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La Tunisie Medicale Jan 2024Pediatric end-stage renal disease is a rare but severe condition that causes numerous complications and impairs the quality of life of children. Kidney transplantation...
INTRODUCTION
Pediatric end-stage renal disease is a rare but severe condition that causes numerous complications and impairs the quality of life of children. Kidney transplantation is the therapy of choice in pediatric end-stage renal disease.
AIM
Our study aimed to identify the predictive factors of renal graft failure after kidney transplantation in Tunisian children and young adults.
METHODS
We conducted a retrospective bicentric study of children and young adults (age≤20 years) who had undergone renal transplantation between 1989 and 2019 in Tunisia. We analyzed long-term survival rates and complications after pediatric kidney transplantation and searched for predictive parameters for graft dysfunction. We used a univariate and a multivariate analysis to identify predictive factors of graft survival.
RESULTS
A total of 112 patients underwent 115 kidney transplantations. Graft failure occurred in 30% of the cases. The overall 1-, 3-, 5- and 10-year graft survival rates were 92%, 89.1%, 85.9% and 74.5% respectively. The following parameters strongly influenced graft survival: immunosuppressive regimen including an association other than Mycophenolate mofetil- tacrolimus and corticosteroids (p=0.002), year of transplant (p<0.0001 for 1987-2000), deceased donor (p = 0.039), underlying etiology of end-stage renal disease (p=0.045), occurrence of acute or chronic rejection (p<0.001), a urine protein greater than 0.3 g/l per day (p=0.002), post-transplant urologic complications (p=0.002), five-year creatinine level>1.28 mg/dl (p<0.001). The overall 1-, 3-, 5- and 10-year patients survival rates were 97%, 95%, 90.2% and 84.4% respectively.
CONCLUSIONS
Our study identified several predictive factors of graft failure in Tunisian children and young adults undergoing renal transplantation.
Topics: Humans; Child; Young Adult; Adult; Retrospective Studies; Quality of Life; Immunosuppressive Agents; Kidney Diseases; Tacrolimus; Kidney Failure, Chronic; Mycophenolic Acid
PubMed: 38545728
DOI: 10.62438/tunismed.v102i1.4328 -
Expert Opinion on Drug Safety Apr 2024The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate...
OBJECTIVE
The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned.
METHODS
The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs.
RESULTS
Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia.
CONCLUSION
The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies.
EXPERT OPINION
The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.
Topics: Humans; Tacrolimus; Pharmacovigilance; Kidney Transplantation; Immunosuppressive Agents; Cyclosporine; Mycophenolic Acid; Methotrexate; Data Mining; Graft Rejection
PubMed: 38533933
DOI: 10.1080/14740338.2024.2327503 -
Frontiers in Molecular Biosciences 2024Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is widely used for maintenance immunosuppression in transplantation. The gastrointestinal...
Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is widely used for maintenance immunosuppression in transplantation. The gastrointestinal toxicity of MMF has been widely uncovered. However, the comprehensive metabolic analysis of MMF-induced toxicity is lacking. This study is aimed to ascertain the metabolic changes after MMF administration in mice. A total of 700 mg MMF was dissolved in 7 mL dimethyl sulfoxide (DMSO), and then 0.5 mL of mixture was diluted with 4.5 mL of saline (100 mg/kg). Mice in the treatment group ( = 9) were given MMF (0.1 mL/10 g) each day via intraperitoneal injection lasting for 2 weeks, while those in the control group ( = 9) received the same amount of blank solvent (DMSO: saline = 1:9). Gas chromatography-mass spectrometry was utilized to identify the metabolic profiling in serum samples and multiple organ tissues of mice. The potential metabolites were identified using orthogonal partial least squares discrimination analysis. Meanwhile, we used the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (http://www.kegg.jp) to depict the metabolic pathways. The percentages of lymphocytes in spleens were assessed by multiparameter flow cytometry analysis. Compared to the control group, we observed that MMF treatment induced differential expression of metabolites in the intestine, hippocampus, lung, liver, kidney, heart, serum, and cortex tissues. Subsequently, we demonstrated that multiple amino acids metabolism and fatty acids biosynthesis were disrupted following MMF treatment. Additionally, MMF challenge dramatically increased CD4 T cell percentages but had no significant influences on other types of lymphocytes. MMF can affect the metabolism in various organs and serum in mice. These data may provide preliminary judgement for MMF-induced toxicity and understand the metabolic mechanism of MMF more comprehensively.
PubMed: 38516185
DOI: 10.3389/fmolb.2024.1332090 -
International Journal of Biological... Apr 2024The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence...
The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence spectroscopy. Dynamic light scattering and scanning electron microscopy were used to figure out the structure of MPA-Complex (MPA-C). The binding affinity between MPA and BSA was determined, yielding a Kd value of (12.0 ± 0.7) μM, and establishing a distance of 17 Å between the BSA and MPA molecules. The presence of MPA prompted protein aggregation, leading to the formation of MPA-C. The cytotoxicity of MPA-C and its ability to fight Junín virus (JUNV) were tested in A549 and Vero cell lines. It was found that treating infected cells with MPA-C decreased the JUNV yield and was more effective than free MPA in both cell line models for prolonged time treatments. Our results represent the first report of the antiviral activity of this type of BSA-MPA complex against JUNV, as assessed in cell culture model systems. MPA-C shows promise as a candidate for drug formulation against human pathogenic arenaviruses.
Topics: Humans; Serum Albumin, Bovine; Mycophenolic Acid; Molecular Docking Simulation; Virus Replication; Junin virus; Antiviral Agents
PubMed: 38513897
DOI: 10.1016/j.ijbiomac.2024.131023 -
Frontiers in Cardiovascular Medicine 2024Chronic kidney disease (CKD) significantly increases cardiovascular risk and mortality, and the accumulation of uremic toxins in the circulation upon kidney failure...
Chronic kidney disease (CKD) significantly increases cardiovascular risk and mortality, and the accumulation of uremic toxins in the circulation upon kidney failure contributes to this increased risk. We thus performed a screening for potential novel mediators of reduced cardiovascular health starting from dialysate obtained after hemodialysis of patients with CKD. The dialysate was gradually fractionated to increased purity using orthogonal chromatography steps, with each fraction screened for a potential negative impact on the metabolic activity of cardiomyocytes using a high-throughput MTT-assay, until ultimately a highly purified fraction with strong effects on cardiomyocyte health was retained. Mass spectrometry and nuclear magnetic resonance identified the metabolite mycophenolic acid-β-glucuronide (MPA-G) as a responsible substance. MPA-G is the main metabolite from the immunosuppressive agent MPA that is supplied in the form of mycophenolate mofetil (MMF) to patients in preparation for and after transplantation or for treatment of autoimmune and non-transplant kidney diseases. The adverse effect of MPA-G on cardiomyocytes was confirmed , reducing the overall metabolic activity and cellular respiration while increasing mitochondrial reactive oxygen species production in cardiomyocytes at concentrations detected in MMF-treated patients with failing kidney function. This study draws attention to the potential adverse effects of long-term high MMF dosing, specifically in patients with severely reduced kidney function already displaying a highly increased cardiovascular risk.
PubMed: 38510194
DOI: 10.3389/fcvm.2024.1346475 -
The Ocular Surface Apr 2024To clinically define a subset of patients with chronic ocular Stevens-Johnson syndrome non-responders (SJS-NR) and analyze their cytokine profile compared to clinical...
PURPOSE
To clinically define a subset of patients with chronic ocular Stevens-Johnson syndrome non-responders (SJS-NR) and analyze their cytokine profile compared to clinical responders (SJS-CR).
METHODS
A total of 32 SJS cases (n = 32, 64 eyes) managed over a period of three years were segregated into clinical responders (n = 24, 48 eyes) and non-responders (n = 8, 16 eyes). Cases were determined as non-responders based on persistent, refractory, and non-mechanical inflammation of the conjunctiva. Age- and sex-matched healthy controls (n = 25, 50 eyes) were recruited. Tear specimens collected using Schirmer's strip were profiled for 27 cytokines using an immunoassay-based 27-bioplex array.
RESULTS
Tear cytokine profiling revealed 18 cytokines to be differentially expressed in SJS-NR compared to SJS-CR. While PDGF-BB, IL-4, IL-1β, VEGF, IL-12p70, IFN-γ, IL-9, and IL-1RA were upregulated, GM-CSF, eotaxin, IP-10, IL-10, MCP-1, G-CSF, IL-6, IL-13, and bFGF were downregulated in SJS-NR compared to SJS-CR. The cytokines IL-13, IL-10, and IP-10 were decreased in both SJS-NR and SJS-CR compared to controls.
CONCLUSION
The inflammation in SJS-NR continues to worsen despite the correction of mechanical causes, resulting in progressive deterioration of the cornea. The cytokine profile of SJS-NR was remarkably different from that of SJS-CR, indicating a T helper 2-type protective proliferative response and an impaired migratory potential of the conjunctival epithelium. These factors could possibly lead to poor healing of the corneal epithelium in a markedly pro-inflammatory and pro-angiogenic milieu. The top four differentially expressed cytokines, PDGF-BB, IL-4, IL-10, and IL-6, are proposed as potential biomarkers of SJS-NR.
Topics: Stevens-Johnson Syndrome; Cytokines; Humans; Male; Female; Young Adult; Adult; Middle Aged; Tears; Cornea; Down-Regulation; Immunomodulation; Immunosuppression Therapy; Mycophenolic Acid
PubMed: 38490474
DOI: 10.1016/j.jtos.2024.03.007 -
Pharmacological Reports : PR Jun 2024Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study...
BACKGROUND
Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study describes the liquid chromatography tandem mass spectrometry (LC-MS/MS) method developed for saliva MPA and MPAG determination in children with nephrotic syndrome.
METHODS
The mobile phase consisted of methanol and water at gradient flow, both with 0.1% formic acid. Firstly, 100 µL of saliva was evaporated at 45 °C for 2 h to dryness, secondly, it was reconstituted in the mobile phase, and finally 10 µL was injected into the LC-MS/MS system. Saliva from ten children with nephrotic syndrome treated with mycophenolate mofetil was collected with Salivette.
RESULTS
For MPA and MPAG, within the 2-500 ng/mL range, the method was selective, specific, accurate and precise within-run and between-run. No carry-over and matrix effects were observed. Stability tests showed that MPA and MPAG were stable in saliva samples if stored for 2 h at room temperature, 18 h at 4 °C, and at least 5 months at - 80 °C as well as after three freeze-thaw cycles, in a dry extract for 16 h at 4 °C, and for 8 h at 15 °C in the autosampler. The analytes were not adsorbed onto Salivette cotton swabs. For concentrations above 500 ng/mL, the samples may be diluted twofold. In children, saliva MPA and MPAG were within the ranges of 4.6-531.8 ng/mL and 10.7-183.7 ng/mL, respectively.
CONCLUSIONS
The evaluated LC-MS/MS method has met the validation requirements for saliva MPA and MPAG determination in children with nephrotic syndrome. Further studies are needed to explore plasma-saliva correlations and assess their potential contribution to MPA monitoring.
Topics: Humans; Saliva; Mycophenolic Acid; Nephrotic Syndrome; Tandem Mass Spectrometry; Child; Glucuronides; Drug Monitoring; Male; Female; Chromatography, Liquid; Child, Preschool; Adolescent; Reproducibility of Results; Immunosuppressive Agents
PubMed: 38485859
DOI: 10.1007/s43440-024-00574-9 -
Seminars in Respiratory and Critical... Jun 2024Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for... (Review)
Review
Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.
Topics: Humans; Lung Diseases, Interstitial; Arthritis, Rheumatoid; Immunosuppressive Agents; Disease Progression; Antirheumatic Agents; Abatacept; Prognosis; Mycophenolic Acid; Rituximab; Vital Capacity; Pyridones; Randomized Controlled Trials as Topic; Azathioprine; Indoles
PubMed: 38484788
DOI: 10.1055/s-0044-1782218 -
Transplantation Direct Apr 2024Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated...
BACKGROUND
Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated noninvasive biomarker for active rejection in kidney transplant (KTx). Evidence supporting dd-cfDNA testing use in IST management is limited.
METHODS
In this single-center observational study, dd-cfDNA testing was performed in 21 KTx patients considered good candidates for mycophenolic acid (MPA) reduction. Patients with dd-cfDNA <1% at the first visit (enrollment) had their MPA dosage reduced; those with dd-cfDNA ≥1% had their MPA dosage maintained. Patients were monitored with dd-cfDNA for 6 additional visits.
RESULTS
Of 21 patients enrolled in the study, 17 were considered low risk for rejection by dd-cfDNA and underwent MPA reduction; 4 patients were considered high risk for rejection by dd-cfDNA and had their initial MPA dosage maintained. Of the 4 patients considered high risk for rejection by dd-cfDNA, 1 experienced chronic allograft nephropathy and graft loss, and another received an indication biopsy that showed no evidence of rejection. Of the 17 patients considered low risk for rejection by dd-cfDNA, none experienced allograft rejection. dd-cfDNA was used for surveillance in a 6-mo period following MPA reduction; no untoward results were noted.
CONCLUSIONS
This proof-of-concept study reports the use of dd-cfDNA to directly inform IST management in a cohort of KTx who were candidates for IST reduction.
PubMed: 38481964
DOI: 10.1097/TXD.0000000000001610 -
Epidemiology and Health 2024This study developed an algorithm for identifying pregnancy episodes and estimating the last menstrual period (LMP) in an administrative claims database and applied it...
Identifying pregnancy episodes and estimating the last menstrual period using an administrative database in Korea: an application to patients with systemic lupus erythematosus.
OBJECTIVES
This study developed an algorithm for identifying pregnancy episodes and estimating the last menstrual period (LMP) in an administrative claims database and applied it to investigate the use of pregnancy-incompatible immunosuppressants among pregnant women with systemic lupus erythematosus (SLE).
METHODS
An algorithm was developed and applied to a nationwide claims database in Korea. Pregnancy episodes were identified using a hierarchy of pregnancy outcomes and clinically plausible periods for subsequent episodes. The LMP was estimated using preterm delivery, sonography, and abortion procedure codes. Otherwise, outcome-specific estimates were applied, assigning a fixed gestational age to the corresponding pregnancy outcome. The algorithm was used to examine the prevalence of pregnancies and utilization of pregnancy-incompatible immunosuppressants (cyclophosphamide [CYC]/mycophenolate mofetil [MMF]/methotrexate [MTX]) and non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy in SLE patients.
RESULTS
The pregnancy outcomes identified in SLE patients included live births (67%), stillbirths (2%), and abortions (31%). The LMP was mostly estimated with outcome-specific estimates for full-term births (92.3%) and using sonography procedure codes (54.7%) and preterm delivery diagnosis codes (37.9%) for preterm births. The use of CYC/MMF/MTX decreased from 7.6% during preconception to 0.2% at the end of pregnancy. CYC/MMF/MTX use was observed in 3.6% of women within 3 months preconception and 2.5% during 0-7 weeks of pregnancy.
CONCLUSIONS
This study presents the first pregnancy algorithm using a Korean administrative claims database. Although further validation is necessary, this study provides a foundation for evaluating the safety of medications during pregnancy using secondary databases in Korea, especially for rare diseases.
Topics: Infant, Newborn; Pregnancy; Humans; Female; Premature Birth; Pregnancy Outcome; Immunosuppressive Agents; Cyclophosphamide; Lupus Erythematosus, Systemic; Mycophenolic Acid; Republic of Korea
PubMed: 38476014
DOI: 10.4178/epih.e2024012