We report the two-year follow-up of a trial comparing the three-month postgraft discontinuation of either cyclosporine (CsA) or mycophenolate mofetil (MMF) from a triple-drug regimen after de novo renal transplantation. Methods. One hundred and eight patients were enrolled in this study and randomized to be withdrawn from CsA (MMF group, n=54) or MMF (CsA group, n=54). Results. Despite an increased risk of acute rejection and a lower, but nonsignificant, two-year graft survival, CsA withdrawal induced a sustained improvement of the renal function. At one year, the chronic allograft damage index was similar in both the MMF and CsA groups. However, CsA elimination resulted in a higher incidence of C4d deposits, irrespective of the occurrence of a prior acute rejection. While this finding could suggest a risk of chronic rejection in the MMF group, the outcome did not appear to be related to the C4d status. Moreover, logistic regression analysis showed that only two factors, acute rejection and the one-year glomerular filtration rate level, were predictive of a significant decline of the renal function at two years. Conclusions. These results point out the need to secure the minimization of the calcineurin inhibitors after renal transplantation, in order to reduce the risk of acute rejection in these patients, because this strategy allows the improvement of the one-year renal function which is predictive of a chronic allograft dysfunction.