• Humans
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/complications
• Lung Diseases, Interstitial/drug therapy
• Lung Diseases, Interstitial/etiology
• Antirheumatic Agents/therapeutic use
• Antirheumatic Agents/adverse effects
• Aged
• Patient-Centered Care
• Quality of Life

• R01 AR080659 NIAMS NIH HHS
• R01 AR077607 NIAMS NIH HHS
• P30 AR070253 NIAMS NIH HHS
• P30 AR072577 NIAMS NIH HHS
• R01 HL155522 NHLBI NIH HHS
• Llura Gund Award Gordon and Llura Gund Foundation

• SARS-CoV-2
• anti-COVID-19 mRNA vaccination
• inflammatory autoimmune diseases
• liver transplantation
• mycophenolate

• Humans
• COVID-19
• Liver Transplantation
• SARS-CoV-2
• Follow-Up Studies
• Prospective Studies
• Antiviral Agents
• Autoimmune Diseases/drug therapy
• Enzyme Inhibitors
• Immunosuppressive Agents/adverse effects

• Ministero della Salute
• Regione Piemonte

• Immunosuppression
• autoimmune disease
• coronavirus disease 2019
• dermatological agents
• dermatology

• India
• adolescent
• graft survival
• kidney transplantation
• pediatric
• survival rate

• Adolescent
• Child
• Female
• Graft Survival
• Humans
• Immunosuppression Therapy/methods
• Incidence
• India/epidemiology
• Kidney Transplantation
• Male
• Postoperative Complications/epidemiology
• Retrospective Studies
• Tertiary Care Centers

• IA/CPHE/14/1/501501 DBT-Wellcome Trust India Alliance

• infection risk
• kidney transplant risk
• lymphocytes
• natural killer cells
• score

• Graft survival
• Kidney transplantation
• Urinary microbiota
• Urinary tract infection

Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.

• Kidney transplantation
• Calcineurin inhibitor
• Withdrawal
• Sparing
• Cyclosporine
• Tacrolimus
• Renal function
• Graft survival

Immunosuppressants such as mycophenolate mofetil (MMF) have the capacity to inhibit microglial and astrocytic activation and to reduce the extent of cell death after neuronal injury. This study was designed to determine the effective neuroprotective time frame in which MMF elicits its beneficial effects, by analyzing glial cell proliferation, migration, and apoptosis.

Using organotypic hippocampal slice cultures (OHSCs), temporal dynamics of proliferation and apoptosis after N-methyl-D-aspartate (NMDA)-mediated excitotoxicity were analyzed by quantitative morphometry of Ki-67 or cleaved caspase-3 immunoreactive glial cells. Treatment on NMDA-lesioned OHSCs with mycophenolate mofetil (MMF)100 μg/mL was started at different time points after injury or performed within specific time frames, and the numbers of propidium iodide (PI)⁺ degenerating neurons and isolectin (I)B₄⁺ microglial cells were determined. Pre-treatment with guanosine 100 μmol/l was performed to counteract MMF-induced effects. The effects of MMF on reactive astrocytic scar formation were investigated in the scratch-wound model of astrocyte monolayers.

Excitotoxic lesion induction led to significant increases in glial proliferation rates between 12 and 36 hours after injury and to increased levels of apoptotic cells between 24 and 72 hours after injury. MMF treatment significantly reduced glial proliferation rates without affecting apoptosis. Continuous MMF treatment potently reduced the extent of neuronal cell demise when started within the first 12 hours after injury. A crucial time-frame of significant neuroprotection was identified between 12 and 36 hours after injury. Pre-treatment with the neuroprotective nucleoside guanosine reversed MMF-induced antiproliferative effects on glial cells. In the scratch-wound model, gap closure was reached within 48 hours in controls, and was potently inhibited by MMF.

Our data indicate that immunosuppression by MMF significantly attenuates the extent of neuronal cell death when administered within a crucial time frame after injury. Moreover, long-lasting immunosuppression, as required after solid-organ transplantation, does not seem to be necessary. Targeting inosine 5-monophosphate dehydrogenase, the rate-limiting enzyme of purine synthesis, is an effective strategy to modulate the temporal dynamics of proliferation and migration of microglia and astrocytes, and thus to reduce the extent of secondary neuronal damage and scar formation.