Mireille Kianda

Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.

Background With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence. Methods Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients’ persistence and implementation of each regimen. Results Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035). Conclusions Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

Conversion From Prograf to Advagraf Among Kidney Transplant Recipients Results in Sustained Decrease in Tacrolimus Exposure

Background. Advagraf is a slow release form of tacrolimus with once-daily formulation. The potential advantages of Advagraf are better adherence and a safer profile by avoiding toxic peak concentrations. In this study, we evaluated the required daily doses of tacrolimus and subsequent blood levels on conversion from Prograf to Advagraf among kidney transplant recipients. Methods. We retrospectively reviewed data from 55 patients for whom a switch from Prograf to Advagraf was identified. Tacrolimus daily doses and concomitant blood levels were analyzed at several time points ranging from 3 months before to 6 months after conversion. Results. We observed a significant increase in tacrolimus daily doses, starting with a dose of 0.063 mg/kg of Prograf, increasing up to 0.081 mg/kg of Advagraf at 6 months (P<0.0001). After conversion, we observed a quick and sustained decrease in trough tacrolimus levels, decreasing from 8.05 ng/mL at day 0 to 6.30 ng/mL at day 180 (P=0.0009). At 6 months, 35% of patients experienced a decrease in trough levels of more than 30%. Creatinine values remained stable over time, and no patient experienced an acute rejection episode. Conclusions. Contrary to the manufacturer instructions, we found a significant decrease in tacrolimus exposure after switching to Advagraf. Therefore, the switch from Prograf to Advagraf should be performed under close medical supervision.

Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study

BACKGROUND Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. METHODS A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). RESULTS In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). CONCLUSION Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.

Kianda MN, Wissing KM, Broeders NE, Lemy A, Ghisdal L, Hoang AD, Mikhalski D, Donckier V, Vereerstraeten P, Abramowicz D. Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.
Clin Transplant 2011: 25: 576–583.

Ticlopidine and clopidogrel, sometimes combined with aspirin, only minimally increase the surgical risk in renal transplantation: a case–control study

BACKGROUND Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS Platelets were administered to 7 cases (37%) versus 0 controls (P<0.001). A single case (5.3%) presented with significant bleeding during surgery following an implantation biopsy, and required 4 red bood cell (RBC) units. During the first day, 3 of the 19 cases (16%) and 1 of the 39 controls required RBC (P=0.1). No reoperation was performed for bleeding. After the transplant, clopidogrel or ticlopidine was resumed in only two patients. The platelet count and haemoglobin were similar between cases and controls at Day 30. No cardiovascular event occurred in cases or controls during the first month post-transplantation. At 5 years, graft and patient survival was similar in cases and controls. CONCLUSIONS Clopidogrel and ticlopidine, sometimes in combination with ASA, are associated with a low risk of bleeding during renal transplantation and does not seem to be a contraindication for renal transplant surgery.

Shipping donor kidneys within Eurotransplant: outcomes after renal transplantation in a single-centre cohort study.

BACKGROUND Shipment of organs during the allocation process aims to improve human leucocyte antigen (HLA) matching but can also have a detrimental effect by prolonging cold ischaemia. The overall effect of organ exchange on post-transplant outcomes in the Eurotransplant (ET) region has not been investigated. METHODS This is a retrospective single-centre cohort study to investigate the effect of shipment of renal allografts on cold ischaemia times and the incidence of acute rejection (AR) and graft survival in 661 transplantations of deceased donor kidneys. RESULTS Forty-six per cent (N = 301) of the patients received a locally procured and 54% (N = 360) a shipped donor kidney. Locally procured donors tended to be older, more often hypertensive and had less frequently died from trauma. Recipients of shipped kidneys were at higher immunological risk, being younger, more frequently retransplanted and immunized against HLA antigens. Shipped kidneys had a 2.2-h prolongation of cold ischaemia time (18.0 versus 20.2 h; P < 0.0001) but significantly less HLA A, B and DR mismatches (2.20 versus 2.84; P < 0.0001). Recipients of shipped kidneys had an increased incidence of first-year AR [19 versus 13%; odds ratio 1.62 (1.06-2.49); P = 0.026] and death-censored graft loss [hazard ratio 1.6 (1.1-2.4); P = 0.01] that was no longer statistically significant after adjustments for risk factors by multivariable modelling. CONCLUSIONS Shipment of kidneys in the ET region is associated with a modest increase in cold ischaemia time and significantly better HLA matching. This allows for successful transplantation of higher risk patients with no significant penalty with regard to AR rates or death-censored graft survival.

Prospective randomized study of conversion from tacrolimus to cyclosporine A to improve glucose metabolism in patients with posttransplant diabetes mellitus after renal transplantation

Tacrolimus (TAC) increases the risk of posttransplant diabetes (PTDM) compared with cyclosporine A (CYC). The present 12‐month, multicenter, investigator‐driven, prospective, randomized study was designed to assess whether conversion from tacrolimus to CYC can reverse PTDM after renal transplantation. Predominantly white patients with PTDM according to the 2005 American Diabetes Association criteria were randomized to either replacement of TAC with CYC or continuation of their TAC‐based regimen after stratification for type of glucose‐lowering therapy, steroid therapy, and hepatitis C status. At 12 months, 14 of 41 patients with complete data in the CYC arm (34%; 95%CI 19%‐49%) were free of diabetes, whereas this was the case in only 4 of 39 patients (10%; 95%CI 3%‐20%) in the TAC arm (P = .01). At 12 months, 39% of patients in the CYC arm were off glucose‐lowering medication vs 13% of patients in the TAC arm (P = .01). The CYC group decreased glycated hemoglobin level during the 12‐month follow‐up, resulting in significantly lower levels compared with the TAC group (6.0 ± 0.9% vs 7.1 ± 1.7% at 12 months; P = .002). In conclusion, replacement of TAC with CYC significantly improves glucose metabolism and has the potential to reverse diabetes during the first year after conversion. (EU Clinical Trials Register No. 2006‐001765‐42)

Conversion From Tacrolimus to Cyclosporine A Improves Glucose Metabolism in Patients With New Onset Diabetes After Transplantation: Interim Analysis of a Prospective and Randomized Study.: Abstract# 1393

1394 Is Hypomagnesemia a Novel Risk Factor for New-Onset Diabetes Mellitus After Kidney Transplantation? J. Huang, O. Famure, Y. Li, S. Kim. Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada. Background: New-onset diabetes after transplantation (NODAT) increases the risk of cardiovascular events and graft failure among kidney transplant recipients. Some studies have suggested a link between hypomagnesaemia (HypoMg) and NODAT but this association remains controversial. Methods: A cohort study was conducted in 948 non-diabetic patients who received a kidney transplant from 1 Jan 2000 to 31 Dec 2011 (with follow-up to 30 Jun 2012). HypoMg was defi ned as a serum magnesium (Mg) < 0.74 mmol/L. NODAT was diagnosed based on the American Diabetes Association criteria. Cox proportional hazards models were fi tted to examine the association of baseline Mg (at 1-month), time-varying Mg (every 3-months), and rolling average Mg (during 1-, 2-, or 3-month windows) with NODAT, while adjusting for other covariates. Results: Over 4,005.2 person-years of follow-up (median follow-up 3.3 years), 206 NODAT events were observed. The Cox proportional hazards models suggested an inverse relation between baseline serum Mg and NODAT (hazard ratio [HR] 1.21 per 0.1 mmol/L decrease in Mg [95% CI: 1.04, 1.41], P = 0.01). Similar results were observed for rolling average Mg levels during the previous 1-month (HR 1.28 [95% CI: 1.09, 1.49]; P = 0.002), 2-months (HR 1.28 [95% CI: 1.08, 1.53]; P = 0.01) and 3-months (HR 1.25 [95% CI: 1.03, 1.52]; P = 0.03). Patients with HypoMg (vs. normal Mg) were consistently associated with a signifi cant 50 to 80% increase in the relative hazard for developing NODAT in baseline and rolling average Cox proportional hazards models. Interestingly, conventional time-varying models (with changes in Mg measured at discrete time points over follow-up) did not show a signifi cant association between HypoMg and NODAT. Conclusion: Our results suggest that HypoMg, measured longitudinally, is an independent risk factor for NODAT in kidney transplant recipients. The role of magnesium supplementation to reduce the risk of NODAT requires further study. DISCLOSURE: Kim, S.: Grant/Research Support, Astellas Pharma Canada, Novartis Pharma Canada, Genzyme Canada. Abstract# 1395 New Onset Diabetes After Kidnet Transplantation Despite the Use of a Steroid-Sparing Regime Is Associated With a Higher Mortality From Cardiac Causes. D. Moutzouris, C. Baker, N. Kumar, M. Willicombe, R. Corbett, N. Duncan, J. Galliford, A. McLean, D. Taube. Imperial College Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom. Purpose New-onset diabetes after transplantation [NODAT] is associated with increased cardiovascular risk and reduced patient survival. We have also shown that patients who develop NODAT, despite the use of a steroid sparing immunosuppressive regime have reduced patient survival. In this study, we investigate the causes of death in these patients developing NODAT. Methods In a retrospective, single centre study, we report the outcomes of 920 patients [552m, 368f, mean age 47±13.3 yrs, range 18-78, mean follow up 57.6±30 mths], receiving a steroid sparing, tacrolimus based regime after monoclonal antibody induction. Steroids were stopped 7 days post kidney transplantation and only reintroduced to treat rejection. We excluded patients with history of diabetes mellitus. Results Overall, 169/920 [18.4%] patients developed NODAT, defi ned as diabetes requiring diet control [19.9%], oral hypoglycaemics [62.0%], insulin [15.7%] or both [2.4%]. Cumulative patient survival in the NODAT+ and NODAT– groups at 1, 3, 5 years post transplant was 98.2%, 93.6%, 90.2% and 98.5%, 97%, 94.8%, respectively (p=0.032). Cumulative graft survival in the NODAT+ and NODATgroups at 1,3 and 5 years was 98.2%, 92.3%, 87% and 95.7%, 92%, 87.9%, respectively (p=0.547). The cumulative incidence of NODAT was 9.5%, 14.2% and 16.5% at 1, 3 and 5 years after transplantation, respectively. During follow up, there were 71 cardiac events, 22 of which occurred in patients with NODAT [1 STEMI, 9 non-STEMIs, 9 episodes of cardiac arrhythmia and 3 cardiac deaths]. In NODATpatients, there were 49 cardiac events (4 STEMI, 18 NSTEMI, 24 episodes of cardiac arrhythmia and 3 cardiac deaths). The NODAT+ group had an increased risk of cardiac events (12.4% vs. 6.5%, p=0.009) and death (10.1% vs. 4.9%, p=0.011). Patients with NODAT had reduced coronary event-free survival (log rank p=0.017) and overall survival (log rank p=0.032). Older age (p<0.001) and development of NODAT (p=0.041) increased the risk for a cardiac event. Conclusions This study shows that patients who develop NODAT despite the use of a steroid-sparing regime have a higher incidence of cardiac events and impaired patient survival. 1395 New Onset Diabetes After Kidnet Transplantation Despite the Use of a Steroid-Sparing Regime Is Associated With a Higher Mortality From Cardiac Causes. D. Moutzouris, C. Baker, N. Kumar, M. Willicombe, R. Corbett, N. Duncan, J. Galliford, A. McLean, D. Taube. Imperial College Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom. Purpose New-onset diabetes after transplantation [NODAT] is associated with increased cardiovascular risk and reduced patient survival. We have also shown that patients who develop NODAT, despite the use of a steroid sparing immunosuppressive regime have reduced patient survival. In this study, we investigate the causes of death in these patients developing NODAT. Methods In a retrospective, single centre study, we report the outcomes of 920 patients [552m, 368f, mean age 47±13.3 yrs, range 18-78, mean follow up 57.6±30 mths], receiving a steroid sparing, tacrolimus based regime after monoclonal antibody induction. Steroids were stopped 7 days post kidney transplantation and only reintroduced to treat rejection. We excluded patients with history of diabetes mellitus. Results Overall, 169/920 [18.4%] patients developed NODAT, defi ned as diabetes requiring diet control [19.9%], oral hypoglycaemics [62.0%], insulin [15.7%] or both [2.4%]. Cumulative patient survival in the NODAT+ and NODAT– groups at 1, 3, 5 years post transplant was 98.2%, 93.6%, 90.2% and 98.5%, 97%, 94.8%, respectively (p=0.032). Cumulative graft survival in the NODAT+ and NODATgroups at 1,3 and 5 years was 98.2%, 92.3%, 87% and 95.7%, 92%, 87.9%, respectively (p=0.547). The cumulative incidence of NODAT was 9.5%, 14.2% and 16.5% at 1, 3 and 5 years after transplantation, respectively. During follow up, there were 71 cardiac events, 22 of which occurred in patients with NODAT [1 STEMI, 9 non-STEMIs, 9 episodes of cardiac arrhythmia and 3 cardiac deaths]. In NODATpatients, there were 49 cardiac events (4 STEMI, 18 NSTEMI, 24 episodes of cardiac arrhythmia and 3 cardiac deaths). The NODAT+ group had an increased risk of cardiac events (12.4% vs. 6.5%, p=0.009) and death (10.1% vs. 4.9%, p=0.011). Patients with NODAT had reduced coronary event-free survival (log rank p=0.017) and overall survival (log rank p=0.032). Older age (p<0.001) and development of NODAT (p=0.041) increased the risk for a cardiac event. Conclusions This study shows that patients who develop NODAT despite the use of a steroid-sparing regime have a higher incidence of cardiac events and impaired patient survival. Abstract# 1396 Validity of Glycated Haemoglobin for Diagnosing New Onset Diabetes After Renal Transplantation. I. Eide,1 T. Halden,1 A. Aasberg,2 E. Storset,1 A. Hartmann,1 M. von During,1 T. Jenssen.1,3 1Department of Organ Transplantation, Oslo University Hospital, Oslo, Norway; 2Department of Pharmaceutical Biosciences, University of Oslo, Oslo, Norway; 3Department of Medicine, University of Tromso, Tromso, Norway. Introduction: HbA1c ≥ 6.5% has been accepted in the US and Europe as a diagnostic criterion for diabetes in the general population. Oral glucose tolerance test (OGTT) has up till now been the gold standard for diagnosing diabetes in renal transplant recipients (RTRs). Normal fasting plasma glucose (FPG) concentrations but elevated post-challenge glucose concentrations (2hPG) is frequently the only sign of diabetes in RTRs. Objectives: The aim of the present study was to assess whether the HbA1c criterion matches the OGTT criterion in RTRs. Methods: In this observational study 1645 adult RTRs with no prior diabetes were studied. They were transplanted between 1999 and 2011, and underwent an OGTT and measurement of HbA1c 10 weeks after transplantation. New onset diabetes after transplantation (NODAT) was defi ned as having a positive OGTT (FPG ≥ 7.0 mmol/L and/or 2hPG ≥ 11.1 mmol/L). The predictive value of HbA1c for detecting NODAT was assessed. Results: NODAT was diagnosed in 91 patients by the OGTT. Sixty-three of these patients (69.2%) had a normal HbA1c. In 127 patients with HbA1c ≥ 6.5% 56 patients (44.1%) did not meet the OGTT criterion for NODAT. HbA1c ≥ 6.5% and/or FPG ≥ 7.0 mmol/L diagnosed 52 out of 91 patients (57.1%, fi gure 1). Conclusion: Using the HbA1c criterion alone for the diagnosis of NODAT, less than one third of cases were detected. Using FPG and/or HbA1c as diagnostic criterion, three out of fi ve cases with NODAT were detected, underscoring the importance of performing OGTT for diagnosing diabetes in RTRs. 1396 Validity of Glycated Haemoglobin for Diagnosing New Onset Diabetes After Renal Transplantation. I. Eide,1 T. Halden,1 A. Aasberg,2 E. Storset,1 A. Hartmann,1 M. von During,1 T. Jenssen.1,3 1Department of Organ Transplantation, Oslo University Hospital, Oslo, Norway; 2Department of Pharmaceutical Biosciences, University of Oslo, Oslo, Norway; 3Department of Medicine, University of Tromso, Tromso, Norway. Introduction: HbA1c ≥ 6.5% has been accepted in the US and Europe as a diagnostic criterion for diabetes in the general population. Oral glucose