Search

• In a real-world experience, mycophenolate mofetil (MMF) dose reduction is common in the first year after kidney transplantation. • Viral reactivation and medication related side effects are common causes for physician-directed MMF dose reduction. • Physician-directed MMF dose was not associated with increased risk of rejection or allograft inflammation in the first post-kidney transplant year. • DSA formation at 1-year was comparable between those on low dose and those on standard dose MMF. • Long-term death censored graft survival and patient survival were comparable between standard MMF dose and physician-directed MMF dose reduction. Mycophenolate mofetil (MMF) dose is commonly reduced after kidney transplantation (KT). This study examined MMF dosing in the first 5 years after KT to determine if a lower MMF dose impacted outcomes. We retrospectively studied 432 recipients who underwent KT between February 2012 and February 2015 in 3 centers. Induction was with IL-2 receptor blocker (23%) or depleting antibody (67%) and maintenance was with calcineurin inhibitor, MMF 1.5 to 2g/day and in 70% prednisone. MMF dose was reduced within the first post-KT year as clinically indicated or for elevated mycophenolic acid (MPA) levels. All 432 patients underwent 1-year protocol biopsy. Donor-specific antibodies (DSAs) were assessed at 1 year. At 1 year, 219 KT recipients (51%) received standard MMF (> 1 g/day) and 213 (49%) received low MMF (≤ 1 gr/d). Low MMF was for clinical indication (49%) or elevated MPA level (51%). At 1 year, there was no difference in rejection rate, type and degree of rejection, degree of inflammation, or DSA formation between the low and standard MMF groups (P = not significant [NS]). The reason for MMF dose reduction did not impact outcome. By 5 years, 69% of the KT recipients were on ≤ 1 g/d MMF. The 5-year patient and death-censored graft survival were comparable between the low and standard MMF groups. Almost 50% of KT recipients were on low dose MMF at 1 year and this percentage increased by 5 years. We did not observe a difference in outcomes between those on standard or low MMF dose regardless of the reason for dose reduction. Physician-directed MMF dose-reduction may be safe but randomized studies are needed to validate this finding. [ABSTRACT FROM AUTHOR]

• Eleven UGT SNP loci were simultaneously assessed and a comprehensive analysis of their effects conducted, along with clinical factors, on mycophenolic acid metabolism. • Patients who carry the UGT1A9 rs2741049 TT genotype might be at a greater risk of a lower dose-adjusted MPAG C 0. • UGT2B7 rs7662029 GG genotype carriers may face a higher risk of AcMPAG C 0 after high-dose adjustment. This study aimed to evaluate the effects of UDP-glucuronosyltransferase (UGT) polymorphisms on mycophenolic acid (MPA) metabolism in renal transplant patients. A total of 11 single nucleotide polymorphisms (SNPs) of UGT1A1, UGT1A7, UGT1A8, UGT1A9, UGT1A10 , and UGT2B7 were genotyped in 79 renal transplant patients. The associations of SNPs and clinical factors with dose-adjusted MPA area under the plasma concentration-time curve (AUC/D), the dose-adjusted plasma concentration (C 0 /D) of 7-O-MPA-glucuronide (MPAG), and the dose-adjusted plasma concentration (C 0 /D) of acyl MPAG (AcMPAG) were analyzed. In the univariate analysis, UGT1A1 rs4148323, age, and anion gap were associated with MPA AUC/D. MPA AUC/D was higher in patients with the GA genotype of UGT1A1 rs4148323 compared to patients with the GG genotype. UGT1A1 rs4148323, UGT1A9 rs2741049 and clinical factors, including age, serum total bilirubin, adenosine deaminase, anion gap, urea, and creatinine, were associated with MPAG C 0 /D. UGT2B7 rs7438135, UGT2B7 rs7439366, and UGT2B7 rs7662029 also were associated with AcMPAG C 0 /D. Multiple linear regression analysis showed that UGT1A9 rs2741049 and indirect bilirubin were negatively correlated with MPAG C 0 /D (P =.001; P =.039), and UGT2B7 rs7662029 was positively correlated with AcMPAG C 0 /D (P =.008). This study demonstrates a significant influence of UGT1A9 rs2741049 and UGT2B7 rs7662029 polymorphisms on the metabolism of MPA in vivo. [ABSTRACT FROM AUTHOR]

• This study evaluated the efficacy and safety of mycophenolate mofetil associated with tacrolimus in patients undergoing kidney-pancreas and kidney transplants. • The main adverse events are infection, anemia, leukopenia, nausea, and diarrhea. • Tacrolimus monotherapy and mizoribine may be associated with a lower risk of infections. This study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. A systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. Thirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). Gastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections. [ABSTRACT FROM AUTHOR]

To describe and establish the efficacy and safety of Mycophenolate Mofetil (Micoflavin) in patients with de novo renal transplantation during one-year post-transplant follow-up. As secondary objectives, the behavior of mycophenolic acid (MPA) C0 levels in this population, the relationship between MPA levels and renal function of the grafts, the incidence of acute rejection, and the incidence of adverse effects were evaluated. A prospective cohort study was conducted on patients who received a first kidney transplant from a deceased donor between March 1, 2021, and February 28, 2022, at the Alma Mater of Antioquia Hospital of the Antioquia's University, in Medellín, Colombia. MPA C0 levels were taken from the patients on days 15, 30, 90, 180, and 360 after the kidney transplantation. Patients presented MPA therapeutic levels in the study. The average of the MPA levels in the population was 2.5 µg/mL, with an IQR of 2.13 to 3.32. There were 5 acute rejections (27%), but none of the patients with acute rejection presented subtherapeutic levels of mycophenolate. No significant relationship was observed between mycophenolic acid levels and rejection (P =.255). The patients who completed the study had no gastrointestinal intolerance to mycophenolate, cytomegalovirus infections, or significant hematological complications. MMF (Micoflavin) maintained mycophenolic acid levels C0 within the therapeutic range, was well tolerated and without the presence of significant adverse events, and maintained stable renal function throughout the follow-up period in the population studied. [ABSTRACT FROM AUTHOR]

• Chronic pain treatment in patients with end-stage kidney disease is complex and still a challenging task in clinical practice. • The benefit of using cannabidiol in the treatment of chronic pain has been reported recently. • Cannabidiol is metabolized by cytochrome P450 and UDP-glucuronosyltransferase enzymes, and it can also act either as an inhibitor or an inducer of these enzymes. • Cannabidiol was also found to be a potent inhibitor of carboxylesterases in vitro. • This case report shows cannabidiol's impact on cyclosporine and mycophenolate mofetil metabolism in a patient with end-stage kidney disease with kidney transplantation. [Display omitted] Kidney transplantation remains the optimal therapy for many patients with end-stage kidney disease (ESKD). Chronic pain is one of the most common and distressing symptoms among patients with ESKD, and its treatment is a complex and challenging task to accomplish. The benefits of cannabidiol (CBD) in chronic pain treatment have been reported recently. Cannabidiol is metabolized by cytochrome P450, mainly CYP3A4 and CYP2C19, and can also undergo direct conjugation via UDP-glucuronosyltransferase enzymes, with a growing body of evidence suggesting it is also a potent inhibitor or inducer of these pathways. Cannabidiol was also found to be a potent inhibitor of carboxylesterases in vitro. Because cytochrome P450 enzymes and carboxylesterases are also responsible for the clearance and activation of immunosuppressants, respectively, drug-drug interactions are likely to occur. Here, we report a pharmacokinetic drug interaction between CBD and cyclosporine and mycophenolate mofetil in a patient with ESKD with a kidney transplantation. It is thus crucial to take into account these interactions and monitor drug levels to avoid drug toxicity or a lack of efficacy. This study is in accordance with the guidelines of the Declaration of Helsinki and the Declaration of Istanbul. [ABSTRACT FROM AUTHOR]

• Tacrolimus and corticosteroid combined with or without mycophenolate mofetil were evaluated. • Biopsy proven acute cellular rejection (Risk Analysis Index score ≥4) incidence was 3.4% in the full-analysis set study group (not in the control group). • Biopsy proven acute cellular rejection, hepatitis B virus recurrence, mortality, or graft failure were not overserved in the per-protocol set. • No significant differences in serious adverse events between the study and control groups were found. • The triple-drug regimen is safe and effective in living donor liver transplantation patients with hepatitis B virus. Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell + My-rept + corticosteroid) and the control group (dual-drug regimen: TacroBell + corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P =.468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P =.376). Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV. [ABSTRACT FROM AUTHOR]

The COVID-19 vaccine will be safe and effective in solid organ transplant recipients (SOTs). However, the blunted antibody responses were also of concern. Few studies have reported prolonged serologic follow-up after 2 doses of BNT162b2 vaccine in SOTs. We performed a single-center, prospective observational study of 78 SOTs who received 2 doses of BNT162b2 vaccine. We identified the trajectory of antibody titers after vaccination among SOTs with or without mycophenolate mofetil (MMF) or withdrawn from MMF. We found low seroconversion rates (29/42: 69%) and low antibody titers in SOTs treated with MMF. An inverse linear relationship between neutralizing antibody titers and MMF concentration was confirmed in restricted cubic spline plots (P for effect <.01, P for nonlinearity =.08). For the trajectory of antibody responses, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at the first visit after 2 doses of vaccine (P for effect <.01, P for nonlinearity <.05, and P for interaction <.01). We identified increased B-cell counts after withdrawal from MMF (P <.01). The recovery of antibody responses was seen in SOTs withdrawn from MMF. The trajectories of antibody responses were modified by MMF administration. [ABSTRACT FROM AUTHOR]

• A rare case of disseminated angiosarcoma early after kidney transplant. • The resolution of metastatic disease with sirolimus monotherapy is remarkable • The patient has a functional graft and is clinically cancer-free after 16 months. Angiosarcoma is a rare, almost universally fatal malignant neoplasm in kidney transplant recipients. No evidence-based guidelines are available for disseminated disease. Here, we report a case of a 66-year-old woman who developed disseminated angiosarcoma 4 months after living nonrelated kidney transplant. She underwent only 2 rounds of chemotherapy because of intolerable adverse effects. Her mycophenolic acid and tacrolimus were withdrawn and sirolimus use was started. In addition to its immunosuppressant effects, sirolimus has been shown to have antineoplastic properties. Remarkably, at almost 2 years post-transplant, the patient has had complete resolution of all gross metastatic disease with only immunosuppressant medication changes. This case highlights the interesting possibility that sirolimus is an effective adjunct treatment for disseminated angiosarcoma in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

• Everolimus (EVR) had virtually no influence on area under the concentration-time curve for MPA from 0 to 12 hours (MPA-AUC0-12) per dose. • MPA-AUC0-12 per dose did not correlate with EVR-AUC0-12 per dose. • EVR can be safely combined with mycophenolate mofetil after kidney transplantation. Despite a growing need for everolimus (EVR) to reduce calcineurin inhibitor toxicity in kidney transplantation (KTx), the influence of EVR on the pharmacokinetics of mycophenolic acid (MPA), a mycophenolate mofetil (MMF) active metabolite, is obscure, and no suitable limited sampling strategy (LSS) for MPA when EVR is concomitantly present exists. We aimed to investigate the influence of EVR on MPA pharmacokinetics in KTx. This study complied with all principles of the Declaration of Helsinki. Twenty patients were initially administered tacrolimus, MMF, and methylprednisolone and then received EVR 4 months after KTx. Approximately 4 weeks before and after EVR administration, the estimated value of the area under the concentration-time curve for MPA from 0 to 12 hours (MPA-AUC0-12) was calculated using MPA blood concentration just before and 1, 2, 4, and 6 hours after MMF administration. We compared several MPA pharmacokinetics parameters before and after EVR addition and determined the best estimation equation for LSS of MPA-AUC0-12. Although MPA-C6 per dose (MPA-C6/D) significantly decreased after EVR addition (from 3.4 [±2.2] ng/mL/g to 2.5 [±0.9] ng/mL/g), MPA-C0/D, -C1/D, -C2/D, -C4/D, and MPA-AUC0-12/D showed no significant change. MPA-AUC0-12/D did not correlate with EVR-AUC0-12/D. The best estimation equation for LSS of MPA-AUC0-12 by 2 time points was [(2.94 × C2) + (5.09 × C4) + 5.32] (R 2 = 0.73) and [(5.70 × C0) + (1.39 × C1) + 22.45] (R 2 = 0.72) before and after EVR addition, respectively. EVR can be safely combined with MMF after KTx once our results have been reevaluated. [ABSTRACT FROM AUTHOR]

• For ABO-incompatible kidney transplant recipients, is everolimus with reduced-dose tacrolimus regimen an acceptable regimen compared with mycophenolate mofetil with standard-dose tacrolimus? • We carried out a retrospective single-center cohort study with 1-year follow-up. • There were no significant differences between the 2 regimens. One of the major barriers for long-term renal graft survival is considered to be calcineurin inhibitor nephrotoxicity, contributing to chronic graft dysfunction. Thus, recent immunosuppressive strategies are focused on regimens that can reduce or avoid exposure to calcineurin inhibitors. Herein, we carried out a small-scale pilot study to assess whether everolimus (EVR) with reduced-dose tacrolimus (Tac) is an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant compared with mycophenolate mofetil (MMF) with standard-dose Tac. This retrospective single-center cohort study included patients who underwent ABO-incompatible kidney transplant at our institution between January 2016 and December 2019. Those whose immunosuppressive regimen was changed by reasons other than rejection during the 1-year follow-up period were excluded. A total of 24 patients were enrolled in this study: 10 patients who received an EVR with reduced-dose Tac regimen and 14 patients who received an MMF with standard-dose Tac regimen. Tac trough levels in the EVR group were significantly lower than those in the MMF group (P <.001). No patients died or lost their grafts during the follow-up period. There were no significant differences in renal function, proteinuria, and prevalence of hyperlipidemia between the 2 groups at 1 year after transplant. There were no significant differences in the incidence of rejection (acute cellular rejection, steroid-resistant acute cellular rejection, acute antibody-mediated rejection) and infection (cytomegalovirus viremia, cytomegalovirus disease, BK viremia, BK virus nephropathy) between the 2 groups. Comparable with MMF with standard-dose Tac, EVR with reduced-dose Tac might be an acceptable immunosuppressive regimen for patients with de novo ABO-incompatible kidney transplant. [ABSTRACT FROM AUTHOR]

The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression. We studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B). We analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P =.003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P =.006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group. The use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients. [ABSTRACT FROM AUTHOR]

Currently, immunosuppression schemes are age-independent; however, physiological changes may alter drugs' pharmacokinetics in the older population. We compared mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) pharmacokinetics among patients aged <60 and >60 years on the seventh day after renal transplantation. We included 7 and 10 renal transplant recipients, aged >60 and <60 years, respectively, treated with mycophenolate mofetil. MPA and MPAG concentrations were determined using the high-performance liquid chromatography method with ultraviolet detection (HPLC-UV). Noncompartmental pharmacokinetic analysis was performed. In patients aged >60 years, mean MPA and MPAG concentrations before the next dose and ratio of MPAG area under the concentration-time curve (AUC 0-12) to MPA AUC 0-12 were higher by 1.6-fold, 1.4-fold, and 1.9-fold, respectively. Other MPAG concentrations appeared to be slightly higher (1.2- to 1.5-fold) in older patients. MPA apparent clearance was similar in both groups, whereas volume of distribution at steady state was slightly higher (1.6-fold) in patients aged >60 years. The variability of most MPA and some MPAG pharmacokinetics was greater in patients aged >60 years. The MPA AUC 0-12 target was achieved in 40% and 14% of patients aged <60 and >60 years, respectively. The highest MPAG concentrations and AUC 0-12 were observed for patients with the lowest glomerular filtration rate. Higher variability of MPA and MPAG pharmacokinetic parameters, MPA AUC 0-12 above the reference range, higher values of MPAG pharmacokinetics in patients with lower glomerular filtration rates, as well as lower proportion of patients achieving MPA targets all indicate the need for therapeutic drug monitoring in renal transplant recipients aged >60 years and to verify target MPA AUC 0-12 for this population. [ABSTRACT FROM AUTHOR]

• A patient may be treated with casirivimab-imdevimab after kidney transplant. • Casirivimab-imdevimab can prevent COVID-19 from becoming severe. • Everolimus may inhibit the spread of the SARS-CoV-2 and prevent its replication. Casirivimab-imdevimab is a cocktail of 2 monoclonal antibodies designed to prevent infection by SARS-CoV-2, the virus that causes COVID-19. Casirivimab-imdevimab has been approved in Japan for treating mild to moderate COVID-19; however, to our knowledge, there are no reports of its use after kidney transplant from a live donor. Everolimus, an antineoplastic chemotherapy drug, is expected to be effective in inhibiting the spread of SARS-CoV-2 and preventing its replication, which may facilitate treatment. Here, we report a case of COVID-19 infection after kidney transplant that was initially treated with casirivimab-imdevimab and mycophenolate mofetil but was later changed to everolimus. A 47-year-old man underwent living donor kidney transplant from his mother in 2017. Immunosuppression therapy was underway through the administration of tacrolimus, mycophenolate mofetil, and methylprednisolone. In early September 2021, he was diagnosed as having COVID-19 and was hospitalized on day 3. On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient started an everolimus regimen on day 5. The clinical course was successful without rejection. There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable. We could safely treat a patient with casirivimab-imdevimab after kidney transplant. It is suggested that casirivimab-imdevimab can prevent COVID-19 from becoming severe and can be administered without worsening renal function. In addition, everolimus may have inhibited the spread of the virus and prevented it from replicating. [ABSTRACT FROM AUTHOR]

Introduction of rituximab in the desensitization protocols for ABO-incompatible (ABOI) kidney transplantation (KTX) has afforded excellent results. However, the acceptability of minimal dosage of rituximab in these protocols remains to be defined. Sixty-three patients who underwent ABOI KTX were included in this study. The desensitization protocol consisted of plasmapheresis, tacrolimus, mycophenolate mofetil, methylprednisolone, intravenous immunoglobulin, basiliximab, and low-dose rituximab (100 mg/body). We evaluated the efficacy, safety, and long-term outcome of this protocol (group R, n = 39) and compared them with those of patients who underwent splenectomy (group S, n = 24). Graft and patient survival at 10 years after KTX were comparable between the groups (94.4% [group R] vs 95.4% [group S] and 94.6% [group R] vs 95.8% [group S], respectively). The incidence of acute antibody-mediated rejection (AAMR) was similar in the 2 groups (10.2% vs 12.5%). There were no significant differences in the incidence of chronic active antibody-mediated rejection. Of the patients, 7 developed AAMR and 3 of these patients (1 in group R and 2 in group S) lost their grafts. There were no significant differences in the incidence of chronic active antibody-mediated rejection. The incidence of postoperative cytomegalovirus infection in group R was significantly lower than that in group S. Furthermore, the incidence of postoperative late-onset neutropenia was low in group R. A low-dose rituximab regimen for ABOI KTX is acceptable for preventing AAMR with a low incidence of delayed adverse events. • Low-dose rituximab regimen for ABO-incompatible kidney transplantation afforded excellent long-term graft and patient survival. • The incidence of rejection associated with ABO-incompatible kidney transplantation was comparable to that associated with the conventional splenectomy regimen. • The incidence of postoperative cytomegalovirus infection associated with ABO-incompatible kidney transplantation was significantly lower than that associated with the conventional splenectomy regimen. • A low incidence of postoperative late-onset neutropenia was observed. [ABSTRACT FROM AUTHOR]

Conversion from calcineurin inhibitor (CNI)-based to belatacept-based immunosuppression has become common; however, numerous protocols have emerged in lieu of a standardized protocol. The purpose of this study was to characterize belatacept conversion protocols from multiple centers and observe outcomes. This was a retrospective study that included Kaiser Permanente Southern California members. The primary outcome was rejection 6 months after conversion and secondary outcomes included change in serum creatinine and graft loss. Seventy-eight patients were included. Thirteen distinct protocols were identified from 8 different transplant centers. Protocols varied by initial dose, induction schedule, and CNI taper. The observed rate of rejection was 6%. There was a trend toward an association of rejection with lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dosing postconversion. Graft survival was 88% and patient survival was 94%. There was a significant improvement in creatinine after conversion. Those with early conversions and creatinine >2.0 mg/dL at the time of conversion had the best response. A large variety of belatacept conversion protocols were identified. Protocols were defined by the initial dose, induction regimen, and CNI taper. Rejection rates were low and may be influenced by exposure to maintenance immunosuppression during and after conversion. Most patients showed stabilization and improvement in creatinine postconversion, with the largest effect in those with an early conversion and serum creatinine >2.0 mg/dL. • A large variety of belatacept conversion protocols are being used and vary by initial belatacept dose, induction frequency, and calcineurin inhibitor (CNI) tapering scheme. • Renal function improved significantly in those without postconversion rejection. On the contrary, those with rejection did not experience an improvement in renal function. • The most robust improvement in kidney function was seen in those converted within 1 year of transplant with a creatinine ≥2.0 mg/dL at the time of conversion. • Lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dose tended to be associated with rejection. • Attention should be paid to CNI tapering regimen, CNI exposure, and maintenance mycophenolic acid dosing during conversion to prevent rejection. [ABSTRACT FROM AUTHOR]

Transplantation of African American (AA) compared to non-AA donor kidneys is generally associated with inferior outcomes. It is unclear whether enhanced genetic risk associated with AA donor kidneys would be counterbalanced by favorable immunologic matching when AA donor kidneys are transplanted into AA recipients. We aimed to compare the outcomes of AA vs non-AA deceased-donor kidneys (DDKs) stratified by kidney donor profile index (KDPI) that were transplanted into AA recipients. Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, we identified AA DDK recipients from 2000 to 2015 who received peri-operative induction followed by calcineurin inhibitor/mycophenolate mofetil maintenance. These patients were divided into 4 KDPI groups (0%-20%, 21%-50%, 51%-85%, and 86%-100%). Adjusted long-term graft and patient outcomes were compared between AA recipients of kidneys from AA vs non-AA donors in each KDPI category using a multivariable Cox model. Among a total of 17,516 AA DDK transplant recipients, 3303 were in KDPI 0%-20% (AA donor = 239; non-AA donor = 3064), 5821 in KDPI 21%-50% (AA donor = 1414; non-AA donor = 4407), 6364 in KDPI 51%-85% (AA donor = 1619; non-AA donor = 4745), and 2028 in KDPI 86%-100% (AA donor = 932; non-AA donor = 1096) groups. Adjusted overall graft, death-censored graft, and patient survival were similar between AA recipients of AA vs non-AA donor kidneys across all KDPI groups. Our study showed similar outcomes for transplanting AA vs non-AA deceased-donor kidneys into AA recipients despite the generally observed inferior outcomes associated with AA donor kidney transplantation. • The study utilized analysis of OPTN/UNOS database. • The study analyzed the outcomes of transplanting kidneys from African American donors to African American recipients. • The study looked at the impact of ethnicity matching on transplant outcomes in African American kidney transplant recipients. [ABSTRACT FROM AUTHOR]

It is still unclear whether mycophenolic acid (MPA) doses should be adjusted for older patients. Therefore, we compared the pharmacokinetics of MPA, mycophenolic acid glucuronide (MPAG), and free MPA (fMPA) between older and younger renal transplant recipients. We included 12 patients <60 years and 6 patients >60 years within the first year after renal transplantation, who were receiving enteric-coated mycophenolate sodium, tacrolimus, and steroids. Blood samples were collected up to 12 hours after drug administration. MPA and fMPA pharmacokinetics were similar for patients <60 and >60 years; however, the MPA area under the concentration-time curve from 0 to 12 hours (AUC 0-12) was 1.2-fold lower in the older patients. MPAG pharmacokinetics were more than 1.5-fold higher in patients >60 years, which might be related to deteriorated renal function in older people. Moreover, the mean (MPAG AUC 0-12)/(MPA AUC 0-12) ratio was more than 2-fold higher in patients >60 years. The second maximal MPA concentration was more frequently observed in patients <60 years, although all patients received tacrolimus. The percentage of patients with MPA concentration before the next drug dose (C trough) and AUC 0-12 within and below target was the same in both groups. All patients >60 years had MPA AUC 0-12 >30 μg·h/mL within 22 to 114 days after transplantation. MPA therapeutic monitoring should be recommended in enteric-coated mycophenolate sodium--treated patients >60 years because MPA AUC 0-12 exceeded the recommended value in half of the studied patients. • Similar mycophenolic acid (MPA) pharmacokinetics were observed for patients <60 and >60 years. • MPA area under the concentration-time curve was 1.2-fold lower in older patients. • MPA glucuronide pharmacokinetics was about 1.5-fold higher in patients >60 years. • A second maximal MPA concentration was more frequent in patients <60 years. • MPA therapeutic monitoring would be useful because the area under the curve was above target in 50% of patients >60 years. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non–Hodgkin lymphoma in the posttransplant setting. Treatment is based on chemotherapy; surgery is still debated and should be performed in very select cases. We observed 2 patients out of 300 who underwent lung transplantation in the Nouvel Hopital Civil between 2013 and 2019 with primary hepatic lymphoma. Chemotherapy with a rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone protocol was performed in all patients. Mycophenolate mofetil was interrupted before treatment, and everolimus was introduced after chemotherapy by associating tacrolimus withdrawal. One patient showed complete remission; after 7 years, no recurrence has been noticed. The second is still undergoing chemotherapy with no signs of disease progression. DLBCL risk is higher in solid organ transplant recipients than in the general population. Primary hepatic lymphoma diagnosis is often difficult and based on histologic findings after initial clinical and radiological suspicion of primary or secondary liver neoplasia. Diagnosis is challenging because no clinical, radiological, or biological features exist. Biopsy is always indicated for histologic confirmation. Chemotherapy is the mainstay of therapy, but surgery may be indicated in very select patients. [ABSTRACT FROM AUTHOR]

Tacrolimus and mycophenolic acid (MPA) are the most important immunosuppressive drugs in modern heart transplantation. The pharmacokinetics of tacrolimus are best described by a 2-compartment model. MPA has very variable pharmacokinetics. The aim of this research was to compare kinetics of the immunosuppressants' blood levels in a group of patients with and without graft rejection. The study was a retrospective analysis of 39 consecutive adult orthotopic heart transplantations (OHT): 10 (9 men and 1 woman) in group R had graft rejection (ISHLT >2) in the first biopsy and 29 (22 men and 7 women) in group C were without rejection. Ischemic cardiomyopathy occurred in 2 of 7 and nonischemic cardiomyopathy in 8 of 22 (group R and group C, respectively). Patients did not differ between groups except diabetes, which occurred more often in group R. Immunosuppressive drug levels were: group R and group C, respectively, 2.13 ± 0.49 and 2.11 ± 0.72 μg/mL; P =.93 for mycophenolate mofetil (MMF) and 9.42 ± 1.76 and 9.63 ± 2.30 ng/mL; P =.75 for tacrolimus. ICU stay was 14 ± 11 vs 15 ± 15 days; P =.76. There were 2 of 6 primary graft failures, 1 of 1 neurologic complications, and 0 of 6 reoperations (P <.05) in group R and group C, respectively. One patient died from group C in 30 days. During the hospital stay the incidence of graft rejection was diagnosed in 20 patients (16men and 4 women) (ISHLT >2 in endomyocardial biopsy) in the study population. Monitoring of tacrolimus concentration in the early post--heart transplant period does not identify patients with rejection in the authors' study. Monitoring concentration of MMF does not identify patients with rejection. Further investigation is needed to evaluate factors responsible for post--heart transplant rejection in the early phase. • Tacrolimus and mycophenolic acid blood concentrations do not preclude cellular rejection in the early postoperative period after heart transplantation. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection (AMR) is related to a poor prognosis in graft survival, with 27% to 40% of patients experiencing graft loss within the first year. The mechanism of damage in AMR is mediated by donor-specific antibodies (DSA). No standard treatment for AMR exists, and conventional management includes high doses of steroids, plasmapheresis, intravenous immunoglobulin, and either rituximab or bortezomib. Because of the high cost of these medications and the lack of prospective studies to evaluate their efficacy and safety, their routine use is limited. In the following study, we describe the use of bortezomib for the treatment of AMR in 5 renal transplant recipients with a 24-month follow-up and compare this case with the reviewed literature. Five cases of AMR diagnosed by biopsy are reported, and these patients received bortezomib at a rate of 1.3 mg/m2 on days 1, 4, 8, and 11; plasmapheresis; and 1 patient received 30 g of intravenous immunoglobulin. All patients received his or her first transplant; 4 were from a cadaveric donor, and 1 patient received thymoglobulin at a standard dose. All patients had maintenance therapy based on cyclosporine, mycophenolate mofetil, and prednisone, with an average baseline creatinine level of 1.3 mg/dL. The average days until rejection event were 952 days. AMR treatment with bortezomib was effective, showing stable renal function at 24 months. Patients had adequate tolerance for administration. So far, these results contrast with the literature reviewed, so additional studies and follow-up are required for a new evaluation. • Antibody-mediated rejection (AMR) is related to a poor prognosis in graft survival. • There is no standard treatment for AMR. • Because of the high cost of medications and the lack of prospective studies to evaluate their efficacy and safety, their routine use is limited. • Bortezomib is an effective and safe medication in the management of AMR. [ABSTRACT FROM AUTHOR]

There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P =.0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P =.0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy. • Replacement of calcineurin inhibitor (CNI) immunosuppressive maintenance regimens with everolimus plus mycophenolate can reduce deterioration of renal function induced by CNIs. • CNI withdrawal in selected patients years after transplantation seems to be safe in terms of late acute rejection and could protect against cardiac allograft vasculopathy. • An everolimus plus mycophenolate immunosuppressive regimen could be effective in reducing negative cardiac remodeling, probably due to different factors. [ABSTRACT FROM AUTHOR]

The lowering of calcineurin inhibitor exposure is possibly considered as the proper strategy to prevent calcineurin inhibitor–induced nephrotoxicity in kidney transplant. This clinical study was designed to compare the efficacy and tolerability of reduced-dose tacrolimus with standard-dose mycophenolate mofetil (MMF) vs standard-dose tacrolimus with reduced-dose MMF. A prospective, multicenter, open-label, randomized, and parallel-group clinical trial was conducted at 4 transplant centers in Korea. A total sample size was 108, and eligible patients were randomly assigned in a 1:1 ratio to either reduced-dose tacrolimus with standard-dose MMF (the study group) or standard-dose tacrolimus with reduced-dose MMF (the control group) for 6 months in de novo kidney transplant recipients. Graft function, the incidence of efficacy failure, and adverse events were compared. The mean estimated glomerular filtration rate at 6 months post-transplantation was 69.83 ± 16.68 mL/min/1.73 m2 in the study group and 69.92 ± 17.55 mL/min/1.73 m2 in the control group (P >.05). The overall incidence of biopsy-proven acute rejection was 3.64% (n = 2) in the study group, compared to 3.77% (n = 2) in the control group (P >.05). There was no graft loss, death, or loss of follow-up in either group. In conclusion, the results suggest that tacrolimus minimization with standard-dose MMF provides adequate immunosuppression with proper renal function and similar rate of incidence of acute rejection compared with the regimen including standard-dose tacrolimus with reduced-dose MMF. [ABSTRACT FROM AUTHOR]

Practically all kidney allograft recipients require immunosuppressive therapy to prevent rejection and loss of the allograft. The aim of this study was to determine the occurrence of biopsy-proven acute rejection in low–immunologic risk kidney transplant recipients according to the type of induction (basiliximab vs low-dose of rabbit antithymocyte globulin [rATG], 3.5 mg/kg). A total of 125 patients after primary kidney transplant were included in the retrospective analysis with 6-month follow-up. The immunosuppression regimen included tacrolimus, mycophenolic acid, and corticoids. We did not find any significant difference in the occurrence of acute rejection or difference in the occurrence of infection complications. Patients in the rATG group had a significantly longer period of cold ischemia, more frequently received kidney transplants from expanded criteria donors, and had significantly more mismatches in HLA-DR. Delayed graft function (DGF) was identified as an independent risk factor for biopsy-proven acute rejection (hazard ratio, 3.4859; P =.003). There was comparable incidence of DGF between the 2 groups despite that there were several factors that are more commonly associated with DGF in the rATG group. Patients with low immunologic risk and high risk of DGF benefit from the rATG induction in dose of 3.5 mg/kg without the increased risk of infection complications with the assumption of good graft function in long-term post-transplant period. • Retrospective analysis compares 2 groups of patients (basiliximab vs low-dose rabbit antithymocyte globulin [rATG]) with low immunologic risk after kidney transplant with 6-month follow-up. • Analysis aimed to determine the occurrence of acute rejection within the monitored period and to identify risk factors for the development of acute rejection in this "nonrisk" group of patients. • Induction with rATG in a dose of 3.5 mg/kg is safe also for this group of patients, it does not represent any increased risk of infectious complications, and it is clearly beneficial for patients with high risk of delayed graft function. • Our analysis even confirmed as much as 2 times higher probability of a good graft function 6 months after transplant in patients with rATG in induction. [ABSTRACT FROM AUTHOR]

Mycophenolic acid (MPA) is one of the main immunosuppressive regimens used after kidney transplantation (KT). The less expensive, generic form of mycophenolate mofetil (MMF) (Immucept®) is recently available in Thailand. Comparisons of the pharmacokinetic profiles between the original and generic forms of MMF among post-KT patients are limited. This prospective cohort study recruited KT patients receiving stable doses of MMF 1000 mg daily along with tacrolimus and steroids. All participants were prescribed CellCept® 500 mg every 12 hours for at least 2 weeks before measuring the MPA area under the curve from 0 to 12 hours (AUC 0-12). CellCept® was switched to Immucept® 500 mg every 12 hours for 2 weeks and MPA AUC 0-12 was remeasured. Twenty patients with a median follow-up time of 35.4 (11.13–198.83) months were enrolled. Mean MPA AUC 0-12 of Immucept® was higher than CellCept® without statistical significance (48.27 ± 2.31 μg⋅hr/mL vs 42.19 ± 15.20 μg⋅hr/mL; P value =.59). No difference was revealed regarding the minimum measured concentration, maximum measured concentration, and time point with maximum concentration between both drugs. While on CellCept®, 5 patients (25%) had an MPA AUC 0-12 < 30.0 μg⋅hr/mL, but 3 patients (15%) had MPA AUC 0-12 < 30.0 μg⋅hr/mL when receiving Immucept®. However, 3 (15%) and 6 (30%) patients had MPA AUC 0-12 > 60.0 μg⋅hr./mL when treated with CellCept® and Immucept®, respectively. Generic MMF exhibited a comparable pharmacodynamic profile as the original formulation. MPA AUC 0-12 was more than 30.0 μg⋅hr/mL among most patients receiving MMF 1000 mg/day. • Less expensive generic mycophenolate mofetil (MMF, Immucept®) provided a comparable mycophenolic acid area under the curve (MPA AUC) as the original formulation. • Target MPA AUC was achieved in most Thai kidney transplant patients receiving mycophenolate mofetil (MMF) 500.0 mg twice daily. • The abbreviated model to predict MPA AUC 0-12 of MMF had high precision. • The use of bioequivalent, generic MMF is economically suitable for a middle- to low-income country. [ABSTRACT FROM AUTHOR]

The most effective immunosuppressant protocol in kidney transplantation (KT) is the combination of a calcineurin inhibitor, steroid, and mycophenolate mofetil (MMF) until now. However, MMF withdrawal (MW) is performed for many reasons, and the clinical course of the KT recipients after MW is not clearly known. The purpose of this study was to investigate the clinical outcomes of KT after MW. We retrospectively analyzed the medical records of 626 KT recipients between 2000 and 2016. We evaluated the incidence of biopsy-proven acute rejection (BPAR), graft and patient survival rates, and risk factors related with graft failure. The proportion of MW was 33.2% (208 of 626 patients). The median time between KT and MW was 6.4 months (range, 3.2–32.1 months). The common causes of MW were infection (70.7%), hematologic abnormalities (9.1%), and gastrointestinal trouble (7.7%). The incidence of BPAR was significantly higher in the MW group compared with the MMF continuation group (27.4% vs 8.9%, respectively, P <.001). Death-censored graft survival and patient survival rates were significantly lower in the MW group compared with the MMF continuation group (P <.001; P <.001, respectively). In the multivariate analysis, BPAR after MW was an independent risk factor for graft failure (hazard ratio 6.058, 95% confidence interval, 3.172–11.569, P <.001). The incidence of rejection, graft failure, and patient mortality in KT were high after MW. Therefore, MW should be considered carefully. • The most common cause of mycophenolate mofetil (MMF) withdrawal was infection. • The rate of cytomegalovirus infection was the highest among all infections. • The incidence of acute rejection was significantly higher in the MMF withdrawal group. • Graft and patient survival were significantly lower in the MMF withdrawal group. • Acute rejection by MMF withdrawal was an independent risk factor for graft failure. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil has improved long-term outcomes of kidney transplantation. However, the impact of mycophenolic acid (MPA) trough level on the development of de novo donor-specific anti-HLA antibody (DSA) is unclear. We examined the relation between MPA trough level and de novo DSA development. We retrospectively studied 617 kidney recipients whose MPA trough level and de novo DSA data were available. All patients underwent primary kidney transplant from living donors from 2008 to 2014, and were chronically treated with a calcineurin inhibitor, mycophenolate mofetil, and +/- steroids. They were equally divided into 4 groups according to the mean trough level of MPA (mMPA) at 1 year post-transplantation: Group 1, mMPA < 2.14 ng/mL (n = 152); Group 2, mMPA 2.14-2.83 ng/mL (n = 157); Group 3, mMPA 2.83-3.57 ng/mL (n = 153); and Group 4, mMPA ≥ 3.57 ng/mL (n = 155). The groups were compared by incidence rate of de novo DSA, graft survival rate, and renal function. The incidence rates of de novo DSA were 33.3% in Group 1, 23.7% in Group 2, 22.9% in Group 3, and 30.3% in Group 4 (P =.158). Although there was no significant difference in graft survival rates, a significant difference of renal functions was noted: the higher the renal function, the lower the MPA trough level. The mMPA trough level at 1 year post-transplantation was not statistically associated with the incidence rate of de novo DSA after kidney transplantation. • There was no significant correlation between the trough level of mycophenolic acid and graft survival rate. • There was no correlation between the trough level of mycophenolic acid and the development of de novo donor specific anti-HLA antibody. • Mycophenolate mofetil administered at a dosage of approximately 1000 mg/d may not pose a serious problem in kidney transplantation even if the trough level of mycophenolic acid is low. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the safety and sustainability of mammalian target of rapamycin inhibitor (m-TORi)-based treatment protocols in renal transplant patients. We retrospectively evaluated a total of 206 patients who were switched to low-dose calcineurin inhibitors (CNI) + m-TORi or mycophenolate mofetil (MMF) + m-TORi treatment protocols in the first 3 months of renal transplantation between January 2010 and August 2011 in our center. Demographic and laboratory features of the patients were recorded. Of the patients included in the study, 89 (43.2%) were female and 117 (56.8%) were male. The mean age was 41.9 ± 13.8 years. Panel reactive antibody was negative in 95% of the recipients. One hundred thirty-four (65%) patients received anti-thymocyte globulin induction therapy. Initially, 108 patients were treated with cyclosporine and 98 (47.6%) were treated with tacrolimus-based regimens. One hundred thirty-five patients (65.5%) were switched to low-dose CNI + m-TORi and 71 patients (34.5%) were switched to MMF + m-TORi. The mean switching time was 3 months. At the end of the study, 161 patients (78.2%) were still continuing the m-TORi treatment protocol and 45 patients (21.8%) could not continue for various reasons (11.4% proteinuria, 5.5% edema, 2.9% acute rejection, 1% acne + oral aphthae, 1% neuropathy). The biopsy-proven acute rejection rate was 4.5% (n = 9). The mean duration of sustainability of m-TORi treatment protocol was 84.15 ± 6.79 months. Mean serum creatinine of patients who were still continuing m-TORi was 1.42 ± 1.09 mg/dL. Switching to m-TORi in the early posttransplant period is a safe and sustainable treatment approach. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) is mainly used in conjunction with calcineurin inhibitors as an additional immunosuppressive for renal sparing after liver transplantation. However, few reports about MMF use in infants after living donor liver transplantation (LDLT) are available. The purpose of this study was to examine the efficacy and safety of MMF in infants. This study enrolled infants younger than 1 year of age who received LDLT at our institution. Patients received oral MMF twice daily. The initial dose was 40 to 50 mg/kg/d, which was increased to a target mycophenolic acid (MPA) trough level of 2 mg/L. Body weight, height, MMF dose, MPA trough level, acute cellular rejection (ACR) episodes, pathologic findings, and adverse effects were analyzed. Allograft fibrosis was graded using the Meta-analysis of Histological Data in Viral Hepatitis score. Patients received MMF for refractory ACR (n = 2), fulminant hepatitis (n = 2), and pre-existing antibodies (n = 1). Original diseases were biliary atresia (n = 3) and fulminant hepatitis (n = 2). Mean age at transplant was 8 months (range 3-10 months). The last available mean trough level was 2.7 mg/L. The mean dose was 66 mg/kg/d or 1429 mg/m2/d at the time of the last available through level. The regression line for MMF dose and MPA trough level was y = 1.8 × 10-3 x. The correlation coefficient was 0.65. All allografts showed F1 to F2 fibrosis. Two patients discontinued MMF because of infection and bone marrow suppression, respectively. Two patients converted to everolimus. One patient continued on MMF. After LDLT, infants require a higher MMF dose than older patients based on trough levels, but allograft fibrosis can progress. • Infants require a higher mycophenolate mofetil (MMF) dose than older patients based on trough levels. • MMF stopped recurrent acute cellular rejection and recurrent fulminant hepatitis. • MMF cannot prevent allograft fibrosis progression. [ABSTRACT FROM AUTHOR]

A 19-year-old Japanese male recipient, who received a living related kidney transplantation from his father at 5 years old, was hospitalized for second renal transplantation from a cadaveric donor. The recipient had had an antibody-mediated rejection (AMR) to the first transplanted kidney. HLA typing of A, B, and DRB showed 2 of 6 mismatches. Lymphocyte cytotoxicity test (LCT) and flow cytometry crossmatches (FCXM) were negative on T cells. Tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab induction were used as the standard immunosuppressive therapy. After second renal transplantation, his serum creatinine level favorably decreased until postoperative day (POD) 7, but his serum creatinine level raised from POD 8. We performed steroid pulse and intravenous immunoglobulin (IVIG). The episode biopsy showed AMR although FCXM and LCT were still negative on T cell. To determine the cause of AMR, we examined LABScreen single antigen test (One Lambda, Canoga Park, Calif., United States), and there was a donor-specific antibody (DSA) that is DQB8 in pre- and post-second renal transplantation. The DSA was suspected de novo DSA for the first transplanted kidney. AMR was successfully treated with plasma exchange, IVIG, and rituximab. [ABSTRACT FROM AUTHOR]

Abstract The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production. Methods A single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and February 2016. Results A total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242). Conclusion The risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects. Highlights • Acute rejection increased risk of posttransplant de novo HLA antibody. • Low-dose CNI therapy tended to increase risk of de novo HLA antibody. • Intensified MPA dosing therapy may prevent de novo HLA antibody production. • Graft loss with immunosuppression withdrawal may cause HLA antibody production. [ABSTRACT FROM AUTHOR]

Background Malnutrition is known to increase morbidity and mortality in renal transplant recipients, whereas little is known about genetic predisposition to low body mass index (BMI) in the transplant setting. Inosine monophosphate dehydrogenase (IMPDH) regulates intracellular fat accumulation, pre-adipicytes maturation, and is a target of mycophenolic acid (MPA) used as a standard immunosuppressant. We hypothesized that MPA may interfere with fat tissue formation and weight gain in kidney transplant recipients and this process may be modified by IMPDH1 or IMPDH2 (genes encoding constitutive and inducible IMPDH) small nucleotide polymorphism variants. Study Design In an observational longitudinal study of kidney transplant recipients treated with mycophenolate mofetil, genetic factors were IMPDH1 (rs2278294, rs2278293) and IMPDH2 (rs11706052) allelic variants, the main outcome was the time-dependent change in BMI, and secondary outcomes were occurrence of BMI below 18.5 or 20 kg/m 2 . Results In a study group of 190 patients, no association was found between BMI changes and rs11706052 and rs2278293 variants. In terms of rs2278294, we found that allele G was associated with significantly slower BMI gain in a dominant model of inheritance. Concerning secondary endpoints, none of the AA carriers were underweight at 6 months post-implantation, while at least 2% of G allele carriers were underweight. From the first post-transplant year, all AA carriers had BMI above 20 kg/m 2 , while among G allele carriers at least 10% had BMI < 20 kg/m 2 by generalized estimating equations. Conclusion Based on our results, we postulate that MPA derivates influence post-transplant BMI and potentially also body fat content. In consequence, genotyping rs2278294 would potentially allow clinicians to personalize MPA treatment. [ABSTRACT FROM AUTHOR]

Background Donor final serum creatinine (SCr) is a dynamic variable and is 1 of 10 factors used in calculating kidney donor profile index (KDPI). We hypothesize that deceased-donor kidneys (DDKs) with higher SCr were likely accepted for transplantation if procurement biopsy findings were favorable and with long-term outcomes no worse than kidneys with lower final SCr within a KDPI group. Methods Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, we identified DDK transplant recipients from 2000 to 2015 who received induction and calcineurin inhibitor/mycophenolate mofetil maintenance. Patients were divided into 4 KDPI groups: 0–20%, 21%–50%, 51%–85%, and >85%. In each KDPI category, long-term outcomes were compared, with the use of Cox models, between patients who received kidneys with final SCr >2 versus ≤2 mg/dL. Results A total of 59,644 patients were divided into KDPI groups 0–20% (SCr >2 mg/dL, n = 478; SCr ≤2 mg/dL, n = 14,769), 21%–50% (SCr >2 mg/dL, n = 1,592; SCr ≤2 mg/dL, n = 17,762), 51%-85% (SCr >2 mg/dL; n = 1,388, SCr ≤2 mg/dL, n = 18,024), and >85% (SCr >2 mg/dL, n = 349; SCr ≤2 mg/dL, n = 5,282). Adjusted overall graft failure risks (hazard ratio [HR] 0.88, P = .04; HR, 0.86, P = .007) and patient death risks (HR, 0.86, P = .04; HR, 0.84, P = .01) for final SCr >2 versus ≤2 mg/dL groups were lower in KDPI categories 21%-50% and 51%-85%, respectively, with similar death-censored graft failure risks. Discussion Outcomes of transplanting DDKs with elevated final SCr are no worse than transplanting kidneys with lower final SCr, highlighting the limitation of the single value of final SCr as a variable for calculating KDPI. [ABSTRACT FROM AUTHOR]

Purpose To assess the pharmacokinetic properties of mycophenolate mofetil (MMF) dispersible tablets and capsules by the enzyme multiplied immunoassay technique (EMIT) in Chinese kidney transplant recipients in the early post-transplantation phase and to develop the equations to predict mycophenolic acid (MPA) area under the 12-hour concentration-time curve (AUC 0-12h ) using a limited sampling strategy (LSS). Methods Forty patients who underwent renal transplantation from brain-dead donors were randomly divided into dispersible tablets (Sai KE Ping; Hangzhou Zhongmei Huadong Pharma) and capsules (Cellcept; Roche Pharma, Why, NSW, Australia) groups, and treated with MMF combined with combination tacrolimus and prednisone as a basic immunosuppressive regimen. Blood samples were collected before treatment (0) and at 0.5,1, 1.5, 2, 4, 6, 8, 10, and 12 hours post-treatment and 7 days after renal transplantation. Plasma MPA concentrations were measured using EMIT. LSS equations were identified using multiple stepwise linear regression analysis. Results The peak concentration ( C max ) in the MMF dispersible tablets (MMFdt) group (7.0 ± 2.8) mg/L was reduced compared with that in the MMF capsules (MMFc) group (10.8 ± 6.2 mg/L; P = .012); time to peak concentration in the MMFdt group was 3.2 ± 2.3 hours, which was nonsignificantly elevated compared with that of the MMFc group (2.2 ± 1.7 hours). Three-point estimation formulas were generated by multiple linear regression for both groups: MPA-AUC MMFdt = 3.542 + 3.332C 0.5h + 1.117C 1.5h + 3.946C 4h (adjusted r 2 = 0.90, P < .001); MPA-AUC MMFc = 8.149 + 1.442C 2h + 1.056C 4h + 7.133C 6h (adjusted r 2 = 0.88, P < .001). Both predicted and measured AUCs showed good consistency. Conclusions After treatment with MMF dispersible tables or MMF capsules, the C max of MPA for the MMFdt group was significantly lower than that of the MMFc group; there was no significant difference in other pharmacokinetic parameters. Three-time point equations can be used as a predictable measure of the AUC 0-12h of MPA. [ABSTRACT FROM AUTHOR]

Background The development of immunosuppressants improved the short-term outcomes of deceased donor kidney transplantation (DDKT), but the long-term survival rate was not improved. Methods The study included 127 patients who received first-time kidneys from deceased donors at Keimyung University Dongsan hospital between October 1994 and June 2007. We analyzed the clinical features of recipients with long-term allograft survival. Results The mean follow-up period was 163 months. Among the 127 recipients, 53 (41.7%) maintained allograft survival for more than 10 years (AS group), 58 (45.7%) lost allograft function (AL group), and 16 (12.6%) were lost to follow-up. The 5- and 10-year allograft survival rates were 84.7% and 65.5%. The 5- and 10-year patient survival rates were 95.9% and 92.5%. The patient survival rate was significantly higher in the AS group than in the AL group. In the AS group, the use of basiliximab and mycophenolate mofetil (MMF) were significantly higher, and the number of HLA-DR mismatches and the incidence of rejection and infection were significantly lower. In multivariate Cox proportional hazards analysis, the use of MMF reduced the risk of allograft loss (hazard ratio [HR], 0.361; 95% confidence interval [CI], 0.172–0.757; P = .007). On the other hand, the incidence of rejection, hepatitis B virus-related liver cirrhosis (HBV-LC), and viral infection were independent risk factors for allograft loss (HR, 5.327; 95% CI, 2.813–10.090; P < .001; HR, 5.862; 95% CI, 1.891–18.168; P = .002; HR, 2.614; 95% CI, 1.355–5.043; P = .004, respectively). Conclusion For long-term survival of allograft kidney in DDKT, it is important to use appropriate immunosuppressants including MMF and prevent complications such as rejection, HBV-LC, and viral infection. [ABSTRACT FROM AUTHOR]

Background Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). Methods Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy-confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). Results Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5–15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). Conclusions Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate-release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.gov NCT00189839 ; NCT00717470 . [ABSTRACT FROM AUTHOR]

Background BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies. Methods We performed a prospective, single-center, randomized, open label pilot trial to evaluate the impact of mycophenolate mofetil (MMF) withdrawal with conversion to the mTORi everolimus versus a 50% reduction of the MMF dose for the treatment of BKV infection after kidney transplantation. Patients maintained on tacrolimus, MMF, and corticosteroids that developed BK viremia or BK viruria ≥1 × 10 6 copies/mL were eligible. The primary endpoint was a >50% reduction of BK viruria or clearance of viremia at 3 months postrandomization. Results Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively ( P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively ( P = .47). Conclusion Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance. [ABSTRACT FROM AUTHOR]

Background IgA nephropathy (IGAN) rarely can present as a crescent and progressive form leading to end-stage renal disease (ESRD) in a short period of time. Recurrence of IGAN after kidney transplantation is frequent, and complement components such as C3, C4d, and C5 seem to be involved. We present a case of a young male patient with ESRD caused by rapidly progressive IGAN and who demonstrated rapid recurrence of crescentic IGAN after kidney donation. Case Report In September 2014, a 28-year-old male patient was hospitalized due to IGAN with 60% of crescents. Cyclophosphamide, steroids, and plasmapheresis did not prevent ESRD. After 8 months of peritoneal dialysis, the patient received a blood group–compatible living donor kidney from his 57-year-old mother. Immunosuppression consisted of tacrolimus, mycophenolic acid, and steroids without induction therapy. Acute graft failure occurred 2 months later, and graft biopsy results revealed recurrence of crescentic IGAN. Cyclophosphamide was added to tacrolimus and steroid treatment, but graft function could not be restored despite viable kidney tissue in repeated biopsy specimens. Rescue therapy with 4 single doses of eculizumab was introduced while hemodialysis had already been initiated. After a cumulative dose of 1800 mg of eculizumab, kidney function did not recover. Conclusions In this case, eculizumab was not effective in treating IGAN recurrence after transplantation. Therapy was started late when hemodialysis had already been initiated; an earlier start of therapy might be more effective. [ABSTRACT FROM AUTHOR]

Background Generic immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). Objective This study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500-mg tablets in liver transplant recipients. Setting The setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. Method A phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. Results All enrolled patients and their liver grafts had survived for 24 weeks post-transplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. Conclusion In conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant. [ABSTRACT FROM AUTHOR]

Background Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. Materials and Methods A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. Results The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups ( P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI ( P < .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group ( P < .05). However, no differences were found according to genotype distribution in all groups ( P > .05). Conclusion Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects. [ABSTRACT FROM AUTHOR]