Sylvie Lavaud

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12‐month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration‐controlled doses or fixed‐dose MMF. A novel Bayesian estimator of MPA AUC based on three‐point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration‐controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration‐controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg•h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg•h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

Virological and histological responses to one year alpha-interferon-2a in hemodialyzed patients with chronic hepatitis C

Background: α-Interferon-2a (IFNα) alone is a therapy of limited proven benefit for non-uremic patients with chronic hepatitis C virus (HCV) infection. In dialyzed patients, such an effect is suggested on small short-term studies without sufficient clinical and virologic follow-up to document any sustained effect. Protocol: Twelve chronically hemodialyzed patients with chronic hepatitis C and waiting for renal transplantation were included in a prospective open study of treatment with IFNα. We used, as did others, doses of 3 million units (MU), three times a week, but for a longer period of treatment of 12 months. Follow-up was continued for 6 months after the end of IFNα in order to document any sustained biochemical, virological and histological responses. Results: Aminotransferase levels returned to the normal range within 1–2 months of treatment in all patients in whom they had been elevated at baseline. At 1 month of treatment, serum HCV-RNA was not detected in 5 (41%) patients and in 9 (75%) at 12 months. A sustained virological response was documented in 4 (33%) patients 6 months after the end of treatment. Relapse occurred in 5 patients within 2 months after IFNα withdrawal. HCV genotype was not predictive of any sustained response. At inclusion, using the histologic Metavir scoring system, half of the patients had low-grade cytolytic activity and none had cirrhosis. After IFNα, liver biopsy specimens were available from 9 patients and showed histologic improvement in 3. IFNα tolerance was poor, inducing a 5% mean weight loss and the acute rejection of two nonfunctioning kidney grafts. Conclusion: This study documents that administration of IFNα at 3 MU three times a week, for 12 months, in hemodialysis patients with chronic hepatitis C was efficient for clearing the serum of HCV-RNA in 75% of the patients. A sustained response was maintained in one third of these patients after cessation of IFNα, and was predicted by the early serum clearance of the virus within the first 2 months of treatment. We confirm that a 12-month treatment period carries a higher sustained response rate than shorter treatment periods. These encouraging results call for larger studies in uremic patients, using IFNα alone or in association with new antiviral drugs.

Long-term follow-up of acute renal failure caused by angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors are useful in the treatment of hypertension and heart failure. However, acute renal failure (ARF) may occur in patients who are taking these drugs in situations associated with decreased glomerular filtration pressure, such as dehydration caused by acute diarrhea or diuretic therapy. Sixty-four patients who were admitted to the intensive care unit for ARF associated with ACE inhibitor therapy were followed for more than 5 years. In this historical retrospective study, we documented that 45 patients were treated for hypertension (group I) and 19 were treated for heart failure (group II). Their mean age was 71.2+/-11.6 years. Patients with ARF presented with overt dehydration in 91% and 84% of the cases in groups I and II, respectively. Hypovolemia was caused by diuretics or gastrointestinal fluid loss. Bilateral artery-renal stenosis or stenosis in a solitary kidney was documented in 22% and 10% of patients in groups I and II, respectively. The probability of survival was 91% and 49% at 1 year and 64% and 18% at 5 years, for groups I and II, respectively. Acute renal failure required hemodialysis in seven patients, but none of them became dialysis dependent. In the subgroup of patients with preexisting chronic renal failure, all the patients except for one who belonged to group II died within 2 years. In both groups, after resolution of ARF, plasma creatinine concentration returned to baseline level and the course of renal function was not significantly worsened. In conclusion, ARF associated with ACE inhibitors is likely to occur in many patients without renal artery stenosis after unexpected dehydration, especially in older patients with congestive heart failure. In both groups of patients, in the absence of preexisting chronic uremia, recovery of renal function occurred without sequelae, even after an episode of acute tubular necrosis requiring dialysis.

Assessment of the heparin-binding AN69 ST hemodialysis membrane: II. Clinical studies without heparin administration.

Binding polyanionic unfractionated heparin over the modified AN69 polyacrylonitrile membrane, the surface electronegativity of which has been neutralized by polyethyleneimine (AN69-ST), renders the membrane more hemocompatible. This property was tested in two groups of long-term hemodialysis patients. Results were rated as massive or partial clotting of a dialyzer at the end of the session. Group I patients were included in a prospective, cross-over study comparing standard dialysis with hemodialysis without systemic administration of unfractionated heparin (n = 12, 123 sessions). In all instances, priming was made with 2 l saline containing 5,000 IU/l heparin. Only patchy or partial clotting was observed in 11% and 39% of the sessions with standard and heparin-free administration, respectively. Group II patients were included in an open, observational pilot study testing the effects of the heparin-coated membrane, without systemic administration of heparin, in patients at high risk of bleeding (n = 68, 331 sessions). Massive clotting was observed in six sessions only (less than 2%) and normal or slightly patchy dialyzers were found in 88% of the sessions. It is concluded that the dialysis AN69 ST membrane, after adequate priming at bedside, can be used without systemic administration of heparin for hemodialysis in patients at high risk of bleeding.

Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies.

The AN69 ST membrane was designed to render the surface of the native polyacrylonitrile polymer less cationic. This was achieved by layering the membrane with the polycationic biopolymer polyethyleneimine. This new membrane is able to bind heparin to its surface, through electrical interactions, without altering the reactivity of the sulfonate groups of the membrane, regularly distributed in the membrane bulk. The kinetics of unfractionated or low-molecular-weight heparins were studied in vitro and in vivo in sheep. Encouraging results were obtained indicating that heparin-coated hemodialyzers are potent anticoagulants. Priming the AN69 ST membrane-equipped hemodialyzer with heparin, as in regular hemodialysis, could allow drastic reduction of heparin consumption in hemodialysis.

Evaluation of sample bias for measuring plasma iohexol clearance in kidney transplantation.

Background. Plasma clearance of iohexol (PCI) is becoming a commonly used standard tool in many clinical trials to evaluate the glomerular filtration rate (GFR). However, most studies performing PCI use only early plasma samples (2, 3, and 4 hr). This study aims to evaluate the role of early and late plasma sampling in the precision of PCI calculation in transplant recipients. Methods. We evaluated 342 renal transplant recipients for both renal clearance (RC) and plasma clearance, using iohexol and six blood samples (2, 3, 4, 5, 6, and 24 hr). Patients were divided into three subgroups according to RC: <30, 30 to 60, and >60 mL/min/1.75 m2. Results. A simplified technique using early plasma samples overestimated GFR with a mean difference between plasma clearance and RC of 53.3%, 25.7%, and 12.5% for the three subgroups, respectively. This difference decreased to 8.8%, 6.3%, and 5.5%, respectively, when the 24-hr sample was included in plasma clearance calculation. Conclusion. These results demonstrate that GFR evaluation by PCI in renal transplant recipients requires a late plasma sample.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended‐criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow‐up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Frequent occurrence of parvovirus B19 DNAemia in the first year after kidney transplantation

Described for the first time in 1986, Parvovirus B19 (B19V) infection in kidney transplant recipients remains little‐known and probably underestimated. The aims of this study were to establish B19V infection frequency during the first year after kidney transplant and to determine predisposing factors and manifestations of the infection in renal transplant recipients. Sixty consecutive adult patients, transplanted less than a year before, were included in this study. B19V and other opportunistic viral infections were detected retrospectively in plasma samples collected every 15 days during the first 3 months and every month from 3 months to 1 year following the kidney transplant. Demographic characteristics, immunosuppressive treatment and biological findings were recorded on each sampling date. Six patients (10%) presented B19V viremia, while eight CMV (13.3%), seven EBV (11.7%), five HHV‐6 (8.3%), five BKV (8.3%), and two adenovirus (3.3%) infections were detected. The mean value of B19V viral load was 149 UI/ml. B19V infections were either reactivation or reinfection due to genotype two in five cases, while one case of primary infection with genotype 1 was observed. Neither risk factors nor biological consequences of B19V infection have been identified. These results rank B19V third among opportunistic viral infections occurring during the first year after a kidney transplant. With regard to this high incidence, and even if the risk factors and biological consequences of the infection should be assessed in larger studies, the question of systematic screening and follow‐up of B19V infection in kidney transplant recipients is relevant. J. Med. Virol. 85: 1115–1121, 2013.

Serum and Tissue Accumulation of Advanced Glycation End-Products Correlates with Vascular Changes.

1. Mamas M, Dunn WB, Neyses L, Goodacre R. The role of metabolites and metabolomics in clinically applicable biomarkers of disease. Arch Toxicol 2011; 85(1):5–17. 2. Kell DB, Brown M, Davey HM, Dunn WB, Spasic I, Oliver SG. Metabolic footprinting and systems biology: the medium is the message. Nature reviews Microbiology 2005; 3(7):557–65. 3. Dunn WB, Summers A, Brown M, Goodacre R, Lambie M, Johnson T, et al. Proof-of-principle study to detect metabolic changes in peritoneal dialysis effluent in patients who develop encapsulating peritoneal sclerosis. Nephrol Dial Transplant 2012; 27(6):2502–10. 4. Kasper DC, Herman J, De Jesus VR, Mechtler TP, Metz TF, Shushan B. The application of multiplexed, multi-dimensional ultra-high-performance liquid chromatography/tandem mass spectrometry to the high-throughput screening of lysosomal storage disorders in newborn dried bloodspots. Rapid Commun Mass Spectrom 2010; 24(7):986–94. 5. Rhee EP, Thadhani R. New insights into uremia-induced alterations in metabolic pathways. Curr Opin Nephrol Hypertens 2011; 20(6):593–8. 6. Schefold JC, Zeden JP, Fotopoulou C, von Haehling S, Pschowski R, Hasper D, et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant 2009; 24(6):1901–8. 7. Pawlak K, Mysliwiec M, Pawlak D. Haemostatic system, biochemical profiles, kynurenines and the prevalence of cardiovascular disease in peritoneally dialyzed patients. Thromb Res 2010; 125(2):e40–5. 8. Kratochwill K, Boehm M, Herzog R, Lichtenauer AM, Salzer E, Lechner M, et al. Alanyl-glutamine dipeptide restores the cytoprotective stress proteome of mesothelial cells exposed to peritoneal dialysis fluids. Nephrol Dial Transplant 2012; 27(3):937–46. doi: 10.3747/pdi.2014.00118

Use of Belatacept as Rescue in Kidney Graft Recipients With Intolerance to Calcineurin Inhibitors: A French Multicenter Report of 36 Cases.: Abstract# B976

B976 Use of Belatacept as Rescue in Kidney Graft Recipients With Intolerance to Calcineurin Inhibitors: A French Multicenter Report of 36 Cases. Y. Le Meur,1 F. Aulagnon,2 D. Bertrand,3 A. Heng,4 S. Lavaud,5 S. Caillard,6 H. Longuet,7 A. Grall,1 C. Legendre.2 1, Brest, France; 2Hopital Necker, Paris; 3, Rouen; 4, Clermont-Ferrand; 5, Reims; 6, Strasbourg; 7, Tours. Belatacept is indicated as an alternative to CNIs in de novo renal transplantation. Because this drug avoids toxicity of CNIs some physicians were tempted to use it as a rescue molecule in case of intolerance to CNIs. We report 36 cases of a switch from CNI to belatacept in 7 transplant centers in France. Patients: We studied 16 male and 20 female (mean age 61 years, 31/36 deceased donors), with low immunological risk. The immunosuppressive regimen included induction therapy (22 anti IL-2R, 12 ATG), CNIs (8 csa, 28 tac), steroids and mycophenolates. 34/36 patients had a graft biopsy before switch. Two groups of patients were identifi ed. In group 1 (G1, n=18, 17/18 Extended Criteria donors) switch was performed early, before 6 months (median date: day 96) and indications were delayed graft function or low GFR; with evidence on the biopsy of vascular lesions of the donor, tubular necrosis and in one case microangiopathy. Two patients were switched for extra indications: one for non compliance and diabetes, one for neurological toxicity. In group 2 (G2, n=18), the switch was performed later (median date: day 500), indication was deteriorating GFR, with FIAT, chronic vascular lesions and suspicion of CNI nephrotoxicity on biopsy . One patient was switched because of pancreatitis due to tac. Belatacept was administrated every two weeks during two months and then monthly. Results: In G1 there is one death and 3 grafts were lost. The remaining grafts are functioning well with a decrease of the mean creatinine level respectively: 303, 164 and 190 μmol/l (p<0.01) before switch, at nadir and at the last visit (median followup: 260 days). In G2, all grafts are functioning with a non signifi cant decrease of the mean creatinine level respectively: 222, 134 and 189 μmol/l before switch, at nadir and at the last visit (median follow-up: 347 days). The 2 cases of non renal toxicities of CNI improved as well. Tolerance of belatacept was good. Overall, only one patient had an acute rejection episode. Six patients had infectious complications : 2 norovirus diarrhoea, 1 pneumonia, 1 cutaneous cellulitis, 1 mycobacterium infection. Conclusions: Use of belatacept as rescue seems promising and improves GFR. In particular, an early switch in patients receiving ECD kidneys and with severe CNI nephrotoxicity could save some grafts. DISCLOSURES: Le Meur, Y.: Other, BMS, speaker fees, Novartis, travel grant and speaker fees, Roche, consulting fees, Genzyme, speaker fees. Legendre, C.: Other, Alexion, travel grant and speker fees, Novartis, travel grant and speker fees. Abstract# B977 Donor Specifi c Antibody (DSA) Formation in Tacrolimus-Based, Mycophenolate vs mTOR Immunosuppression Regimens. Z. Mithani, O. Adebiyi, J. Gralla, P. Klem, J. Cooper, A. Wiseman. Transplant Center, Nephrology, University of Colorado, Aurora, CO. B977 Donor Specifi c Antibody (DSA) Formation in Tacrolimus-Based, Mycophenolate vs mTOR Immunosuppression Regimens. Z. Mithani, O. Adebiyi, J. Gralla, P. Klem, J. Cooper, A. Wiseman. Transplant Center, Nephrology, University of Colorado, Aurora, CO. The infl uence of mTOR inhibition upon DSA formation and later clinical events is controversial, with small reports suggesting a higher rate of DSA with mTOR but experimental data suggesting potential inhibitory signaling pathways. Prior clinical studies did not include regimens with tacrolimus (TAC) and/or prednisone (P) with adequate controls. We compared de novo DSA formation (DSA+) rates between two common immunosuppression regimens (TAC/MPA/P vs. lower exposure TAC/ mTOR/P) and clinical outcomes Methods: 66 kidney and SPK recipients on TAC (lo)/mTOR/P (36 with everolimus, 30 with sirolimus) from hospital discharge were compared in a case-control study to 132 patients on TAC/MPA/P, matched for age, gender, race, and type/timing of transplant from 2007-2012. DSA assessment was performed prospectively at time of transplant and at 1, 6, 12, and 24 months post-transplant using single antigen beads. We compared de novo DSA formation ( ≥500 MFI), proteinuria, GFR and acute rejection (AR) between the two groups. Results: With a mean follow up of 796 days, TAC (lo)/mTOR had a higher proportion DSA+ at all time points but did not meet statistical signifi cance. By one year, DSA+ rates were 35% with TAC (lo)/mTOR vs 28% with TAC/MPA (OR 1.37; 95% CI 0.69-2.75; p= 0.37) There was no signifi cant difference between the two arms when comparing clinical outcomes, including GFR at 12 months, proteinuria at 12 months and AR at 12 months. N Tac at 1y (ng/ml) DSA by 1y DSA overall GFR at 1y (ml/min) Proteinuria at 1y (g/d) Acute Rejection, 1y Tac(lo)/mTOR 66 5.4* (p=0.04) 35% 36% 56.8 0.28 9.1% Tac/MPA 132 6.5 28% 34% 55.7 0.21 11.8% When comparing Sirolimus vs Everolimus, there was no signifi cant difference in DSA formation or clinical outcomes. Neither the type of DSA (class I vs class II) nor strength of DSA (MFI) were signifi cantly different among groups. Comparing those that formed DSA vs those that did not, GFR was not different at 1 year but proteinuria was signifi cantly higher in DSA+ vs DSA(0.35 vs 0.17g/d, p=0.03). Conclusion:In kidney and SPK transplant patients on TAC/prednisone regimens, mTOR inhibition was associated with similar rates of DSA formation compared to MPA. Our study did not demonstrate a difference in GFR, proteinuria or acute rejection at one year between the two arms. mTOR therapy is neither protective nor permissive in DSA formation or downstream clinical surrogates of antibodymediated injury. DISCLOSURES: Wiseman, A.: Other, Novartis, consultant, Tolera, consultant, Astellas, consultant. Abstract# B978 The Safety of Lower Doses of Immunosuppressants in RituximabTreated Kidney Transplantation. C. Baek,1 M. Kim,1 J. Kim,1 W. Yang,1 D. Han,2 S. Park.1 1Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of; 2Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of. Background: Rituximab, an anti-CD20 antibody, effectively depletes B lymphocytes and is used in ABO-incompatible or HLA-sensitized kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressants in rituximab-treated kidney transplantation are appropriate. We studied the safety of lower doses of immunosuppressants in rituximab-treated kidney transplantation. Methods: We previously reported the results of retrospective study that showed serious infectious complications were increased in rituximab-treated kidney transplant recipients. In this study, we prospectively evaluated 72 patients who used lower doses of maintenance immunosuppressants (tacrolimus, mycophenolate mofetil (MMF) and methylprednisolone) compared to previous study as a new protocol (group 1). Sixty-seven patients of study group in the previous report served as control group (group 2). Results: The doses of MMF (in grams/day) at the following times postoperatively were lower in group 1 than in group 2: 1month: 0.95±0.241vs. 1.26±0.42, p = 0.000; 3 months: 0.93±0.30 vs. 1.14±0.51, p = 0.007; 6 months: 0.94±0.26 vs. 1.07±0.50, p = 0.095; 1 year: 0.93±0.28 vs. 0.88±0.52, p = 0.637; 2 years: 1.08±0.20 vs. 0.69±0.55, p = 0.252). The doses of tacrolimus and methylprednisolone were also signifi cantly lower in group 1. Total infection occurred more often in group 2 (29.2% vs. 52.2%, p = 0.006). The incidence of CMV infection was also higher in group 2 (2.8% vs. 16.4%, p = 0.007). One patient of group 1 and 2 patients in group 2 died of infection. The reduction of maintenance immunosuppressants did not increase the incidence of acute rejection in group 1 (4.2% in group 1 vs. 4.5% in group 2, p = 1.000). If patients who died with functioning graft were excluded, graft survival was 100% in group 1 and 98.5% in group 2 (p = 0.482). Serum creatinine levels postoperatively were not higher in group 1 than in group 2. Conclusion: Lower doses of maintenance immunosuppressants reduced the incidence of infection without increasing rejection or graft loss and it might be adequate to reduce the doses of maintenance immunosuppressants in rituximabtreated kidney transplantation. B978 The Safety of Lower Doses of Immunosuppressants in RituximabTreated Kidney Transplantation. C. Baek,1 M. Kim,1 J. Kim,1 W. Yang,1 D. Han,2 S. Park.1 1Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of; 2Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of. Background: Rituximab, an anti-CD20 antibody, effectively depletes B lymphocytes and is used in ABO-incompatible or HLA-sensitized kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressants in rituximab-treated kidney transplantation are appropriate. We studied the safety of lower doses of immunosuppressants in rituximab-treated kidney transplantation. Methods: We previously reported the results of retrospective study that showed serious infectious complications were increased in rituximab-treated kidney transplant recipients. In this study, we prospectively evaluated 72 patients who used lower doses of maintenance immunosuppressants (tacrolimus, mycophenolate mofetil (MMF) and methylprednisolone) compared to previous study as a new protocol (group 1). Sixty-seven patients of study group in the previous report served as control group (group 2). Results: The doses