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Current Opinion in Nephrology and... May 2024As the most common primary glomerulonephritis, immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of kidney failure and mortality. Until recently,... (Review)
Review
PURPOSE OF REVIEW
As the most common primary glomerulonephritis, immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of kidney failure and mortality. Until recently, therapeutic options were limited. Fortunately, there have been numerous recent clinical trials demonstrating efficacy of new therapies in slowing chronic kidney disease (CKD) progression at varying stages of disease.
RECENT FINDINGS
The TESTING trial has provided high-quality evidence for slowing estimated glomerular filtration rate (eGFR) decline with a reduced-dose glucocorticoid regimen, while demonstrating an improved safety profile. Targeted-release budesonide represents a well tolerated therapy for reducing eGFR decline. Mycophenolate mofetil may reduce CKD progression in some populations, while hydroxychloroquine is efficacious in reducing proteinuria. Sodium-glucose cotransporter (SGLT2) inhibitors and sparsentan are effective therapies for CKD due to IgAN, but should not be used in lieu of disease-modifying immunosuppressive therapy. Many new therapies are approaching readiness for clinical use.
SUMMARY
Numerous therapeutic options now exist and include disease-modifying and nephroprotective drugs. Identifying the right treatment for the right patient is now the clinical challenge and, with new drugs on the horizon, represents the primary unmet research need in this rapidly-developing field.
Topics: Humans; Glomerulonephritis, IGA; Standard of Care; Renal Insufficiency, Chronic; Mycophenolic Acid; Glucocorticoids; Proteinuria
PubMed: 38411173
DOI: 10.1097/MNH.0000000000000979 -
Frontiers in Immunology 2023Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.
METHODS
We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.
RESULTS
Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).
DISCUSSION
This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.
Topics: Humans; Adult; Immunosuppressive Agents; Lupus Nephritis; Network Meta-Analysis; Treatment Outcome; Cyclophosphamide; Tacrolimus; Azathioprine; Mycophenolic Acid; Glucocorticoids; Bone Marrow Diseases; Kidney Failure, Chronic; Recurrence; Herpes Zoster; Neoplasms
PubMed: 37901212
DOI: 10.3389/fimmu.2023.1232244 -
Pharmacogenomics May 2024This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The... (Review)
Review
This scoping review explores the impact of genetic polymorphisms on the pharmacokinetics and treatment responses of mycophenolic acid (MPA), an immunosuppressant. The study includes 83 articles from 1226 original studies, focusing on transplantation (n = 80) and autoimmune disorders (n = 3). Genetic variants in uridine 5'-diphospho-glucuronosyltransferase ( and ) and transmembrane transporters ( and ) significantly affected MPA's pharmacokinetics and susceptibility to its adverse effect. Whereas variants in several genes including , , and have been associated with a higher risk of transplant rejection. However, there is a lack of studies on MPA's impact on autoimmune disorders and limited research on the Asian population. The findings underscore the need for further research on MPA's impact across different populations and diseases, particularly among other Asian ethnic groups, to advance personalized medicine in MPA therapy.
PubMed: 38884938
DOI: 10.1080/14622416.2024.2344430 -
Chinese Medical Journal Jan 2024Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased... (Review)
Review
Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased mortality. Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids, mycophenolate mofetil, and calcineurin inhibitors. Although therapeutic regimens have evolved over the years, they have inherent limitations, including non-specific targeting, substantial adverse effects, high relapse rates, and prolonged maintenance and remission courses. These drawbacks underscore the need for targeted therapeutic strategies for LN. Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity. This review provides an overview of the current evidence on targeted therapies for LN, elucidates the biological mechanisms of responses and failure, highlights the challenges ahead, and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.
Topics: Humans; Calcineurin Inhibitors; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid
PubMed: 38057972
DOI: 10.1097/CM9.0000000000002959 -
Pediatric Research Dec 2023To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN).
BACKGROUND
To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN).
METHODS
In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed.
RESULTS
The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy.
CONCLUSIONS
Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN.
IMPACT
The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.
Topics: Humans; Child; Lupus Nephritis; Immunosuppressive Agents; Tacrolimus; Cyclophosphamide; Retrospective Studies; Mycophenolic Acid; Glucocorticoids; Treatment Outcome
PubMed: 37488301
DOI: 10.1038/s41390-023-02747-3 -
International Journal of Antimicrobial... May 2024Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem...
Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC=0.05 µM and 0.3 µM, respectively) and HCMV (IC=10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI=0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI=0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human C values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections.
Topics: Humans; Immunosuppressive Agents; Antiviral Agents; Adenoviruses, Human; Cytomegalovirus; Drug Synergism; Inhibitory Concentration 50; Mycophenolic Acid; Tacrolimus; Cyclosporine; Cytomegalovirus Infections
PubMed: 38401774
DOI: 10.1016/j.ijantimicag.2024.107116 -
Therapeutic Drug Monitoring Aug 2023Volumetric absorptive microsampling (VAMS) is an emerging technique that may support multisample collection to enhance therapeutic drug monitoring in solid organ...
BACKGROUND
Volumetric absorptive microsampling (VAMS) is an emerging technique that may support multisample collection to enhance therapeutic drug monitoring in solid organ transplantation. This review aimed to assess whether tacrolimus and mycophenolic acid can be reliably assayed using VAMS and to identify knowledge gaps by providing granularity to existing analytical methods and clinical applications.
METHODS
A systematic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed, Embase, and Scopus databases were accessed for records from January 2014 to April 2022 to identify scientific reports on the clinical validation of VAMS for monitoring tacrolimus and mycophenolic acid concentrations. Data on the study population, sample sources, analytical methods, and comparison results were compiled.
RESULTS
Data from 12 studies were collected, including 9 studies pertaining to tacrolimus and 3 studies on the concurrent analysis of tacrolimus and mycophenolic acid. An additional 14 studies that provided information relevant to the secondary objectives (analytical validation and clinical application) were also included. The results of the clinical validation studies generally met the method agreement requirements described by regulatory agencies, but in many cases, it was essential to apply correction factors.
CONCLUSIONSS
Current evidence suggests that the existing analytical methods that use VAMS require additional optimization steps for the analysis of tacrolimus and mycophenolic acid. The recommendations put forth in this review can help guide future studies in achieving the goal of improving the care of transplant recipients by simplifying multisample collection for the dose optimization of these drugs.
Topics: Humans; Tacrolimus; Mycophenolic Acid; Drug Monitoring; Tandem Mass Spectrometry; Organ Transplantation; Blood Specimen Collection; Dried Blood Spot Testing
PubMed: 36728554
DOI: 10.1097/FTD.0000000000001066 -
Journal of Pharmaceutical and... Sep 2023Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) used to prevent rejection in organ transplant patients. The purpose of this study is to develop a...
Development of a novel UPLC-MS/MS method for the simultaneous quantification of mycophenolic mofetil, mycophenolic acid, and its major metabolites: Application to pharmacokinetic and tissue distribution study in rats.
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) used to prevent rejection in organ transplant patients. The purpose of this study is to develop a sensitive LC-MS/MS method to simultaneously quantify MMF, MPA, and two major metabolites, mycophenolic acid-glucuronide (MPAG) and Acyl-mycophenolic acid-glucuronide (AcMPAG) and applied this method in a pharmacokinetic (PK) and tissue distribution study. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Protein precipitation with a mixture of methanol: acetonitrile (2:1, v:v) was used to process the plasma samples and tissue samples. Separation was achieved using an Ultra Biphenyl 5 µm column (100 × 2.1 mm) with 0.1% formic acid in water (A) and acetonitrile (B) as the mobile phases. Quantification analysis was performed under positive ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 1.22 - 1250.00 nM for all four analytes with correlation coefficient values > 0.99. The method was reproducible, with intra- and inter-day accuracy ranging from 85.0 ± 11.2-108.3 ± 6.50 for all analytes in both plasma, liver and intestine homogenates. The extraction recovery and matrix effect of plasma sample using a mixture methanol/acetonitrile (2:1, V:V) can achieve an acceptable range (<20%), but extraction recovery and matrix effect of AcMPAG decreased to 64.10 ± 15.42 in the liver and intestine homogenates. The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage conditions. The validated method was successfully applied to quantify MMF, MPA, MPAG, and AcMPAG in a rat PK study. The PK results showed MPA was the major form exposed in the plasma in rats after oral administration of MMF, but the major metabolites in the rat's tissue disposition were MPAG.
Topics: Rats; Animals; Mycophenolic Acid; Glucuronides; Chromatography, Liquid; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Methanol; Tissue Distribution
PubMed: 37478553
DOI: 10.1016/j.jpba.2023.115504 -
Journal of Pharmaceutical Sciences Jun 2024The goal of this study was to evaluate whether topical administration of tacrolimus (TAC) and mycophenolic acid (MPA) at the transplant site enables vascularized...
AIM
The goal of this study was to evaluate whether topical administration of tacrolimus (TAC) and mycophenolic acid (MPA) at the transplant site enables vascularized composite allograft (VCA) survival with significant minimization of the dose and adverse effects of systemic TAC (STAC) immunosuppression.
MATERIALS AND METHODS
Lewis (Lew) rats received orthotopic hind limb allotransplants from fully mismatched Brown Norway (BN) donors. Group 1 (Controls) received no treatment. Other groups were treated with STAC at a dose of 1 mg/kg/day for 7 days. On post-operative day (POD) 8, the STAC dose was dropped to 0.1 mg/kg/day for Group 2 and maintained at 1 mg/kg for Group 3. Group 4 received topical application of TAC and MPA on the transplanted (Tx) limb starting POD 8 without STAC. Group 5 received topical TAC and MPA on the contralateral non-Tx limb and Group 6 received topical TAC and MPA on the Tx limb starting POD 8 along with low dose STAC (0.1 mg/kg/day). Treatment was continued until the study end point was reached, defined as either grade 3 rejection or allograft survival exceeding 100 days. .We conducted sequential LC-MS/MS measurements to assess TAC and MPA concentrations in both blood/plasma and allograft tissues. Additionally, we evaluated markers indicative of organ toxicity associated with STAC immunosuppression.
RESULTS
Compared to controls, topical therapy with TAC+MPA significantly prolonged allograft survival beyond 100 daysat very low dose STAC (0.1 mg/kg/day) (Group 6). The histopathological assessment of the grafts was consistent with the clinical outcomes. .Drug levels in blood/plasma remained low or undetectable, while allograft tissues showed higher drug concentrations compared to contralateral limb tissues (P<0.05). . Urinary creatinine clearance remained within the normal range at 2.5 mL/min.
CONCLUSION
Combination therapy with topical TAC and MPA synergizes with a very low dose, corticosteroid- free-STAC regimen and facilitates rejection-free, prolonged VCA survival without morbidity.
Topics: Animals; Tacrolimus; Mycophenolic Acid; Immunosuppressive Agents; Rats, Inbred Lew; Graft Survival; Rats; Administration, Topical; Male; Rats, Inbred BN; Graft Rejection; Immunosuppression Therapy; Vascularized Composite Allotransplantation; Drug Synergism; Composite Tissue Allografts; Allografts
PubMed: 38309457
DOI: 10.1016/j.xphs.2024.01.015 -
Transplantation Sep 2023Posttransplant fertility returns quickly, and female recipients of child-bearing age may conceive while on immunosuppression. However, pregnancy after transplantation...
BACKGROUND
Posttransplant fertility returns quickly, and female recipients of child-bearing age may conceive while on immunosuppression. However, pregnancy after transplantation confers risks to the recipient, transplant, and fetus, including gestational hypertension, preeclampsia, gestational diabetes, transplant dysfunction, preterm labor, and low birthweight infants. Additionally, mycophenolic acid (MPA) products are teratogenic. Literature evidence regarding belatacept, a selective T-cell costimulation blocker, during pregnancy and while breastfeeding is extremely limited. When female transplant recipients on a belatacept-based regimen are desirous of pregnancy or at the time of conception, transplant providers manage the immunosuppression regimen in 1 of 2 ways: (1) switch both belatacept and MPA to a calcineurin inhibitor-based regimen with or without azathioprine, which is the more common practice but requires several modifications, having potential negative outcomes; or (2) only switch MPA to azathioprine while continuing belatacept.
METHODS
This case series includes 16 pregnancies in 12 recipients with exposure to belatacept throughout pregnancy and while breastfeeding. Patient information was obtained from several sources, including Transplant Pregnancy Registry International, providers at Emory University, and Columbia University, as well as literature review.
RESULTS
Pregnancy outcomes included 13 live births and 3 miscarriages. No birth defects or fetal deaths were reported in any of the live births. Seven infants were breastfed while their mothers continued belatacept. Outcomes appear comparable to those documented with the administration of calcineurin inhibitors.
CONCLUSIONS
This case series provides data supporting the continued administration of belatacept during pregnancy. Additional research will assist in developing better guidelines to counsel female transplant recipients on belatacept desiring to pursue pregnancy.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Abatacept; Transplant Recipients; Azathioprine; Kidney Transplantation; Graft Rejection; Immunosuppressive Agents; Calcineurin Inhibitors; Pregnancy Outcome; Mycophenolic Acid
PubMed: 37287109
DOI: 10.1097/TP.0000000000004634