Increased incidence of infections following the late introduction of mycophenolate mofetil in renal transplant recipients

Hanvesakul, Raj; Kubal, Chandrashekhar A.; Jham, Seema; Sarkar, Esha; Eardley, Kevin S.; Adu, Dwomoa; Cockwell, Paul

doi:10.1093/ndt/gfn387

Cited by 18 publications

(13 citation statements)

References 23 publications

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“…Recipients of solid-organ transplants who receive MMF as part of their post--transplant immunosuppressive regimen seem to have increased susceptibility to infections [81,82] especially cytomegalovirus [83]. However, infectious complications are seen predominantly more than 1 month after initiation of MMF treatment, thus an association with post-transplant renal insufficiency was assumed [84]. …”

Section: Discussionmentioning

confidence: 99%

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Ebrahimi

Koch

Pieroh

et al. 2012

J Neuroinflammation

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BackgroundImmunosuppressants 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.MethodsUsing 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.ResultsExcitotoxic 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.ConclusionsOur 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.

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Section: Discussionmentioning

confidence: 99%

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Ebrahimi

Koch

Pieroh

et al. 2012

J Neuroinflammation

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“…The rate of recurrent infection also increased significantly post conversion to MMF, with a rate of 6.6% before conversion to MMF and 43.3% post conversion ( P <0.0005). The authors suggest that a possible contributing factor was decreased renal function post transplant, essentially increasing serum levels of MMF with standard doses (6).…”

Section: Infectious Complications Associated With Mmfmentioning

confidence: 99%

“…Its anti‐B‐lymphocytic activity has been targeted for the treatment of rheumatologic disease, and already has proven efficacy against lupus nephritis (4, 5). However, the broad immunosuppressive abilities that make MMF an efficacious drug for transplant and autoimmune diseases might also enhance the risk of infectious complications (6).…”

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confidence: 99%

Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity

Ritter

Pirofski

2009

Transplant Infectious Dis

140

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Mycophenolate mofetil (MMF) is one of the most frequently used immunosuppressive drugs in solid organ transplant recipients. MMF is an inhibitor of inosine-5′-monophosphate, and is able to preferentially inhibit B-cell and T-cell function. The immunosuppressive abilities of MMF have made it one of the most successful anti-rejection drugs in transplant patients, but patients also appear to have increased susceptibility to infections, specifically cytomegalovirus and BKvirus. Despite its association with an increased risk of infection, MMF has also exhibited antimicrobial activity against pathogens including hepatitis C, Pneumocystis jirovecii, and human immunodeficiency virus. A thorough understanding of the functions of MMF on the immune system and interaction with infectious pathogens could be helpful in implementing preventative strategies against opportunistic infections in transplant patients.

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“…We have previously reported an overall incidence of post‐transplant infectious complications of 20.33% (12/59) in children transplanted with induction immunotherapy in the pre‐MMF era in our department (5). In a recent report from the United Kingdom, the infectious complications following the introduction of MMF in a group of adult renal transplant patients on a calcineurin inhibitor withdrawal protocol was assessed (9). In this report, the incidence of infections increased from 26.7% (8/30) prior to the use of MMF to 66.6% (20/30) after its introduction in the study group immunosuppressive protocol.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate mofetil in pediatric renal transplantation: A single center experience

Raheem

Kamel

Daly

et al. 2011

Pediatric Transplantation

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We assessed our long-term experience with regards to the safety and efficacy of MMF in our pediatric renal transplant population and compared it retrospectively to our previous non-MMF immunosuppressive regimen. Forty-seven pediatric renal transplants received MMF as part of their immunosuppressive protocol in the period from January 1997 till October 2006 (MMF group). A previously reported non-MMF group of 59 pediatric renal transplants was included for comparative analysis (non-MMF group). The MMF group comprised 29 boys and 18 girls, whereas the non-MMF group comprised 34 boys and 25 girls. Mean age was 11.7 and 12 yr in the MMF and non-MMF groups, respectively. The incidence of acute rejection episodes was 11 (23.4%) and 14 (24%) in the MMF and non-MMF group, respectively. Two (3.3%) grafts were lost in the non-MMF group compared with one (2.1%) in the MMF group. Twenty-one (44.68%) patients in the MMF group developed post-transplant infections compared with 12 (20.33%) in the non-MMF group (p < 0.0001). In conclusion, the use of MMF in pediatric renal transplantation was not associated with a lower rejection rate or immunological graft loss. It did, however, result in a significantly higher rate of viral infections.

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Increased incidence of infections following the late introduction of mycophenolate mofetil in renal transplant recipients

Abstract: There is significant morbidity associated with an increased incidence of infection after late introduction of MMF at standard doses in renal transplant recipients. This risk may be related to GFR at the time of conversion.

Cited by 18 publications

References 23 publications

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity

Mycophenolate mofetil in pediatric renal transplantation: A single center experience

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