Mycophenolate Sodium Research Articles

ABO incompatible live donor renal transplant. Study of 48 patients after desensitization

BackgroundUntil recently, ABO-incompatible living donor kidney transplantation was regarded as an absolute contraindication. However, this kind of kidney transplantation has been used in the last years, with good results. Objetive0ur objetive is to show the results obtained with this technique in our hospital. MethodsForty-eight patients with a mean age of 50,9±10,9 years were included. Follow-up 44,6±30,9 months. Conditioning: rituximab 375mg/m², tacrolimus, mycophenolate mofetil or mycophenolate sodium, prednisone, plasmapheresis/immunoadsorption and intravenous immunoglobulin. Accepted IgG and IgM titers for transplantation ≤ 1:8. ResultsPreprocess IgG titer 1:124±1:40, IgM titer 1:77±1:55. After 6±3 sessions, IgG decreased to <1:8 in 47 patients and to <1:16 in one. IgM was < 1:/8 in all cases. Twenty-five patients (50 %) presented hematoma, reintervention in 7 (14.6 %); 29 (60 %) required transfusion. Acute rejection occurred in 5 cases (8.7 % at 5 th year). CMV infection 9 (19,7 % at 5th year), BK viremia 5 (12.4 % at 5th year), post-transplant diabetes in 10 (23.4 % at 5th year), and lymphocele in 3 (6,4 % at 5th year). Patient survival was 97 % at 5th year and graft survival 95,7 % at 1st and 93 % at 5th year. Causes of graft loss: thrombosis (n=1) and mixed rejection (n=1) and death (n=2). Serum creatinine levels were 1.43±0.5mg/dl at 1st and 3rd year and 1,3±0,3mg/dl at 5th year. Proteinuria was 0.2±0.2g/24h at 1st and 5th year. ConclusionsABO incompatible living donor kidney transplantation after conditioning with rituximab, plasmapheresis/immunoadsorption and immunoglobulins is a valid option offering excellent outcomes.as survival and acute rejections without increasing infectious complications. An increased tendency towards postoperative bleeding is observed.

Prospective study of the changes in pharmacokinetics of immunosuppressive medications after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8kg/m2 with an excess body weight loss of 54.9%. The AUC24 of all drugs were increased after laparoscopic sleeve gastrectomy by 46%, 55%, 77%, and 74%, respectively. The maximum concentrations were increased for tacrolimus, extended-release tacrolimus, and mycophenolate mofetil by 43%, 46%, and 65%. The apparent total clearances were decreased for tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium by 36%, 57%, and 38%. Laparoscopic sleeve gastrectomy can be associated with significant changes in pharmacokinetics of the drugs evaluated. The mechanism is likely decreased apparent drug clearance due to an increased drug exposure (from a more distal site of intestinal absorption with decreased intestinal metabolism), or decreased clearance (liver metabolism). Adapting the monitoring of immunosuppression will be important to avoid overdosing and potential side effects.

Immunotherapies for thyroid eye disease.

Thyroid eye disease is a complex autoimmune disorder which causes substantial morbidity. It can result in orbital disfigurement, double vision, and visual loss. Consequently, it has a substantial negative effect on quality of life, mental health, and socioeconomic status. Most signs and symptoms of thyroid eye disease (TED) can be explained by the expansion of the orbital contents. Steroids are the mainstay of treatment in TED. However, recurrence may occur once steroids are withdrawn. Furthermore, in most cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required to reduce disfigurement, double vision, and to preserve vision. Therefore, novel, causal, and more efficacious treatment strategies are warranted. In the last decade, the pathophysiology of TED has also been revised with the identification of new potential therapeutic targets. Recent clinical trials have shown that considerable benefit may be derived from the addition of antiproliferative agents (e.g., mycophenolate sodium) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab (anti-IGFR) which appears to substantially reduce proptosis, rituximab (anti-CD20) which reduces inflammation and tocilizumab (anti-IL-6) which potentially benefits both of these parameters. This short review summarizes the recent research developments in this area.

La terapia immunosoppressiva nel trapianto di rene

Immunosuppressive therapy in renal transplantation can be distinguished in induction therapy and maintenance therapy. Induction therapy is an intense immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of acute allograft rejection. In general, the induction immunosuppressive strategies used at kidney transplant centers fall into one of these two categories. One strategy relies upon high doses of conventional immunosuppressive agents, while the other utilizes antibodies directed against T-cell antigens in combination with lower doses of conventional agents. Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and loss of the renal allograft. Although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression. The optimal maintenance immunosuppressive therapy in kidney transplantation is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarily oral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (in non-modified or modified [microemulsion] form), Tacrolimus, everolimus, rapamycin (sirolimus), and Belatacept.

La terapia immunosoppressiva nel trapianto di rene

Immunosuppressive therapy in renal transplantation Immunosuppressive therapy in renal transplantation can be distinguished in induction therapy and maintenance therapy. Induction therapy is an intense immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of acute allograft rejection. In general, the induction immunosuppressive strategies used at kidney transplant centers fall into one of these two categories. One strategy relies upon high doses of conventional immunosuppressive agents, while the other utilizes antibodies directed against T-cell antigens in combination with lower doses of conventional agents. Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and loss of the renal allograft. Although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression. The optimal maintenance immunosuppressive therapy in kidney transplantation is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarily oral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (in non-modified or modified [microemulsion] form), Tacrolimus, everolimus, rapamycin (sirolimus), and Belatacept.

Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant

Median survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus. To compare survival between patients receiving sirolimus plus tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival. This cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance. Cell cycle inhibitor maintenance therapies, including sirolimus (n = 219), mycophenolate mofetil (n = 5782), mycophenolate sodium (n = 408), azathioprine (n = 2556), and concurrent sirolimus plus mycophenolate mofetil (n = 54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared. Survival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes. Among this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus plus tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR], 0.71; 95% CI, 0.56-0.89; P = .003). Chronic rejection incidence (aHR, 0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR, 0.52; 95% CI, 0.31-0.81) were lower with sirolimus plus tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR, 1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR, 0.95; 95% CI, 0.77-1.17), and azathioprine plus tacrolimus (aHR, 0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus plus tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR, 0.48; 95% CI, 0.31-0.76; P = .002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]). Sirolimus plus tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus plus tacrolimus was associated with maximal survival.

Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor.

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single-center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR, n=88), or mycophenolate (r-ATG/MPS, n=83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12months. Secondary endpoints included treatment failure [first biopsy-proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06-0.220, P<0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P=0.021), graft loss (11% vs. 1%, P=0.008), death (10% vs. 1%, P=0.013), and treatment discontinuation (40% vs. 28%, P=0.12) were higher in the r-ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r-ATG/EVR (31.8±18.8 vs. 42.6±14.9, P<0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).

Investigation of the Association Between Total and Free Plasma and Saliva Mycophenolic Acid Concentrations Following Administration of Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients.

Mycophenolic acid (MPA) is commonly used following renal transplant. Saliva MPA concentrations may reflect the pharmacologically active form of MPA in plasma. Therapeutic drug monitoring using saliva is convenient and non-invasive. This study examined the correlation between total and free plasma and saliva MPA concentrations following enteric-coated mycophenolate sodium (EC-MS) administration in renal transplant recipients. Total and free plasma and saliva MPA concentrations were measured simultaneously in 20 adult renal transplant recipients 1-2months' post-transplant. Thirteen samples were taken pre-dose and at specified time points up until 12h post-dose. When considering all time points, correlation between total plasma and saliva MPA was r2 = 0.51 and between free plasma and saliva MPA concentrations r2 = 0.41. The correlation between total plasma MPA area under the concentration-time curve (AUC) or free plasma AUC and saliva MPA AUC was r2 = 0.25 and r2 = 0.13, respectively. The correlation between total plasma MPA AUC and total plasma MPA trough (C0) concentrations was r2 = 0.51, and between total plasma MPA AUC and saliva MPA trough concentrations, r2 = 0.03. Measurement of MPA concentration in saliva cannot currently replace plasma measurement for therapeutic drug monitoring of MPA following EC-MS administration. Additional studies are required to examine the relationship between MPA saliva concentrations and patient outcomes.

The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis.

Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.

MON-198 EVALUATION OF CYTOMEGALO VIRUS (CMV) TREATMENT IN KIDNEY TRANSPLATATION: A MULTI-CENTRAL STUDY IN VIET NAM

Cytomegalovirus (CMV) infection is associated with significantly decreased outcomes of kidney transplantation (KTx). To evaluate the effectiveness of CMV prevention and treatment in KTx patients in Viet Nam was the aim of our multicenter study. We conducted a prospective cross-sectional study about prevention and treatment of CMV in 847 patients (pts) from 7 KTx centers in Viet Nam. The immunosuppressive drugs used depend on each center, with Basiliximab for induction, and with Calcineurin inhibitors (tacrolimus or cyclosporine), Antiproliferative agents (mycophenolate mofetil, or mycophenolate sodium or azathioprine), mTOR inhibitor, steroids for maintenance. CMV prevention was taken with either acyclovir (ACY) (dose 200mgx4) or valganciclovir (VALG) (dose 450mg) for the first 100 to 200 days after KTx. CME infection was diagnosed by CMV-DNA, and treated with intravenous ganciclovir (5mg/kg/12h). Ganciclovir, ACY or VALG dose were adjusted to the kidney function. Preemptive therapy was defined as CMV-DNA, when it was switched from negative to positive even if the number of copies was less than 500 (in the time of CMV prophylaxis, but the patient was in the high risk group (D+/R- or after acute rejection treatment progress). 847 KTx patients from 1992 to 2015, were recruited living and deceased donor transplantation. Mean age: 42.5 ± 12.7yo (11yso; 81yso). Male /female: 576/271. 581/847pts (68.60%) received CMV prevention and 266/847 (31.40%) pts didn't received CMV prevention. Of 581 CMV prevention, 28 proceed CMV infection. All of them were on ACY prevention (except 10pts of D-/R- group). 3/28pts died because of late detective of severe pneumonia (table 1). Table 1CMV risk classificationsCMV risk classificationsTotalPrevention (n=581)Infection (n=189)Pre-emptiveDeathACYValGACYValGGanciclovirACYValGD+/R+796493592802830D+/R-198500000D-/R+1710100000D-/R-154100000Total84751566280283/28 (10.71%)0n=847 (%)581/847 (68.60%)28/581 (4.82%)3/581 (0.52%) Open table in a new tab Of 266pts without CMV prevention, 42pts suffered CMV infection, and all received preemptive therapy. 11/42pts died because of severe pneumonia, too. Table 2CMV risk classifications of CMV non- prevention group treatmentCMV risk classificationsTotalCMV non- preventionCMV infectionPre-emptiveDeathD+/R+796244404011D+/R-196000D-/R+176110D-/R-1510110Total84726642/266 (15.76%)4211/42 (26.19%)n=847 (%)84731.404.96 Open table in a new tab In the non- CMV prevention group, the percentage of infection was triple (42/266, 15.76%) than the acyclovir prevention group (3/581 (0.52%)) with p<0.005, (table 1 and 2). Frequency of CMV in the dialysis community is CMV infection of 95.99%. Valganciclovir was highly efficient for CMV prevention than acyclovir. In our study, aciclovir is still effectively, so we must be to follow-up patients carefully and early convert Aciclovir to ValG or Ganciclovir when the CMV-DNA was switched from negative to positive. CMV prophylaxis should recommended for all of patients even the D-/R- group if they were receiving the high level of immunosuppressive drug. In addition, the level of immunosuppressive drugs should be adjusted to suit each individual.

MON-168 A CASE REPORT OF HUMAN PARVOVIRUS B19 INFECTION IN A RENAL TRANSPLANT PATIENT

Anaemia after kidney transplant has been linked to infection by Parvovirus (PV) B19. Organ transplant patients can have the B19 virus persisting for years due to impairment of the neutralizing antibody response and/or cellular immunity. Up to 39% of kidney transplant (KT) recipients suffer from chronic anaemia. They may acquire symptomatic PV B19 infection from the donor, the community or from reactivation of endogenous latent or persistent virus. PV B19 infection in KT recipients tend to occur within a 6-month period after transplantation when the immuno-suppression (IS) is at the strongest. This case report describes a 49 year old Malay lady who has End Stage Renal Disease secondary to Systemic Lupus Erythematosus. She was on haemodialysis for 17 years before a deceased donor renal transplant in November 2017. Thymoglobulin was used as her induction agent and maintained with mycophenolate sodium (Myfortic) at 360 mg bd, tacrolimus and prednisolone. Her tacrolimus level ranges from 8 to 10 ng/ml. Her baseline haemoglobin (Hb) prior to the renal transplant was 9.7 g/dL. Post operation Hb ranging from 8.5 to 9 g/dL. Iron studies showed adequate iron stores with ferritin and transferrin saturation level of 770ug/L and 93% respectively. There was no evidence of hemolysis and the reticulocyte was 0.19%. Subcutaneous(SC) erythropoietin stimulating agent ( ESA) was started 2 weeks post operation to maintain her Hb level. Despite regular SC ESA injection, her Hb level did not improve and dropped 6 weeks after the operation and became pancytopenia. Her serum creatinine was 180 umol/L. SLE activity markers were negative . Pre-transplant immunoglobulin G (IgG) studies showed positivity to Cytomegalovirus (CMV). For the next 4 months, she required 3 to 4 pints of Red Blood Cells (RBC) transfusions monthly. Oesophagogastroduodenoscopy(OGDS) showed gastric erosion only. CMV PCR sent repeatedly were negative. In May 2018, Parvovirus PCR was found to be positive with positive IgG and negative IgM level. Bone marrow aspiration and trephine (BMAT) showed normo-cellular marrow spaces. Granulopoiesis was present with all stages of maturation seen. Megakaryocytes was morphologically unremarkable. Erythropoieisis was preserved. There were a few intranuclear inclusions seen. The intranuclear inclusions were suggestive of Parvovirus infection ( Figure 1). She received intravenous immunoglobulin (IVIg) with 2g/kg in total. Her Hb level was successfully maintained above 10g/dL without further RBC transfusion. WCC and platelet counts also normalized. Her immunosuppression was changed to combination of everolimus, tacrolimus and prednisolone. Parvovirus PCR in June and July 2018 were consequently negative. In October 2018 her Hb level started to drop again. Repeated Parvovirus PCR taken was positive and she was given IVIg again and responded to treatment. She was discharged to her hometown hospital with close monitoring of Parvovirus PCR and Hb level. Figure 1: Intranuclear inclusions in BMAT This case report suggests the importance of including parvovirus B19 infection in the differential diagnosis of persistent anaemia in organ transplant patients and the need to monitor the PCR closely for reactivation and the role of IVIg with reduced IS as part of the management.

Risk Factors Associated With New-Onset Diabetes After Liver Transplant: A Case Control Study

BackgroundNew-onset diabetes after transplant is a severe complication that can present in liver transplant recipients, negatively impacting quality of life and graft survival. It also contributes to increased risk of infection, cardiovascular disease, and rejection, which are the main causes of death among liver transplant recipients. The aim of the present study was to assess the risk factors associated with new-onset diabetes after transplant. MethodThis was a case control study based on the data from 146 liver transplant patients at a reference hospital. The data from the charts were collected using a 2-part form: Part I (sociodemographic variables) and Part II (clinical variables). ResultsMultiple analysis showed that pre-existing systemic arterial hypertension (odds ratio [OR], 2.65; 95% CI, 1.12–6.28) and the use of sodium mycophenolate associated with tacrolimus (OR, 2.68; 95% CI, 1.02–7.06) increased the risk of new-onset diabetes after transplant. On comparing the anthropometric variables, lipid panel, and blood glucose levels of liver transplant patients with and without diabetes, higher glycemic levels were found in the group with diabetes (P < .001). ConclusionPre-existing systemic arterial hypertension and the associated use of sodium mycophenolate and tacrolimus increased the risk of new-onset diabetes after transplant.

Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN).

Background:Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes.Methods:Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8–12 hours on 3 different occasions. Area under the concentration–time curve between 0 and 12 hours (AUC0-12) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC0-12 in the CC group.Results:Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3; P = 0.01) and dose-normalized C0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g; P = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L; P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration–time curve (P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC0-12 (P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of −22.2, 95% confidence interval 0.19 to 0.55; P = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission.Conclusions:CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.

Trasplante renal de donante vivo ABO incompatible. Estudio de 48 pacientes tras desensibilización

BackgroundABO-incompatible living-donor kidney transplantation was regarded as an absolute contraindication. However, it has been carried out for years with good outcomes. ObjectiveOur aim was to show the results obtained with this technique in our hospital. MethodsForty-eight patients with a mean age of 50.9±10.9 years were included. Follow-up was 44.6±30.9 months. Conditioning: rituximab 375mg/m2, tacrolimus, mycophenolate mofetil or mycophenolate sodium, prednisone, plasmapheresis/immunoadsorption and intravenous immunoglobulin. Accepted IgG and IgM titres for transplantation:<1:8. ResultsPre-process IgG titre 1:124±1:140, IgM titre 1:77±1:55. After 6±3 sessions, IgG decreased to<1:8 in 47 patients and to<1:16 in one. IgM was<1:8 in all cases. Twenty-four patients (50%) had haematoma, 7 re-intervention (14.6%), 29 (60%) required transfusion. At 5 years, acute rejection had occurred in 5 cases (8.7%), CMV infection in 9 (19.7%), BK viraemia in 5 (12.4%), post-transplant diabetes in 10 (23.4%) and lymphocele in 3 (6.4%). Patient survival was 97.1% at 5 years and graft survival 95.7% at one year and 93% at 5 years. Causes of graft loss: thrombosis (n=1); mixed rejection (n=1); and death (n=2). Serum creatinine levels were 1.4±0.4mg/dl at one and 3 years and 1.3±0.3mg/dl at 5 years. Proteinuria was 0.2±0.2g/24h at one, 3 and 5 years. ConclusionsABO-incompatible living-donor kidney transplantation after conditioning with rituximab, plasmapheresis/immunoadsorption and immunoglobulins is a valid option offering excellent outcomes. There is a low incidence of acute rejection and no increase in infectious complications. An increased tendency for postoperative bleeding was found.

Efficacy and Safety of a Quadruple Regimen in Patients with Gastrointestinal Complications after Renal Transplantation

Objectives: The aim of this study was to evaluate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids compared with regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after kidney transplantation. Methods: Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplantations with MPA-related GI complications were enrolled in a single-center, prospective study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group. Thirty-seven recipients were assigned to the low-dose EC-MPS group, and thirty-nine recipients were assigned to the standard-dose MZR group. The three groups were compared with the Gastrointestinal Symptom Rating Scale (GSRS), graft rejection, human leukocyte antigen (HLA) antibody, serum creatinine levels, estimated glomerular filtration rate (eGFR), and incidence of adverse effects. Results: A significant improvement in GI symptoms was observed in all three groups compared with baseline. Renal function was better in the low-dose EC-MPS plus low-dose MZR group. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection with the incidence of hyperuricemia were all significantly lower in the low-dose EC-MPS plus low-dose MZR group. Conclusions: The quadruple regimen may be not only equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplantation but also advantageous for renal function, graft rejection rates, and the incidence of adverse effects. Funding: This study was funded by the Provincial Key Technologies R & D Program of Shandong Province (Grant No. 26010104011025), National Natural Science Foundation of China (Grant No. 81600092), Key Research and Development Plan of Shandong Province (Grant No. 2017GSF218003). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Patients gave their informed consent to be in the study, and the study protocol was approved by the ethics committee of Qilu Hospital of Shandong University, China (2016Qilu Hospital of Shandong University IRB Approval No. 2016041).

259-LB: Stable Graft Function and Glycemic Control after Clinical Islet Transplantation on the Omentum

We have shown safety and efficacy of islet transplantation (ITx) in the omentum using a biological scaffold in 3 subjects with type 1 diabetes (T1D). Two subjects (#1 and #3) achieved primary outcome at 1 year (A1c ≤6.5%; No severe hypoglycemia). Subject 1 developed progressive decline in C-peptide after 15 months likely attributed to change in immunosuppression. Subject 3 has had stable graft function for over 2 years. We report on 18 month follow-up data for subject 3. A 46 y/o woman with T1D of 26 years duration underwent single ITx on the omentum (12,648 IEQ/Kg) using a biologic scaffold under ATG induction and combination mycophenolate sodium and tacrolimus maintenance. Pre-ITx insulin dose was 0.45 units/Kg/day and A1c 6.3%. At 18 months, 90 min C-peptide was 1.49 ng/mL, A1c 5.7%, and insulin dose 0.18 units/Kg/day; 14-day continuous glucose monitoring (Guardian Sensor 3, Medtronic) showed glucose 109±28mg/dL (mean±SD), 92% time in glucose range 70-180 mg/dL, 6% time in &amp;lt;70mg/dL, and 0% time in &amp;lt;54 mg/dL. Mixed meal tolerance test data is shown in Table 1. Decline in BETA-2 score was observed by 1 year followed by stabilization. ITx resulted in stable graft function, excellent glycemic control, minimal glycemic variability, and reduction in hypoglycemia over 2 years. Strategies to improve oxygen delivery and neo-vascularization and minimize immunosuppression are needed to improve long-term outcomes at this site. Disclosure D. Baidal: None. D.M. Berman: None. C. Ricordi: Advisory Panel; Self; Zone Labs. A.M. Alvarez Gil: None. N. Padilla: None. G. Ciancio: None. E. Linetsky: None. R. Alejandro: None. Funding JDRF; The Leona M. and Harry B. Helmsley Charitable Trust; Diabetes Research Institute Foundation, State of Florida; University of Miami Clinical and Translational Science Institute; Sanofi Genzyme

Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report

IntroductionThe immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL. MethodsImmunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function. ResultsThe kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment. ConclusionEarly detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post-Renal Transplant.

Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration-time curve from 0 to 12hours (AUC0-12h ) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC0-12h was 1.70-fold greater with tacrolimus (68.9±30.9mg·h/L) relative to cyclosporine (40.8±17.6mg·h/L); P<.001. Target mycophenolic acid AUC0-12h of 30-60mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P<.001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6±4.7L/h) relative to cyclosporine (20.5±10.0L/h); P<.001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P<0.001; with a 2.9-fold greater mycophenolic acid glucuronide AUC0-12h to mycophenolic acid AUC0-12h ratio (P<.001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2-fold higher with tacrolimus (P<.001) and more prominent in women (P=.017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P<0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post-renal transplant, which could be attributed to differences in enterohepatic circulation.

Evaluation of Renin Angiotensin System (RAS) in Renal Transplant Patients

Kidney transplantation is a surgical process that involves swapping the diseased kidney for a healthy kidney. In Brazil, about 5500 transplants per year are performed. After the transplantation process, the patients started to use immunosuppression therapy for acute rejection prophylaxis. There are two immunosuppressants that are most commonly used, Everolimus, Tacrolimus and Sodium Mycophenolate. Current immunosuppressive regimens are effective in preventing acute rejection but have several adverse events. Among them, hypertension and diabetes probably occurred due to an imbalance in RAS. In view of the above observations, the objective of this study was to verify the expression of the proteins and peptides of the RAS, in order to understand if there were changes in the modulation of the same. Two groups of patients, diabetics (n=10) and non‐diabetics (n=10), all with the underlying disease, hypertension, were analyzed. For this purpose, patients were collected at different times after transplantation: seven days (D7), fourteen days (D14), one month (M1), two months (M2), three months (M3), four months M4), five months (M5) and six months (M6). Patient plasma was prepared separately for albumin removal, and subjected to HiScreen Blue FF (GE Healthcare) (1 × 4.7 ml) affinity column chromatography coupled to Akta FPLC system and equilibrated with 50 mM Monopotassium Phosphate buffer, pH 7.0, under flow rate of 1.0 mL/min. The purification of the samples analyzed for one patient is in the table above.Purified plasma in different times was submitted to western blotting in order to demonstrate the expression of angiotensin converting enzyme (ACE). In the table above, we can see that the ACE expression increased gradually in the times of D7 to M6, coinciding with the detection of more pronounced hypertension in this patient (M6). This pilot study suggests that the healthy kidney is likely to be physiologically modified as a result of medications received by the patient, immunological modulations, leading to hypertension and that RAS is involved in this profile.Support or Funding InformationCAPES and CNPq Purification Sample (days) D7 D14 M1 M2 M3 M4 M5 M6 Times (x) 15,65 12,40 15,40 12,87 14,32 16,55 10,72 17,30 Protein Expression (Arbitrary Units) Expression ACE 190 0,933 1,119 1,390 2,483 2,630 2,517 2,545 4,755 90 0,846 1,200 1,183 1,587 1,839 2,167 2,310 3,158 65 1,625 1,376 1,246 1,420 1,702 1,775 1,687 2,047 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Secular Trends in the Cost of Immunosuppressants after Solid Organ Transplantation in the United States.

Immunosuppressive medications are critical for maintenance of graft function in transplant recipients but can represent a substantial financial burden to patients and their insurance carriers. To determine whether availability of generic immunosuppressive medications starting in 2009 may have alleviated some of that burden, we used Medicare Part D prescription drug events between 2008 and 2013 to estimate the average annualized per-patient payments made by patients and Medicare in a large national sample of kidney, liver, and heart transplant recipients. Repeated measures linear regression was used to determine changes in payments over the study period. Medicare Part D payments for two commonly used immunosuppressive medications, tacrolimus and mycophenolic acid (including mycophenolate mofetil and mycophenolate sodium), decreased overall by 48%-67% across organs and drugs from 2008 to 2013, reflecting decreasing payments for brand and generic tacrolimus (21%-54%), and generic mycophenolate (72%-74%). Low-income subsidy payments, which are additional payments made under Medicare Part D, also decreased during the study period. Out-of-pocket payments by patients who did not receive the low-income subsidy decreased by more than those who did receive the low-income subsidy (63%-79% versus 24%-44%). The decline in payments by Medicare Part D and by transplant recipients for tacrolimus and mycophenolate between 2008 and 2013 suggests that the introduction of generic immunosuppressants during this period has resulted in substantial cost savings to Medicare and to patients, largely reflecting the transition from brand to generic products.