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Polyarteritis nodosa (PAN) is a medium vessel vasculitis with necrotising vascular changes along with multisystemic involvement. Due to variable initial presentations, diagnosis of systemic PAN in children requires a comprehensive work up. In addition, systemic PAN needs an aggressive therapy. Mycophenolate mofetil is an emerging newer alternative for the treatment of PAN. We report a case of childhood systemic PAN who initially presented with subtle signs like reduced sensation over lateral foot, non-deforming arthritis and multiform rashes. After comprehensive aetiological work up, nerve biopsy and supporting evidence clinched the diagnosis. Vasculitis in children presenting with benign subtle signs is sometimes a diagnostic challenge to clinicians. Our case highlights the importance of lateral thinking while dealing with non-specific multisystemic signs. Evidence of successful treatment of PAN with mycophenolate mofetil is gradually being built up. It is also described to result lower relapse and increased treatment free survival rate.

Background: Volumetric absorptive microsampling may reduce the blood collection burden associated with therapeutic drug monitoring of immunosuppression to prevent organ transplant rejection. This work describes the development of a laboratory and analytical technique for quantifying tacrolimus and mycophenolic acid (MPA) from the Tasso-M20™ in human whole blood using bead-based impact-assisted extraction. Results: The sampled blood volume was accurate with estimated volumes within

To predict mycophenolic acid (MPA) exposure in renal transplant recipients using a deep learning model based on a convolutional neural network with bilateral long short-term memory and attention methods.A total of 172 Chinese renal transplant patients were enrolled in this study. The patients were divided into a training group (n = 138, Ruijin Hospital) and a validation group (n = 34, Zhongshan Hospital). Fourteen days after renal transplantation, rich blood samples were collected 0-12 hours after MPA administration. The plasma concentration of total MPA was measured using an enzyme-multiplied immunoassay technique. A limited sampling strategy based on a convolutional neural network-long short-term memory with attention (CALS) model for the prediction of the area under the concentration curve (AUC) of MPA was established. The established model was verified using the data from the validation group. The model performance was compared with that obtained from multiple linear regression (MLR) and maximum a posteriori (MAP) methods.The MPA AUC 0-12 of the training and validation groups was 54.28 ± 18.42 and 41.25 ± 14.53 µg·ml -1 ·h, respectively. MPA plasma concentration after 2 (C 2 ), 6 (C 6 ), and 8 (C 8 ) hours of administration was the most significant factor for MPA AUC 0-12 . The predictive performance of AUC 0-12 estimated using the CALS model of the validation group was better than the MLR and MAP methods in previous studies (r 2 = 0.71, mean prediction error = 4.79, and mean absolute prediction error = 14.60).The CALS model established in this study was reliable for predicting MPA AUC 0-12 in Chinese renal transplant patients administered mycophenolate mofetil and enteric-coated mycophenolic acid sodium and may have good generalization ability for application in other data sets.

A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR =

We herein report a case of systemic sclerosis (SSc)-related pericarditis successfully treated with mycophenolate mofetil (MMF) and low-dose prednisolone (PSL). The patient was a 72-year-old woman with anti-centromere antibody. Her clinical manifestations were Raynaud phenomenon, bilateral pleural effusion, pericardial effusion and skin tightness. Based on the findings of exudative pericardial effusion with the absence of pulmonary arterial hypertension from the results of the cardiac catheter and pericardiocentesis, she was diagnosed with SSc-related pericarditis and treated with PSL10 mg and MMF 1 g per day, leading to the complete resolution of pericarditis. These findings suggested that MMF and low-dose PSL were effective for SSc-related pericarditis.

Microorganisms are known to produce pharmaceutically important secondary metabolites that are used as drug moieties in the treatment of various disorders. Discovery of one such class of drugs called immunosuppressants led the way for new and improved treatment regimens for the cases of organ rejections as well as for autoimmune diseases. Uncovering the role of these secondary metabolites as immunomodulators had increased their demand in the global drug market. However, this was soon overshadowed by the low amount of product obtained after fermentation and tedious downstream processing for the recovery of product. Hence, continuous efforts are being made to enhance their production by unveiling the basic biosynthetic pathways involved in their synthesis. From unearthing these immunosuppressants to their rapid development towards commercialization, these drugs have gained a significant place in the world market. Hence, the present review is focused on the progress and challenges in the production and downstream processing of different immunosuppressants (tacrolimus, cyclosporine, rapamycin, and mycophenolic acid). This is the first review report on how the market demand of immunosuppressants could be fulfilled by exploring biofoundry approaches to achieve the goal.

Most lung transplantation centers prefer triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. However, to prevent complications and comorbidities caused by tacrolimus, replacing the drug with everolimus has been considered.This is a retrospective observational study investigating everolimus switch for different reasons. The population was divided into 3 groups: chronic lung allograft dysfunction (CLAD), kidney impairment, and malignant neoplasm groups. We investigated whether we achieved the goal of the switch and the frequency of rejection, cytomegalovirus and fungal infections, and everolimus adverse effects.Nineteen patients received everolimus therapy, and 5 of these were for CLAD, 7 for tacrolimus nephrotoxicity, and 7 for explant/de novo malignant neoplasm. The patients were followed up for a mean (SD) of 30 (16.7) months under the therapy. The number of acute cellular rejection, cytomegalovirus infection, and aspergillosis infection cases before switch were 7, 13, and 2, respectively, and 7, 2, and 3 after that. The mean values of creatinine and estimated glomerular filtration rate of the whole population after the switch improved with no statistical significance, whereas it was significant in tacrolimus nephrotoxicity group. Three patients in the CLAD group remained stable after switching, whereas 2 progressed. Only 1 of the 7 patients with malignant neoplasms had a recurrence during 31.1 (16.5) months of median follow-up. Eleven cases of everolimus adverse effects occurred in 9 patients (47.3%), with 2 (10.5%) withdrawal events. Kidney impairment (P = .02) and age (P = .05) stood out as significant risk factors for drug adverse effects.After lung transplant, everolimus can be a safe alternative for immunosuppression with acceptable adverse effects.

Objective. Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods. Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30–60 mg·h/L). Results. A total of 96 pediatric patients aged at 13.3 (range 4.3–18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6–18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22–0.46 m2, 180 mg every 24 hours with BSA of 0.47–0.67 m2, 180 mg every 24 hours with BSA of 0.68–0.96 m2, 360 mg every 24 hours with BSA of 0.97–1.18 m2, 540 mg every 24 hours with BSA of 1.19–1.58 m2, and 360 mg every 12 hours with BSA of 1.59–2.03 m2. Conclusion. BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m 2 is warranted.

The study identified factors affecting anti-S immunoglobulin G production after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in kidney transplant recipients.Serum samples were prospectively collected from kidney transplant recipients, live kidney donors, and healthy volunteers 1 month after receiving the second dose of SARS-CoV-2 vaccine, and anti-S immunoglobulin G titers were measured. The mycophenolate mofetil dose was reduced before vaccination in some immunologically low-risk recipients.A total of 151 kidney transplant recipients, 74 live kidney donors, and 50 healthy volunteers were included. Kidney transplant recipients had significantly lower titers of anti-S immunoglobulin G than donors and healthy volunteers (1377 ± 246, 8310 ± 932, and 9908 ± 1040 AU/ml, respectively). Only 67.3% of kidney transplant recipients, compared to 100% of donors and healthy volunteers, were positive for anti-S immunoglobulin G. Among the kidney transplant recipients, the anti-S titer was higher in younger recipients, those with higher peripheral blood lymphocyte counts and glomerular filtration rates, those without a history of antithymocyte globulin use, and those who had discontinued or received a reduced dose of mycophenolate mofetil. Younger age, higher lymphocyte count, glomerular filtration rate, and mycophenolate reduction were significantly associated with anti-S immunoglobulin G 1000 AU/ml in nominal logistic regression analysis. There were no rejection episodes after mycophenolate modification in kidney transplant recipients.Anti-S immunoglobulin G production after vaccination was attenuated in kidney transplant recipients. Mycophenolate mofetil cessation or reduction is a modifiable means to enhance anti-S immunoglobulin G production in immunosuppressed kidney transplant recipients.

Introduction: The occurrence of simultaneous liver kidney transplantation has greatly increased; however, the ideal induction and maintenance immunosuppression remains unknown. Question: This evaluation aimed to determine if corticosteroid only induction in simultaneous liver kidney transplant recipients provided adequate prophylaxis against rejection when compared to basiliximab. Design: This was a single center, retrospective, cohort study of adult simultaneous liver kidney transplant recipients from June 2010 to June 2019 receiving corticosteroid only (N = 41) or basiliximab (N = 42) induction. Results: Liver or kidney biopsy proven acute rejection at 3 months was comparable between the corticosteroid only and basiliximab groups (10% vs 7%, P = .67), which persisted through 12 months posttransplant (15% vs 21%, P = .42). The occurrence of any infection at 3 months was increased in the corticosteroid only group relative to the basiliximab group (41% vs 21%, P = .049). Graft and patient survival at 12 months were similar between groups. Maintenance immunosuppression was overall minimized with a tacrolimus goal of 6-8 ng/mL, mycophenolate mofetil dose reduction to 1000 mg/day by 3 months, and early steroid withdrawal in both groups. Conclusion: Our findings suggested that corticosteroid only induction was an effective strategy for preventing rejection in simultaneous liver kidney transplant recipients, even in combination with reduced maintenance immunosuppression.

Juvenile localized scleroderma (jLS) is a chronic autoimmune and fibrosing disease associated with a high risk for functional impairment. Antifibrotic options are limited, so current treatment strategies are focused on disease activity control. Pediatric rheumatologists are in consensus on the need to treat with systemic immunosuppressants, in particular, methotrexate. However, more than 30% of patients fail initial methotrexate treatment. This review provides an update on current management and reviews reports on potential alternative treatments.An overview of current treatment recommendations and its efficacy are discussed. Recent studies have identified several factors associated with likelihood of treatment response. These include time to initiation of treatment, certain subtypes, and extracutaneous involvement. Findings from recent reports of alternative systemic immunomodulators, including biologic medications, will be summarized.Methotrexate treatment has greatly improved outcome for most jLS patients but a substantial portion have refractory cutaneous and/or extracutaneous disease. Treatment response factors are being identified, which could lead to improved management strategies. Recent studies provide further support on mycophenolate mofetil as an alternative treatment. Data on biologic therapies is encouraging, with data suggesting efficacy for many extracutaneous manifestations but more studies are needed to evaluate these and other options for jLS.

ObjectiveAlthough systemic lupus erythematosus (SLE) disease activity diminishes after starting dialysis, flares have been documented during dialysis. Hence, we studied the various clinical and therapeutic variables of patients with SLE who had a disease flare while on dialysis.MethodsThe medical records of patients with SLE who received dialysis at 2 tertiary referral hospitals in South Korea were reviewed. The disease activity was analyzed in terms of the nonrenal SLE Disease Activity Index (SLEDAI), and the factors associated with SLE flares were evaluated.ResultsOf the total of 121 patients with SLE on dialysis, 96 (79.3%) were on hemodialysis (HD) and 25 (20.7%) were on peritoneal dialysis (PD). During a median follow-up of 45 months (IQR 23-120) after the initiation of dialysis, 32 (26.4%) patients experienced an SLE flare (HD, n = 25; PD, n = 7). The most common features of SLE flare were hematologic (40.6%; thrombocytopenia [31.2%] and leukopenia [21.8%]) and constitutional manifestations (40.6%). Fever was the most common (34.3%) feature among the constitutional symptoms. Treatments for disease flares were based on corticosteroids, and 11 (34.3%) patients required additional immunosuppressants, including cyclophosphamide and mycophenolate mofetil. Nonrenal SLEDAI score before dialysis initiation (HR 1.24, 95% CI 1.12-1.36; P = 0.001) was a significant risk factor for disease flare during dialysis.ConclusionMore than a quarter of the patients with SLE experienced a disease flare during dialysis, which most commonly had hematologic manifestations, particularly thrombocytopenia. Continued follow-up and appropriate treatments, including immunosuppressants, should be considered for patients with SLE receiving dialysis.

Background: Approximately 20% of all cases systemic lupus erythematous (SLE) are juvenile onset. Children and adolescents with SLE usually present with more severe illness and have a higher mortality rate compared to adults with SLE. Adherence to medications in children and adolescents has a major impact on disease control as well as short- and long-term outcomes. Improved understanding of adherence rates, risk factors for non-adherence, and barriers to adherence are essential in order to increase patient adherence with medication regimens. The aim of our study was to evaluate adherence to medications among children and young adults with pediatric-onset SLE and identify barriers for non-adherence by utilizing several adherence evaluation methods. Methods: Adherence to medications of patients aged 12–25, with childhood-onset SLE was assessed as follows: (1). The brief medication questionnaire (BMQ): self-report tool for screening adherence and barriers to adherence. (2). Mycophenolic acid (MPA) serum level. (3). Medication possession ratio (MPR): data assessing 90-day refills and dispense prior to patient’s enrollment was collected. Results: Of the 38 patients who were enrolled in the study, 65% were found to be non-adherent according to at least 1 measurement method. Forty-four percent of patients were found to be non-adherent based on the self-reported questionnaire (BMQ). Of those taking MMF, 33% had an MPA level < 1 mcg/mL and were defined as non-adherent. Seventeen percent of patients were found to be non-adherent according to pharmacy refills rate. Forty-six percent of patients stated that their medications caused side effects, 33% of patients indicated difficulty remembering to take the medications, and 25% reported difficulty paying for medications. The disease activity index (SLEDAI) score of the “adherent group” at diagnosis was significantly lower compared to the “non-adherent” group. Patients with private insurance had more access barriers to obtaining medications compared to patients with public insurance. Conclusion: Non-adherence to medications is highly prevalent among cSLE patients. Higher SLEDAI score is a risk factor for non-adherence. Adherence to medications should be routinely evaluated among adolescence and young adults with cSLE and barriers to adherence need to be addressed to decrease morbidity and improve patient outcomes.

The comparative safety and efficacy of maintenance mycophenolate mofetil (MMF) and cyclosporine (CYC) following rituximab (RTX) in children with steroid-resistance nephrotic syndrome are uncertain.Multicenter randomized controlled trial.Sixty-six children between 2 and 6 years of age with SRNS.Patients were randomized to receive either MMF 1000 mg/mComplete remission and adverse events (AEs).Complete remission was observed in 26 patients (83.1%) in the MMF group compared with 21 patients (61.7%) in the CYC group (p = 0.02). The median time to remission was shorter in the MMF group than in the CYC group (2.64 vs. 3.4 months; hazard ratio [HR], 0.61; 95% CI, 0.74-0.90, p = 0.03). The median time to first relapse was longer in the MMF group compared with the CYC group (10.8 vs. 8.0 months; HR, 1.12; 95% CI, 1.31-1.54, p = 0.01), and this was significantly correlated with the median time to B-cell recovery in the two groups (8.6 vs. 5.2 months in MMF and CYC, respectively, p = 0.02). The overall incidence of adverse drug events was lower in the MMF group compared with the CYC group (59.3% vs. 76.4%, p = 0.03).MMF-RTX is superior to CYC-RTX in maintaining remission with fewer AEs in children with initial SRNS. Additional high-quality randomized control trials with long-term follow-up are needed to identify the long-term potential complications.

Background. Mizoribine (MZR) is widely used in Asia due to its high safety and low cost, and comparative studies of its safety and efficacy with the first-line drug mycophenolate mofetil (MMF) have been carried out. This paper aimed to compare the efficacy and safety of MZR and MMF in immunosuppressive therapy of renal transplantation by meta-analysis. Methods. We searched randomized controlled trials (RCTs) comparing MZR versus MMF for renal transplantation in PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM). Articles were assessed for their risk of bias using the Cochrane Collaboration. Forest plots and funnel plots were also performed on the included articles. Results. A total of twelve studies with 1103 patients were selected in the analysis. No significant difference were observed between the MZR group and the MMF group for the rate of acute rejection (RR = 1.50, 95% CI 1.11 to 2.01, P = 0.008), patient survival (RR = 1.01, 95% CI 0.99 to 1.03, P = 0.56), graft survival (RR = 1.02, 95% CI 1.00 to 1.04, P = 0.12), leucopenia (RR = 0.69, 95% CI 0.44 to 1.10, P = 0.12), and liver damage (RR = 0.72, 95% CI 0.46 to 1.13, P = 0.15). The MZR group was associated with a lower risk of gastrointestinal disorder (RR = 0.28, 95% CI 0.13 to 0.62, P = 0.002) and cytomegalovirus infection (RR = 0.59, 95% CI 0.42 to 0.84, P = 0.003) but had a higher risk of hyperuricemia (RR 1.79, 95% CI 1.17 to 2.75, P = 0.007). No significant publication bias was observed among included studies. Discussion. MZR is similar to MMF in efficacy, and in terms of safety, MZR has a lower risk of gastrointestinal disorder and cytomegalovirus infection but a higher risk of hyperuricemia.

Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations.Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital.Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ .Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

Publisher Copyright: © 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. Background: Paediatric atopic dermatitis (AD) can be burdensome, affecting mental health and impairing quality of life for children and caregivers. Comprehensive guidelines exist for managing paediatric AD, but practical guidance on using systemic therapy is limited, particularly for new therapies including biologics and Janus kinase (JAK) inhibitors, recently approved for various ages in this indication. Objectives: This expert consensus aimed to provide practical recommendations within this advancing field to enhance clinical decision-making on the use of these and other systemics for children and adolescents aged ≥2 years with moderate-to-severe AD. Methods: Nineteen physicians from Northern Europe were selected for their expertise in managing childhood AD. Using a two-round Delphi process, they reached full or partial consensus on 37 statements. Results: Systemic therapy is recommended for children aged ≥2 years with a clear clinical diagnosis of severe AD and persistent disease uncontrolled after optimizing non-systemic therapy. Systemic therapy should achieve long-term disease control and reduce short-term interventions. Recommended are cyclosporine A for short-term use (all ages) and dupilumab or methotrexate for long-term use (ages ≥6 years). Consensus was not reached on the best long-term systemics for children aged 2–6 years, although new systemic therapies will likely become favourable: New biologics and JAK inhibitors will soon be approved for this age group, and more trial and real-world data will become available. Conclusions: This article makes practical recommendations on the use of systemic AD treatments for children and adolescents, to supplement international and regional guidelines. It considers the systemic medication that was available for children and adolescents with moderate-to-severe AD at the time this consensus project was done: azathioprine, cyclosporine A, dupilumab, methotrexate, mycophenolate mofetil and oral glucocorticosteroids. We focus on the geographically similar Northern European countries, whose healthcare systems, local preferences for AD management and reimbursement structures nonetheless differ significantly.

Mycophenolate mofetil (MMF) is an immunosuppressive drug used for the treatment of autoimmune rheumatological diseases. To test the risk of hypothetical drug-induced hypogammaglobulinemia, the aim of this study was to report the trend of the immunoglobulin (Ig) values and of the infectious diseases in children treated with MMF. This study retrospectively evaluated demographic, clinical, and laboratory data of a cohort of patients affected by a chronic rheumatic disease receiving MMF, followed at the Rheumatology Unit of Meyer Children Hospital, Florence. A total of 29 pediatric patients were enrolled. In patients with normal values of immunoglobulins at the baseline, treatment with MMF resulted in a statistically significant reduction of the IgG levels (p = 0.0058) and in a decrease of IgM levels not reaching statistical significance. The levels of IgA were not affected. During the follow-up, seven patients developed an humoral immune defect. The univariate analysis did not identify any risk factors related to the iatrogenic hypogammaglobulinemia. The infection rate during MMF therapy was significantly higher than the 12-month period before therapy (p = 0.006), while the severe infections did not significantly increase (p = 0.1818), even considering only the patients with hypogammaglobulinemia.In pediatric patients with chronic rheumatic diseases, immunological first level tests and serological analyses to screen the protection against the common childhood pathogens are suggested before starting an immunosuppressive drug. These patients should also complete the vaccination schedule. In patients treated with MMF a strict monitoring of Ig is required during treatment and after discontinuation of the drug.• MMF is an immunosuppressive drug initially used for the treatment of the graft-versus-host disease. • Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase, expressed in lymphocytes; therefore, MMF could impair the immune system function.• MMF resulted in a reduction of IgG and an increase of not severe infection rate. • Immunological first level tests, including Ig, lymphocyte subpopulations, and antibody response to vaccines, are suggested in pediatric patients before starting MMF; a strict monitoring of Ig is important before, during, and after MMF treatment.

Despite being the gold-standard treatment for end-stage heart disease, heart transplantation is associated with acute cardiac rejection within 1 year of transplantation. The continuous application of immunosuppressants may cause side effects such as hepatic and renal toxicity, infection, and malignancy. Developing new pharmaceutical strategies to alleviate acute rejection after heart transplantation effectively and safely is of critical importance. In this study, we performed a murine model of MHC-full mismatch cardiac transplantation and showed that the combination of Rhodosin (Rho) and mycophenolate mofetil (MMF) could prevent acute rejection and oxidative stress injury and prolong the survival time of murine heart transplants. The use of Rho plus MMF in allografts improved the balance of Tregs/Teff cells, which had a protective effect on allotransplantation. We also isolated bone marrow-derived dendritic cells (BMDCs) and determined that Rho inhibited DC maturation by promoting mitochondrial fusion mainly through the mitochondrial fusion-related protein MFN1. Herein, we demonstrated that Rho, an active ingredient isolated from the plant Rhodiola rosea with antioxidant and anti-inflammatory activities, could efficiently alleviate acute rejection and significantly prolong murine heart allograft survival when used with a low dose of MMF. More importantly, we found that Rho restrained DC maturation by promoting mitochondrial fusion and decreasing reactive oxygen species (ROS) levels, which then alleviated acute rejection in murine cardiac transplantation. Interestingly, as a novel immunosuppressant, Rho has almost no side effects compared with other traditional immunosuppressants. Taken together, these results suggest that Rho has good clinical auxiliary applications as an effective immunosuppressant and antioxidant, and this study provides an efficient strategy to overcome the side effects of immunosuppressive agents that are currently used in organ transplantation.

ObjectivesPrevious studies have compared mycophenolate mofetil and azathioprine as maintenance therapy for lupus nephritis (LN). Leflunomide is an immunosuppressant widely used in the treatment of rheumatoid arthritis. The aim of this investigator-initiated study was to compare the efficacy and safety of leflunomide versus azathioprine as maintenance therapy for LN.Methods270 adult patients with biopsy-confirmed active LN from 7 Chinese Rheumatology Centres were enrolled. All patients received induction therapy with 6–9 months of intravenous cyclophosphamide plus glucocorticoids. Patients who achieved complete response (CR) or partial response (PR) were randomised to receive prednisone in combination with leflunomide or azathioprine as maintenance therapy for 36 months. The primary efficacy endpoint was the time to kidney flare. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects.ResultsA total of 215 patients were randomly allocated to the leflunomide group (n=108) and azathioprine group (n=107). Kidney flares were observed in 17 (15.7%) leflunomide-treated patients and 19 (17.8%) azathioprine-treated patients. Time to kidney flare did not statistically differ (leflunomide: 16 months vs azathioprine: 14 months, p=0.676). 24-hour proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly. Extrarenal flare occurred in two patients from the azathioprine group and one patient from the leflunomide group. The incidence of adverse events was similar in the 2 groups: leflunomide 56.5% and azathioprine 58.9%.ConclusionsThe efficacy and safety profile of leflunomide are non-inferior to azathioprine for maintenance therapy of LN. Leflunomide may provide a new candidate for maintenance therapy in patients with LN.Trial registration numberNCT01172002.

Background Coronavirus disease 2019 (COVID-19) infection may become more severe in those who have undergone kidney transplantation than in the general population. False-negative reverse transcription-polymerase chain reaction (RT-PCR) results have been reported for COVID-19 infection. Patients might carry infection even though RT-PCR results are negative. Case report A 65-year-old man with a 19-year history of ABO-incompatible kidney transplantation presented with fever and arthralgia. Although the RT-PCR result was negative, a focal slit-glass shadow in the left upper lobe on computed tomography (CT) suggested COVID-19 pneumonia. His symptoms did not improve until after 10 days, and CT showed multiple slit-glass shadows in the bilateral lung fields. However, RT-PCR remained negative. The patient was admitted, and mycophenolate mofetil was discontinued. Anticoagulants were administered on the third day of hospitalization. Because of poor oxygenation, the patient was intubated in the intensive care unit on the fifth day, and sivelestat sodium was administered. The patient was extubated on the 12th day after improvement in oxygenation. There was no exacerbation, and CT showed improvements on day 51. Conclusion We report a case of pneumonia with suspected COVID-19 infection 18 years after living donor kidney transplantation. If COVID-19 is suspected, infection control and aggressive therapeutic interventions should be undertaken while considering the possibility of a positive result.

DNA damage and oncogenic viruses increase the risk of cancer post-kidney transplantation, including skin cancer, Kaposi's sarcoma, oral cancer, and non-Hodgkin lymphoma. Here we report an uncommon case of liver angiosarcoma that occurred 8 years after kidney transplantation. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source.A 57-year-old female patient received a cadaver kidney transplantation 8 years ago. She followed a long-term regimen of tacrolimus, mycophenolate sodium, and everolimus, with good renal function. She received annual regular abdominal ultrasound examinations after kidney transplantation, which showed no findings. The patient suffered from several symptoms for approximately 2 weeks before a scheduled abdominal ultrasound: diarrhea, epigastric pain, abdominal fullness, tea-colored urine, and little stool passage. The abdominal computerized tomography showed multiple hepatic tumors in both the hepatic lobes with engorged vasculatures and mild hemoperitoneum. A liver biopsy revealed the histopathology of angiosarcoma. The patient suffered multiple organ failure within one month of treatment.Various post-transplant malignancies are not uncommon after transplantation, warranting periodic screenings for any symptoms in these patients.

Refereed/Peer-reviewed Aim: To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians. Methods: Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit. Results: No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD = 5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p = .07 and p = .08). Conclusion: There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

To explore the clinical characteristics, treatment protocol and prognosis of children with anti-complement factor H (CFH) autoantibody (Ab)-associated hemolytic uremic syndrome (HUS).Clinical data of 8 patients with anti-CFH Ab-associated HUS who were admitted to Shandong Provincial Hospital from January 2011 to December 2020 were collected retrospectively.The age at disease onset ranged between 5.83 and 13.5 years, with a male: female ratio of 1.67:1. The time of onset was distributed from May to June and November to December. Digestive and upper respiratory tract infections were common prodromal infections. Positivity for anti-CFH Ab and reduced C3 levels were observed among all patients. Heterozygous mutation of the CHFR5 gene (c.669del A) and homozygous loss of the CFHR1 gene [loss2(EXON:2-6)] were found in two patients. All patients received early treatment with plasma exchange and corticosteroid therapy. Six patients were given immunosuppressive agents (cyclophosphamide and/or mycophenolate mofetil) for persistent proteinuria. The follow-up period was 12-114 months. Four of 8 patients achieved complete remission, 3 achieved partial remission, and 1 died. Relapse occurred in two patients.Children with anti-CFH Ab-associated HUS were mainly school-aged and predominantly male, with onset times of summer and winter. Digestive and upper respiratory tract infections were common prodromal infections. Plasma exchange combined with methylprednisolone pulse therapy in the acute phase and cyclophosphamide or mycophenolate mofetil treatment for maintenance can be utilized in children with anti-CFH Ab-associated HUS if eculizumab is not available.

International audience; ObjectivesLupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN.MethodsWIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2–3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events.ResultsBetween 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI −1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups.ConclusionsNon-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares.Trial registration numberNCT01284725.

The objective of the present study was to determine the impact of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA).PubMed, Embase, Web of Sciences, and Scopus were systematically searched to identify relevant studies reporting pharmacokinetic parameters [including trough concentration (C0), maximum concentration (Cmax), time to maximum concentration (Tmax), the dose-adjusted area under the concentration-time curve from time 0-12 hours (AUC0-12 h/D), and half-life (t1/2)], and pharmacodynamic outcomes of MPA (eg, acute graft rejection and adverse drug reactions), with and without PPI administration. Pooled effect estimates were calculated using a random-effects model.Twelve studies involving 473 participants were eligible for inclusion, 11 of which were included in the meta-analysis. PPI exposure was significantly associated with lower C0 [mean difference (MD) = -0.62 mg/L; P = 0.003] lower Cmax (MD = -4.71 mg/L; P = 0.01), and longer Tmax (MD = 0.30 hours; P = 0.0001) of MPA. However, no significant association was observed between PPI exposure and AUC0-12 h/D, t1/2, or any pharmacodynamic outcomes. Based on subgroup analysis, it can be suggested that a significant association between PPI exposure and altered MPA pharmacokinetics was mainly associated with mycophenolate mofetil but not enteric-coated mycophenolate sodium.Coadministration of PPIs and mycophenolate mofetil significantly altered the pharmacokinetics of MPA, particularly by decreasing MPA absorption. However, PPI-MPA interactions did not impact pharmacodynamic outcomes of MPA.

Membranoproliferative glomerulonephritis (MPGN) is the most typical Hepatitis C virus (HCV)-associated glomerulopathy, and the available data about the utilization of direct-acting antivirals (DAA) in HCV-associated glomerulonephritis is inadequate. We evaluated the renal and viral response in two cases of HCV-related MPGN; the first caused by cryoglobulinemia while the second was cryoglobulin-negative. Both patients received immunosuppression besides DAA in different regimens. They achieved partial remission but remained immunosuppression-dependent for more than 6 months after DAA despite sustained virological response, which enabled safer but incomplete immunosuppression withdrawal. Both patients were tested for occult HCV in peripheral blood mononuclear cells and found to be negative. Hence, the treatment of HCV-related MPGN ought to be according to the clinical condition and the effects of drug therapy. It is important to consider that renal response can lag behind the virological response. Resumo A glomerulonefrite membranoproliferativa (GNMP) é a glomerulopatia associada ao vírus mais típico da hepatite C (HCV), e os dados disponíveis sobre a utilização de antivirais de ação direta (AAD) na glomerulonefrite associada ao HCV são inadequados. Avaliamos a resposta renal e viral em dois casos de GNMP relacionados ao HCV; o primeiro causado por crioglobulinemia, enquanto o segundo era negativo para crioglobulina. Ambos os pacientes receberam imunossupressão além de AAD em diferentes esquemas terapêuticos. Eles alcançaram remissão parcial, mas permaneceram dependentes da imunossupressão por mais de 6 meses após os AAD, apesar da resposta virológica sustentada, que permitiu a retirada da imunossupressão mais segura, mas incompleta. Ambos os pacientes foram testados para HCV oculto em células mononucleares do sangue periférico e deram resultados negativos. Portanto, o tratamento do GNMP relacionado ao VHC deve ser de acordo com a condição clínica e os efeitos da terapia medicamentosa. É importante considerar que a resposta renal pode ficar aquém da resposta virológica.

The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-β-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular

Background Current treatment for frequently relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome focuses on immunosuppressive therapies. Although the clinical guideline suggests the use of mycophenolate mofetil (MMF), limited information is available on patients with primary nephrotic syndrome who receive off-label treatment with MMF in Japan. Method The dose, treatment duration, previous treatment, and characteristics of primary nephrotic syndrome patients receiving MMF were investigated using data from a Japanese hospital claims database (April 2008–September 2021). Results Data on 424 primary nephrotic syndrome patients receiving MMF (146 patients Conclusions Our study suggested that off-label use of MMF for primary nephrotic syndrome has increased since 2012 in Japan. The dose of MMF used in patients with primary nephrotic syndrome was generally within the approved dose range for lupus nephritis and transplant-related diseases in Japan.

To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA).PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs).Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757 T C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07-2.40, P = 0.021), while there was no significant association of the IMPDH2 3757 T C polymorphism with acute rejection within 1 year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79-2.80, P = 0.217; ES = 1.44, 95% CI = 0.88-2.36, P = 0.142). The GG genotypes of IMPDH1 125G A and IMPDH1 106G A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11-3.28, P = 0.019) and acute rejection within 1 year (ES = 2.12, 95% CI = 1.45-3.10, P 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275 T A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23-0.84, P = 0.013).IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.

Membranoproliferative glomerulonephritis and renal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranoproliferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during followup. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473GA(p. W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.

Objective We explored damage occurrence in patients with childhood-onset SLE (cSLE) and aimed to predict the risk of organ damage occurrence in time. Methods The retrospective study included patients treated for cSLE at the Centre of Reference for Pediatric and Adolescent Rheumatology of the Republic Croatia over a 29-year period. Results The disease development of 97 patients (77 females) with cSLE was examined. The median (Q1, Q3) follow-up time was 6.5 (2.3, 12.0) years. SDI was determined at 5 time points (6, 12, 24, 36 months, and last follow-up). Thirty-eight patients (48%) had organ damage at the last follow-up. Prepubertal group of patients showed higher SLEDAI scores at the disease onset, while post-pubertal group had significantly lower proportion of patients with relapses. We estimated the time from the first symptom to the moment of damage and our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first 6 years since the diagnosis. The number of 2019 ACR/EULAR classification criteria at the time of diagnosis associated with SDI determined after 1 year of the follow-up period. The patients who received higher doses of glucocorticoids accumulated damage faster and mycophenolate mofetil was found to be a more frequent therapy in patients with SDI ≥3. Conclusion Knowing that damage will most likely happen after the first 6 years after diagnosis in 50% of patients enables physicians to better predict damage occurrence. High number of 2019 ACR/EULAR criteria and treatment with glucocorticoids in childhood-onset SLE are associated with damage accrual and these findings could enable us to detect patients which should be closely monitored for higher risk of damage development.

Background Casirivimab-imdevimab is a cocktail of two 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 coronavirus disease (COVID-19); however, to the best of our knowledge, there are no reports of its use after kidney transplantation from a live donor. Everolimus, 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 following kidney transplantation, that was initially treated with casirivimab-imdevimab and mycophenolate mofetil, but was later changed to everolimus. Case report A 47-year-old man underwent living donor kidney transplantation 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 with COVID-19 and was hospitalized on Day 3 (Table 1). On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient was started on everolimus on Day 5. The clinical course was successful without rejection (Fig. 1). There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable. Conclusion We could safely treat a patient with casirivimab-imdevimab after kidney transplantation. 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.

In simultaneous pancreas-kidney transplantation (SPK) recipients, cytomegalovirus (CMV) infection is a major complication that has been associated with the use of tacrolimus (TAC)-based immunosuppression. As one of the immunosuppressive drug options, the use of mammalian target of rapamycin inhibitors (mTORi) results in reduced rates of CMV infection in the field of solid organ transplantation. However, little is known about mTORi usage in pancreas transplantation. We report a case of recurrent CMV infection that was controlled by the introduction of mTORi (everolimus) in addition to a TAC-based immunosuppression regimen in SPK. A 52-year-old man underwent SPK. Graft duodenal perforation occurred on the 13th day of surgery, and graft duodenal resection was performed after long-term abscess drainage treatment. After graft duodenal resection, he was diagnosed with CMV viremia, and valganciclovir was started. However, because of recurrent febrile neutropenia caused by cytopenia as a side effect of valganciclovir, there was a repeated need for granulocyte-colony stimulating factor treatment. Immunosuppressive drug taper adjustment was attempted to control recurrent CMV viremia, and everolimus was introduced with the aim of reducing the dose of TAC and mycophenolate mofetil. This resulted in a continuously negative CMV antigenemia test and a stable general condition. Understanding the characteristics of various immunosuppressive agents and appropriately controlling and managing infectious diseases is crucial for the good postoperative management of patients with SPK.

Background: Organizing pneumonia (OP) is a rare manifestation of systemic lupus erythematosus (SLE). It has been described in very few case reports. Purpose and Methods: We encountered OP in three patients with SLE in 1 year; two manifested OP as an initial presentation of SLE, while the third manifested OP when SLE relapsed. To elucidate the clinical features and outcomes of OP in patients with SLE, we screened the PubMed database for cases diagnosed with OP either at or after the diagnosis of SLE; the search was restricted to articles that were published after 1990, when OP became widely recognized. Results: We identified 15 cases of OP in patients with SLE. Thus, we analyzed a total of 18 cases (including our three). OP developed at the initial diagnosis of SLE in 15 cases and at relapse of SLE in three cases. In most cases, the disease activity of SLE was moderate or high. In all cases, OP was accompanied by other extrapulmonary symptoms of SLE, namely, fever (77.8%), cutaneous manifestations (61.1%), arthralgia/arthritis (50%), and lupus nephritis (33.3%). Steroid monotherapy or increasing the dose of the steroids was effective in seven cases (38.8%); however, steroid monotherapy was ineffective and led to death due to respiratory failure in two cases (11.1%). Combination therapies of steroids with hydroxychloroquine, azathioprine, tacrolimus, mycophenolate mofetil, intravenous pulse cyclophosphamide therapy, and belimumab were effective in seven cases (38.8%). Conclusions: Based on the review of previously reported and our cases, we concluded that OP is an important pulmonary manifestation of SLE. Clinicians should be aware of it as it may require intensive immunosuppressive therapy either at or after the diagnosis of SLE.

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.

Introduction/objectives Lupus nephritis (LN) is a major and serious complication of systemic lupus erythematosus (SLE) and is associated with morbidity and mortality. The difference in drug cost between mycophenolate mofetil (MMF) and cyclophosphamide (CYC) inducing regimens becomes a relevant and realistic issue, especially in developing countries. Thus, this study aims to estimate and compare the costs and outcomes of CYC and MMF for better allocation of resources to reduce the burden on the Egyptian healthcare system. Methods A prospective, parallel observational study was conducted at Kasr Al-Aini Hospital between 2018 and 2020. One hundred and twenty-two LN patients were followed up monthly during the study period. Remission and maintenance of renal remission were assessed at 6 and 12 months from the start of therapy. Total direct medical costs associated with both regimens were examined. We applied the cost-minimization analysis method from governmental perspective. Besides, a prospective evaluation of reported changes in health-related quality of life using SF-36 was included in our study. Results There was no statistically significant difference in treatment response at 6 and 12 months (RR 0.6 [0.26;1.43] and 0.8 [0.27;2.33]), respectively, as well as the incidence of infection episodes between MMF and CYC group (71.4% versus 70.45%, p > 0.05). The average direct medical expenditures per patient in the MMF group were approximately one and half times more than the CYC group (2339.69 $ versus 1329.03 $, p Conclusion The CYC arm was associated with lower costs than the MMF arm, with equally effective outcomes indicating that CYC is an attractive treatment option.

Renal involvement in patients with systemic lupus erythematosus can lead to significant complications including end-stage renal disease. Treatment of lupus nephritis has evolved over the last several decades, but despite this evolution, many patients fail to achieve remission and often progress to end-stage kidney disease or carry a burden of adverse side effects related to treatment.The recent findings from AURORA 1 and BLISS LN trials led the FDA to approve voclosporin and belimumab for the treatment of lupus nephritis. The AURORA 1 trial demonstrated that voclosporin, a second-generation calcineurin inhibitor, effectively lowers proteinuria in patients with lupus nephritis, when added to mycophenolate mofetil with a better safety profile, compared with other calcineurin inhibitors. The BLISS LN trial revealed better control of disease and lower risk of progression to end stage kidney disease (ESKD) and relapses in patients treated with belimumab in addition to standard therapy.Both voclosporin and belimumab are costly and have not shown any early evidence to revolutionize practice in the management of lupus nephritis. Until more data are made available with future studies or other cost-effective treatment options become available, the widespread adoption and utility of these novel agents remains limited.

Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

ABO-incompatible kidney transplantation (KTP) is effective for avoiding transplantation-related issues. It is a viable alternative to ABO-compatible KTP, as both techniques have similar patient and graft survival rates. However, anti-A/B antibody-mediated rejection (AMR) can occur, resulting in poor long-term graft survival.A 45-year-old man with end-stage renal disease presented with a serum creatinine level of 10.2 mg/dL. We decided to perform KTP with spousal donation. He had panel-reactive antibody class I and II and cross matching test negativity, a 3/6 mismatch on human leukocyte antigen typing, an ABO antibody titer of 1:256, and no donor-specific antibodies. The patient and donor blood types were O+ and A+, respectively. The anti-A/B antibody titer was reduced preoperatively with rituximab (200 mg/body), plasmapheresis, and intravenous immunoglobulin (0.2 mg/kg). Basiliximab and methylprednisolone were used for induction immunosuppression, and tacrolimus, mycophenolate mofetil, and prednisolone were used for maintenance immunosuppression. KTP was successful, and graft function was initially normal. On postoperative day (POD) 5, the serum creatinine level and anti-A/B antibody titer increased from 0.9 mg/dL to 1.9 mg/dL and 1:16 to 1:64, respectively. Graft biopsy revealed acute AMR and tubular injury. We started steroid pulse therapy, plasmapheresis, and subcutaneous bortezomib (2.6 mg, twice a day, every 3 days) with no side effects. The serum creatinine level decreased from 5.7 mg/dL to 1.5 mg/dL on POD 28. Graft biopsy showed no rejection, and normal function was maintained for 40 months.Acute, early anti-A/B AMR was successfully treated with plasmapheresis and bortezomib.

The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2,875 screened citations, we included 12 studies (1,255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95%CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.

Background and objectives: Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis.\ud \ud \ud \ud Design, setting, participants, & measurements: A de novo economic model was developed to estimate the cost-effectiveness of these therapies, including the following health states: “complete response,” “partial response,” and “active disease” defined by eGFR and proteinuria changes, kidney failure, and death. Short-term data and mean cohort characteristics were sourced from pivotal clinical trials of belimumab (the Belimumab International Study in Lupus Nephritis) and voclosporin (the Aurinia Urinary Protection Reduction Active–Lupus with Voclosporin trial and Aurinia Renal Response in Active Lupus With Voclosporin). Risk of mortality and kidney failure were on the basis of survival modeling using published Kaplan–Meier data. Each drug was compared with the standard of care as represented by the comparator arm in its respective pivotal trial(s) using US health care sector perspective, with a societal perspective also explored.\ud \ud \ud \ud Results: In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately $150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69% and 49%, respectively. Cost-effectiveness was dependent on assumptions made regarding survival in response states, costs and utilities in active disease, and the utilities in response states. In the analysis from a societal perspective, the incremental ratio for belimumab was estimated to be approximately $66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year.\ud \ud \ud \ud Conclusions: Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of $100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin.

We reviewed the results of cases of kidney transplant (KTx) that were conducted at the Toda Chuo General Hospital, a private hospital located in Saitama, Japan.A total of 312 patients with end-stage renal failure underwent KTx between January 1992 and December 2019 at Toda Chuo General Hospital. There were 191 men and 121 women. Their mean age was 45.7 years. Of the 312 cases, 310 were living-related KTx, while 2 were deceased donor KTx. The immunosuppressive treatment protocol mainly consisted of 4-drug therapy with methylprednisolone, tacrolimus, mycophenolate mofetil, and basiliximab.Patient survival was 99.7% at 1 year, 99.3% at 5 years, and 97.3% at 10 years. Renal allograft survival was 98.4% at 1 year, 91.7% at 5 years, and 86.5% at 10 years. However, death-censored renal allograft survival was 98.7% at 1 year, 92.4% at 5 years, and 89.0% at 10 years. Among the 312 patients, 33 grafts were lost during the observation period. The loss was because of chronic antibody-mediated rejection in 19 patients, death with function in 6 patients, and acute antibody-mediated rejection in 2 patients.The prognosis of patients and their grafts, which were managed following the immunosuppression protocol at our institute, was relatively good. KTx in a private hospital in Japan is at par with the global standard.

Given prophylactic methotrexate (MTX) is often held in the setting of toxicity we investigated the impact of omitting minidose-MTX dose(s). Outcomes were compared between patients who had 1–3 doses omitted and those who received all four planned doses of minidose-MTX. Of 370 consecutive patients, 50 had MTX dose(s) omitted. When MTX was omitted, initial management was mycophenolate mofetil (MMF; 36/50 patients) with or without corticosteroids (14/50 patients). Rates of grade 3–4 acute GVHD were similar between groups. Omission of minidose-MTX resulted in an increased risk of chronic GVHD (HR 2.27; p = 0.024) and decreased overall survival (HR 1.61; p = 0.024). However, other transplant-related outcomes were comparable. In summary, omission of minidose-MTX doses was not associated with an increased risk of acute GVHD when an alternative was added (e.g. MMF ± corticosteroids). This did not abrogate the increased risk of chronic GVHD or decreased overall survival.

Therapeutic monitoring (TDM) of mycophenolic acid (MPA) has the potential to improve drug inefficacy and toxicities in kidney transplantation. However, measurement of plasma MPA concentrations is laborious and invasive. This study examined the utility of saliva compared with plasma based TDM of MPA. Paired blood and saliva samples were collected from 47 adult kidney transplant recipients pre- and at 1-, 2-, and 4-hours post mycophenolate mofetil administration. No relationship was observed between saliva MPA concentrations and either total or free plasma MPA concentrations (p > 0.05). This suggests that saliva is a poor direct marker of plasma MPA concentrations and therefore should not be used for MPA TDM.

Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options.This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed.Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients.Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE.

Patients aged ≥60 y represent the fastest growing population among kidney transplant recipients and waitlist patients. They show an elevated infection risk and are frequently transplanted with multiple human leukocyte antigen mismatches. Whether the choice of calcineurin inhibitor influences graft survival, mortality, or key secondary outcomes such as infections in this vulnerable recipient population is unknown.A total of 31 177 kidney transplants from deceased donors performed between 2000 and 2019 at European centers and reported to the Collaborative Transplant Study were analyzed using multivariable Cox and logistic regression analyses. All recipients were ≥60 y old and received tacrolimus (Tac) or cyclosporine A on an intention-to-treat basis, combined with mycophenolic acid or azathioprine plus/minus steroids.The risk of 3-y death-censored graft loss and patient mortality did not differ significantly between Tac- and cyclosporine A-treated patients (hazard ratio 0.98 and 0.95, P = 0.74 and 0.20, respectively). No difference was found in the overall risk of hospitalization for infection (hazard ratio = 0.95, P = 0.19); however, a lower incidence of rejection treatment (hazard ratio = 0.81, P0.001) was observed in Tac-treated patients. Assessment of pathogen-specific hospitalizations revealed no difference in the risk of hospitalization due to bacterial infection (odds ratio = 1.00, P = 0.96), but a significantly higher risk of hospitalization due to human polyomavirus infection was found among Tac-treated patients (odds ratio = 2.45, P = 0.002). The incidence of de novo diabetes was higher for Tac-based immunosuppression (odds ratio = 1.79, P0.001).Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in ≥60-y-old kidney transplant recipients.

There seems to be a possible link between nephrotic syndrome (NS) and lymphoproliferative syndrome, but it remains poorly understood.This multicentric and retrospective study focuses on children, who developed idiopathic NS and malignant or benign proliferation between 2000 and 2021.Eleven patients were included, with a median age of 4 years. Only one had a steroid-resistant nephrotic syndrome (SRNS). The maintenance therapy before the proliferation was in majority tacrolimus or mycophenolate mofetil (MMF), but three patients did not receive treatments. The proliferation was mainly a Hodgkin's lymphoma (45%) or a lymphoproliferative disease (36%), in a median time after the NS of two years. Viruses were found in seven cases (EBV in five cases and HHV-8 in two).The association between proliferative syndrome and idiopathic NS may not be fortuitous, possibly with a common lymphocytic disturbance. Genetic analyses could improve the comprehension of these manifestations in the future. A higher resolution version of the Graphical abstract is available as Supplementary information.