Annick Massart

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.

Influenza A/H1N1 Vaccine in Patients Treated by Kidney Transplant or Dialysis: A Cohort Study

BACKGROUND AND OBJECTIVES In 2009, the pandemic influenza A/H1N1 accounted for worldwide recommendations about vaccination. There are few data concerning the immunogenicity or the security of the adjuvanted-A/H1N1 vaccine in transplanted and hemodialyzed patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Sera from 21 controls, 53 hemodialyzed (HD) patients, and 111 renal transplant recipients (RT) were sampled before (T0) and 1 month after (T1) a single dose of Pandemrix® vaccine (GSK Biologicals, AS03-adjuvanted). We measured the neutralizing antibodies against A/H1N1/2009, the geometric mean (GM) titers, the GM titer ratios (T1/T0) with 95% confidence intervals, and the seroconversion rate (responders: ≥4-fold increase in titer). The HLA and MICA immunization was determined by Luminex technology. RESULTS The GM titer ratio was 38 (19 to 78), 9 (5 to 16), and 5 (3 to 6) for controls, HD patients, and RT patients, respectively (P < 0.001). The proportion of responders was 90%, 57%, and 44%, respectively (P < 0.001). In RT patients, the prevalence of histocompatibility leukocyte antigen (HLA) class I, histocompatibility leukocyte antigen class II, and MHC class I-related chain A immunization, was, respectively, 15%, 14%, and 14% before and 14%, 14%, and 11% after vaccination (P = 1, 1, and 0.39). CONCLUSIONS The influenza A/H1N1-adjuvanted vaccine is of limited efficacy but is safe in renal disease populations. The humoral response is lower in transplanted versus hemodialyzed patients. Further studies are needed to improve the efficacy of vaccination in those populations.

The Effects of Racial Differences on Body Composition and Total Body Water Measured by Multifrequency Bioelectrical Impedance Analysis Influence Delivered Kt/V Dialysis Dosing

Introduction: Haemodialysis dosing is traditionally based on urea clearance (Kt/V). Aiming for the same Kt/V target, some racial groups have better survival. We investigated whether body composition differs with ethnicity and may lead to differences in Kt/V delivered. Methods: We compared total body water (TBW) measured by multifrequency bioelectrical impedance analysis (MF-BIA) that calculated from standard anthropometric equations. Results: Three hundred and seventy-one adult patients, with a mean age of 58.2 ± 16.6 years, 60.6% of whom were male, 29.1% diabetic, 38.5% Caucasoid, 29.4% African/Afro-Caribbean, 24.8% South Asian and 5.4% East Asian, were studied. TBW measured by MF-BIA differed significantly from that predicted by anthropometric equations. Body fat of women and diabetics was greater, and muscle mass in South Asians was reduced. The difference between the TBW MF-BIA measurement and that of the equation by Watson et al. [11] was associated with % muscle mass (β -10.8, p < 0.001), age (β 0.23, p < 0.001), serum albumin (β -0.24, p < 0.001), body mass index (β 0.91, p = 0.001) and racial origin (β -9.86, p = 0.04). Conclusions: Variation in body composition between ethnic groups potentially leads to over-estimation of delivered dose for some ethnic groups and underestimation for others when using anthropometric equations. MF-BIA assessments of body water should be evaluated as a method for dosing dialysis patients.

Haemodiafiltration Results in Similar Changes in Intracellular Water and Extracellular Water Compared to Cooled Haemodialysis

Background/Aims: Intradialytic hypotension is the most common complication of modern day haemodialysis (HD). Convective modalities, including haemodiafiltration (HDF) are reported to result in greater cardiovascular stability compared to standard HD, which has been suggested to be due to improved solute transport between compartments. We therefore investigated the effect of treatment on body water by bioimpedance. Methods: We measured the change in extracellular water (ECW) and intracellular water (ICW) in 263 outpatients attending for HD using cooled dialysate and 134 patients for HDF. Results: Patient cohorts were matched for demographics, dialysate composition, ultrafiltration rate, and session duration. The fall in systolic blood pressure following HD was -11.8 mm Hg (-25.3 to 2.3) and not different from that following HDF -12 mm Hg (-27 to 6). Similarly there were no differences in pretreatment serum sodium and dialysate sodium gradient [HD 1 mmol/l (-1 to 3) vs. HDF 2 mmol/l (1 to 4)], or change in serum sodium posttreatment [HD 0 mmol/l (-2 to 2) vs. HDF 1 mmol/l (-1 to 3)]. There were no differences in ICW or ECW pretreatment, and following treatment the reduction in ICW and ECW did not differ [ICW HD -3.5% (-5.7 to -1.8) vs. -4.1% (-6.0 to -1.7), ECW HD -7.1% (-9.4 to -4.7) vs. HDF -7.1% (-9.7 to -4.9)]. Conclusion: We were unable to demonstrate any advantage for HDF over HD using cooled dialysate in terms of changes in blood pressure during a treatment session, or differences in the relative changes in ICW or ECW volumes.

Delayed Graft Function in Kidney Transplants: Time Evolution, Role of Acute Rejection, Risk Factors, and Impact on Patient and Graft Outcome

Background. Although numerous risk factors for delayed graft function (DGF) have been identified, the role of ischemia-reperfusion injury and acute rejection episodes (ARE) occurring during the DGF period is ill-defined and DGF impact on patient and graft outcome remains controversial. Methods. From 1983 to 2014, 1784 kidney-only transplantations from deceased donors were studied. Classical risk factors for DGF along with two novel ones, recipients perioperative saline loading and residual diuresis, were analyzed by logistic regression and receiver operating characteristic (ROC) curves. Results. Along with other risk factors, absence of perioperative saline loading increases acute rejection incidence (OR = 1.9 [1.2–2.9]). Moreover, we observed two novel risk factors for DGF: patients residual diuresis ≤500 mL/d (OR = 2.3 [1.6–3.5]) and absence of perioperative saline loading (OR = 3.3 [2.0–5.4]). Area under the curve of the ROC curve (0.77 [0.74–0.81]) shows an excellent discriminant power of our model, irrespective of rejection. DGF does not influence patient survival (P = 0.54). However, graft survival is decreased only when rejection was associated with DGF (P < 0.001).  Conclusions. Perioperative saline loading efficiently prevents ischemia-reperfusion injury, which is the predominant factor inducing DGF. DGF per se has no influence on patient and graft outcome. Its incidence is currently close to 5% in our centre.

Are serum to dialysate sodium gradient and segmental bioimpedance volumes associated with the fall in blood pressure with hemodialysis

Introduction A fall in blood pressure is the most common complication of outpatient hemodialysis. Several factors have been implicated, including serum sodium to dialysate gradient, ultrafiltration rate, and the amount of fluid to be removed during dialysis. Methods We prospectively audited 400 adult patients attending for their routine midweek hemodialysis session, and recorded changes in mean arterial blood pressure (MAP). Results Mean age 58.4 ± 16.6 years, 60.9% male, 30.7% diabetic, 36.8% Caucasoid, single pool Kt/V 1.57 ± 0.4, and median percentage change in MAP −6.7% (-14.1 to + 2.8). The percentage fall in MAP was greatest for those starting with higher MAPs (β 0.448, F 67.5, p<0.001), greater serum sodium to dialysate sodium gradient (β 0.676, F 5.59, p = 0.019), and age (β 0.163, F 5.15, p = 0.024). In addition, the percentage fall in MAP was greater in those with the lowest segmental extracellular water/total body water (ECW/TBW) ratios in the right arm prior to dialysis (β −477.5, F 7.11, p = 0.008). Conclusions Falls in blood pressure are common during dialysis, and greater for those starting dialysis with the highest systolic pressures, greater dialysate to serum sodium concentration gradient, and also those with the least ECW in the arm. As such, segmental bioimpedance may be useful in highlighting patients at greatest risk for a fall in blood pressure with dialysis.

Genome-wide association study of acute renal graft rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long‐term graft loss. We performed a genome‐wide association study to detect loci associated with biopsy‐proven acute T cell–mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor‐type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

Is There a Role for N-Terminal Probrain-Type Natriuretic Peptide in Determining Volume Status in Haemodialysis Patients?

Background/Aims: Natriuretic peptides have been reported to be a valuable biomarker for predicting cardiac events and mortality for haemodialysis patients. However, there has been a debate as to whether these biomarkers can be used to assess volume overload and help determine dry weight. Methods: We measured the N-terminal probrain natriuretic peptide (NTproBNP) in 366 stable haemodialysis outpatients with a corresponding pre- and post-dialysis multifrequency bioimpedance assessment of extracellular water (ECW)/total body water (TBW). Results: Median age was 61 years (46–73); 58.5% were male, 28.5% diabetic, and 37.7% Caucasoid; 71.1% had a history of hypertension, 8.4% of myocardial infarction, and 9.3% of coronary artery bypass surgery; dialysis vintage was 54 months (22–85.5), and urea reduction ratio was 73.4 ± 7.6%. Median post-dialysis NTproBNP was 179 pmol/l (68–535), pre-dialysis ECW/TBW was 0.393 ± 0.014, and post-dialysis ECW/TBW was 0.385 ± 0.015. On multivariate analysis log NTproBNP was associated with post-dialysis ECW/TBW (β 9.09, 95% CI 3.22–14.95, p = 0.003), mean arterial pressure (β 0.0087, 95% CI –0.0045 to –0.013, p = 0.000), and ultrafiltration rate (ml/kg· h; β 0.038, 95% CI 0.01–0.06, p = 0.001). Conclusion: In this study postdialysis NTproBNP values were correlated with direct assessments of volume status in haemodialysis patients, i.e. by ECW/TBW, or indirect measures of volume overload, i.e. ultrafiltration rate and post-dialysis mean arterial blood pressure. This suggests that serial NTproBNP values may aid clinical assessments of volume status in dialysis patients.

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.

A New HLA Allocation Procedure of Kidneys From Deceased Donors in the Current Era of Immunosuppression

INTRODUCTION It has recently been proposed to replace the current Eurotransplant kidney allocation based primarily on mismatches (MM) at the 3 HLA loci by a simpler system based on full HLA-DR compatibility. The present study analyzes this system in the current era of immunosuppression. METHODS From 1999 to 2012, 723 renal grafts were performed on 586 patients who were treated with a calcineurin inhibitor, mycophenolate mofetil, and in most cases antilymphocyte globulins. Four groups of HLA MM were compared: (A) A+B 2-4/DR 1-2 MM (n = 397), (B) A+B 2-4 MM/DR 0 MM (n = 106), (C) A+B 0-1 MM/DR 1-2 MM (n = 138), and (D) A+B 0-1/DR 0 MM (n = 82). RESULTS Acute rejection episodes were less frequent during the first post-transplantation year in group D than in the other groups (P = .018). Patient survival was lower in group A than in the other groups (P = .008). Immunologic graft survival was higher in group D than in the other groups in univariate (P = .015) and multivariate analyses (P = .033; 96.4% vs 90.1% at 10 years). CONCLUSIONS In the current era of immunosuppression, allocation of kidneys from deceased donors could be performed primarily according to full DR compatibility then to the best A+B matching, affording excellent graft outcome to most recipients.