MMF Treatment Research Articles

Anti-Psoriatic Drug Monomethylfumarate Increases Nuclear Factor Erythroid 2-Related Factor 2 Levels and Induces Aquaporin-3 mRNA and Protein Expression.

Oxidative stress contributes to inflammatory skin diseases, including psoriasis. Monomethylfumarate (MMF) is an antipsoriatic agent with a poorly understood mechanism of action. In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular antioxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis. We tested the hypothesis that MMF enhances Nrf2 activity in keratinocytes, thereby improving their capacity to counteract environmental stresses. We used Western analysis, immunofluorescence, and real-time quantitative reverse-transcription polymerase chain reaction to examine the effect of MMF on the expression of Nrf2 and its targets. We also measured intracellular reactive oxygen species (ROS) levels following MMF treatment. Our data show that MMF increased total and nuclear Nrf2 levels in primary mouse keratinocytes and enhanced mRNA expression of several Nrf2-downstream effectors, including heme oxygenase-1 and peroxiredoxin-6. Moreover, MMF treatment attenuated the generation of ROS following hydrogen peroxide treatment. On the other hand, the expression and membranous localization of aquaporin-3 (AQP3), a glycerol channel implicated in keratinocyte differentiation, was stimulated by MMF, which also enhanced keratinocyte glycerol uptake. The Nrf2 activator sulforaphane also increased AQP3 levels, suggesting that AQP3 expression may be regulated by Nrf2. We show for the first time that MMF stimulates Nrf2 and AQP3 expression and function/activity in keratinocytes. This effect may account, in part, for the previously observed ability of MMF to inhibit proliferation and inflammatory mediator production and promote differentiation in keratinocytes and to treat psoriasis.

Study of the Role of Nicotinamide Phosphoribosyl Transferase/Visfatin in Egyptian Patients with Systemic Lupus Erythematous and Lupus Nephritis

Introduction: Lupus nephritis (LN) is common and carries a high burden of morbidity in SLE patients. The adipokine ‘‘visfatin’’is highly expressed in visceral fat, exerts several pro inflammatory functions and was demonstrated as a marker of endothelial dysfunction (ED) in chronic kidney disease (CKD). Aim of the work: to evaluate the state of serum visfatin in SLE patients and to detect its possible correlation to disease activity and kidney affection. Also, to define a possible correlation between the level of visfatin before and after a treatment regimen of combined mycophenolate mofetil and corticosteroids. Patients and methods: visfatin was assayed using enzyme-linked immunosorbent assay (ELISA), chemical and immunological markers of SLE and LN were measured in 50 SLE patients (included 25 patients with LN and 25 patients without LN), and compared with 25 age and sex matched healthy controls. Disease activity was assessed using SLE Disease Activity Index (SLEDAI). Renal biopsies were taken from LN subgroup and were classified according to the modified WHO classification. [1] Results: There was statistically highly significant difference (P < 0.001) as regards serum visfatin between patients (mean 8.31 ± 3.60, median 8, 64), and controls (mean 4.60 ± 2.01), serum visfatin showed significantly higher levels in LN compared to the non-lupus nephritis group (mean 8.78 ± 3.81 ng/ml,) versus (mean 7.85 ± 3.38 ng/ml,). Also, visfatin level was significantly higher among the active (mean 9.30 ± 3.14,) compared to the inactive group (mean 4.37 ± 2.46). Visfatin had a highly significant positive correlation with SLEDAI, disease duration, corticosteroids treatment duration, ESR and CRP. Also, a significant inverse correlation existed between visfatin, WBCs and Platelets count, correlation studies between visfatin level and low level of C3, C4 were significant. The correlation between serum visfatin level and Carotid artery intima media thickness by carotid Doppler imaging was also significant. There was a significant decrease (P= 0.041) between pre-treatment visfatin level and post treatment level after 3 months of MMF and high dose CS treatment, Visfatin mean decreased from (8.78 ± 3.81 ng/ml) to (8.29 ± 3.44 ng/ml). Conclusion: visfatin is closely associated with SLE activity especially with lupus nephritis revealing the promising role of this adipokine in SLE activity measurement and prediction of renal involvement in SLE patients.

Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS-Related Disorders. Different Bio-Clinical Profile and Similar Response to Treatment: A Single Centre Experience

ALPS is an inherited disorder characterized by lymphoproliferation and autoimmunity that mainly involves blood cells. In the last few years, new disorders other than ALPS have been found to cause lymphoproliferative syndromes, and many patients with similar clinical features but not fitting ALPS diagnostic criteria have been described. In this study we evaluate clinical features and response to the treatment of patients with ALPS and ALPS-related Syndromes (ARS) followed in a single Center.ALPS was defined according to the revised diagnostic criteria (first international Workshop, 2009). ARS was defined as the presence of cytopenia and/or lymphoproliferation and at least one absolute or primary additional criterion for ALPS. Medical records of patients followed in our Center between 2001 and 2014 for these conditions were evaluated.Sixty-five patients (35 males), with median age at diagnosis of 10 years (range 0-39) with ALPS (32) (definitive: 21, probable: 11), or ARS (33) entered this study. A positive history of lymphoproliferation was present in 8/32 (25%) and in 3/33 (9%) of ALPS and ARS subjects, respectively. Lymphoproliferation was present in 51/65 (78%) patients and consisted of isolated lymphoadenopathy (10/51, 19%), isolated splenomegaly (26/51, 51%), or both conditions (15/51, 29%). It was present in 32/32 (100%) and in 19/33 (57%) of patients with ALPS or ARS, respectively. In particular, lymphoadenopathy was present in 17/32 (53%) and in 8/33 (24%) of ALPS and ARS patients, respectively (p 0.04). Splenomegaly was found in 27/32 (84%) and in 14/33 (43%) of ALPS and ARS subjects respectively (p < 0.01) Cytopenia was present in 51/65 (78%) of patients and involved one (28/51, 55%) or more cell lineage in (23/51, 45%). Trilinear cytopenia was present in 7 ALPS patients and in no subjects with ARS (p<0.01). Isolated thrombocytopenia was the most frequent occurring in 4/32 (12%) and in 12/33 (36%) ALPS and ARS, respectively (p 0.03). No statistical difference was found on the incidence of other type of cytopenia between the 2 groups. The median percentage of Double Negative T-cells/total lymphocytes was 2.6 (range 1.5-14.8) and 1.8 (range 0.6-9.2) in ALPS and ARS patients, respectively (p<0.01). Autoantibodies were present in 17/32 (53%) and in 20/33 (58%) ALPS and ARS patients, respectively, being ANA the most frequently found marker (9/17 ALPS, 8/19 ARS). Autoimmune symptoms other than cytopenia were present in 13/32 (41%) and in 5/33 (15%) patients with ALPS and ARS, respectively (p<0.02). The most common symptom was arthritis that was present in 8 patients (4 ALPS, 4 ARS). The other issues consisted of tyroiditis, hepatitis, nephrosis syndrome, eczema, cholangitis, celiac disease, colitis, and psoriasis.Fifty-one/65 (78%) patients required treatment and 10/51 (20%) responded to steroids/Immunoglobulin given as first line therapy. The remaining 41 (80%) patients required further lines of treatment. Thirty-four/41 (83%) received MMF for a median of 314 days with a partial/complete response in 17/25 (68%) evaluable patients, and in particular, in 11/14 (79%) and 6/11 (54%) of ALPS and ARS patients, respectively. Mild side-effects (vomit, gastrointestinal issues, fever, headache) were reported in 5 (15%) patients. Sirolimus was given for a median of 395 days to 18/41 (44%) patients, including 11 patients who had previously failed MMF treatment, and led to a partial/complete response in 12/16 (75%) patients and, in particular, in 5/7 (71%) and 7/9 (78%) of ALPS and ARS patients, respectively. Vomit was reported as side effect in one (6%) patient. Median duration of follow-up was 3.3 years (range 0-12.6)This study confirms the existence of a group of patients who do not fulfil ALPS diagnostic criteria and display a more attenuated bio-clinical phenotype. The presence of lymphoproliferation and elevated DNT is the main feature differentiating ALPS from ARS patients. Trilinear cytopenia is a typical feature of ALPS patients and isolated thrombocytopenia is more frequent in ARS patients. The presence of autoimmune symptoms other than cytopenia is more frequent in ALPS patients. MMF and Sirolimus, which are reported as safe and effective in ALPS patients, may represent a valid option for the treatment of ALPS-related disorders as well. Further studies are needed to identify the immunological defects underlying ARS patients which may help for a better classification of these disorders. DisclosuresDufour:Pfizer: Consultancy.

Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases.

The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/µL, we should be care of occurrence of PJP.

Steroid-resistant acute rejection after cadaveric liver transplantation: Experience from one single center

Steroid-resistant acute rejection (SRAR) is an infrequent event under current immunosuppressant but still a risk factor leading to graft loss and patients' death after liver transplantation. There are several strategies for managing this complication according to current literatures, but none of the treatment seems convincing and widely accepted. Here we retrospectively analyzed the clinical data of a cohort of patients to gain an insight into this complication. A total of 962 adult patients receiving whole liver grafts at a single center between January 2004 and December 2012 were studied. One hundred and forty-two recipients experienced 158 episodes of acute rejection after the operation, 14 recipients had no response to steroid bolus treatment. The clinical data was analyzed retrospectively. Incidence rate of acute rejection after liver transplant in our single center was 14.7% (142/962), among them 8.8% (14/158) were steroid-resistant. These episodes occurred on 19days (6-72days) after the operation, 3 were controlled by anti-T3-receptor antibody (OKT3) treatment, 4 were reversed by IL-2 receptor inhibitors combining with MMF treatment, 2 were reversed by antithymocyte globulin (ATG) treatment. Five did not recover and 2 received retransplantation. Mortality associated with SRAR was 28.6% (4/14, 1 died from acute liver failure, 1 from chronic liver failure, 1 from renal failure after retransplantation and 1 from pulmonary infection after OKT3 treatment). SRAR is a severe complication with high mortality after liver transplantation; ATG might serve as a potential treatment.

Retrospective study of mycophenolate mofetil treatment in IgA nephropathy with proliferative pathological phenotype

Background Mycophenolate mofetil (MMF) and cyclophosphamide (CTX) are widely used in treating various kidney diseases. However, whether they are effective and which one is better for treating IgA nephropathy patients with proliferative pathological phenotype in renal diseases, such as endocapillary proliferation, cellular crescents, and/or capillary loops fibrinoid necrosis is still unknown. We, therefore, initiated a study to compare the effects of MMF and CTX in treating IgA nephropathy with the above pathological lesions. Methods One hundred and nineteen patients with IgA nephropathy who had at least one of the three aforementioned lesions were enrolled. All patients were treated with prednisone; 48 patients received prednisone only (Pred group), 40 received MMF and prednisone (MMF + Pred group), and 31 were treated with CTX and prednisone (CTX + Pred group). The median time of follow-up was 30 months (maximum: 96 months). The primary endpoint was defined as renal survival. The incidence of remission of proteinuria was the secondary endpoint. Results Serum creatinine in all groups declined significantly at different follow-up times (P=0.002), and the differences among the three groups were significant (P&lt;0.001). At 24 months of follow-up, the decline rates were 12.35%, 32.95%, and 24.14% in the Pred, MMF + Pred, and CTX + Pred groups respectively. For urine protein excretion, the decline rates were 49.12% (Pred), 73.67% (MMF + Pred), and 63.53% (CTX + Pred) respectively at 24 months of follow-up. The differences among the three groups were not significant (P=0.714). Renal survival (the primary endpoint) was significantly different (P=0.027); however, the sencondary endpoint was similar for all the three groups (P=0.100). Conclusions For IgA nephropathy patients with endocapillary proliferation, cellular crescents, and/or fibrinoid necrosis of capillary loops, prednisone combined with MMF was more effective in lowering the serum creatinine than with CTX. Combined MMF and prednisone treatment led to a better renal survival compared to that of prednisone with CTX.

Impact of immunosuppression treatment on the improvement in graft survival after deceased donor renal transplantation: a long-term cohort study.

We analyzed graft half-life and attrition rates in 1045 adult deceased donor kidney transplants from 1986-2001, with follow-up to 2011, grouped in two periods (1986-95 vs. 1996-01) according to immunosuppression. The Kaplan-Meier curve showed a significant increase in graft survival during 1996-2001. The uncensored real graft half-life was 10.25 years in 1986-95 and the actuarial was 14.58 years in 1996-2001 (P&lt;0.001). The attrition rates showed a significantly greater graft loss in 1986-95, even excluding the first year from the analysis. The decline in renal function was significantly less pronounced in 1996-2001, indicating better preservation of renal function, despite the increase in donor age and stroke as the cause of donor death. The parsimonious Cox multivariate model showed donor age, acute rejection, panel reactive antibody, cold ischemia time and delayed graft function were significantly associated with a higher risk of graft loss. In contrast, the risk of graft loss fell by 21% in 1996-2001 compared with 1986-95. A similar reduction (25%) was observed when MMF treatment was entered into the multivariate model instead of study period. Long-term graft survival improved significantly in 1996-2001 compared to 1986-1995 despite older donor age. Modern immunosuppression could have contributed to the improved kidney transplant outcome.

Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats

We designed experiments to test the hypothesis that Dahl salt-sensitive (SS) rats are sensitive to high-fat diet (HFD)–induced hypertension and renal injury via an inflammatory mechanism. Twelve-week-old Dahl SS rats were maintained on a normal diet (ND; 14% fat), HFD (59% fat), or HFD supplemented with the lymphocyte immunosuppressive agent, mycophenolate mofetil (HFD + MMF; 30 mg/kg/day orally in diet), for a period of 4 weeks. Mean arterial pressure (MAP), metabolic parameters, T lymphocyte (CD3+) localization, and renal structural damage were assessed during the studies. Four weeks of HFD significantly elevated MAP and visceral adiposity without changing circulating levels of lipids or adipokines. Immunohistochemical analysis demonstrated that SS rats on HFD had significantly greater numbers of CD3+ cells in renal glomerular and medullary areas compared to ND SS rats. Additionally, HFD led to increased glomerular injury, but did not alter renal medullary injury. Chronic MMF treatment in HFD-fed Dahl SS rats reduced MAP, visceral adiposity, infiltration of CD3+ cells in the glomerulus, as well as glomerular injury. However, MMF treatment did not alter HFD-induced infiltration of CD3+ cells in the renal medulla. In conclusion, Dahl SS rats are sensitized to HFD-induced hypertension and renal glomerular injury via infiltration of T lymphocytes.

THU0260 Low Risk of Renal Flares and of Negative Outcomes in Women with Lupus Nephritis Conceiving after Switching Mycophenolate Mofetil to Azathioprine

BackgroundA growing number of women with Lupus nephritis (LN) wish to fulfil their desire for having a child. A common concern is the optimal choice of immunosuppressive treatment during the...

Mycophenolate mofetil in multiple sclerosis: a multicentre retrospective study on 344 patients

ObjectivesMycophenolate mofetil (MMF) is an immunosuppressive agent, sometimes used as a disease-modifying therapy for multiple sclerosis (MS). Several studies have reported the relative safety of this treatment but, to date,...

Long-term data on corticosteroids and mycophenolate mofetil treatment in lupus nephritis

We investigated the long-term outcome of patients with proliferative LN treated with CSs and MMF. This was a single-centre retrospective study on patients with biopsy-proven class III/IV ± V LN treated with prednisolone and MMF continuously as both early and maintenance immunosuppression. Sixty-five patients were included, and followed for 91.9 (47.7) months. All received prednisolone and MMF as induction immunosuppression. In 31 patients, maintenance immunosuppression comprised prednisolone and MMF only (MMF-MMF group). MMF was replaced with AZA in 23 patients (MMF-AZA), and with calcineurin inhibitors (CNIs) in 11 patients (MMF-CNI) at sometime during follow-up. Ten-year patient and renal survival rates were 91% and 86%, respectively, and were similar in the three groups. MMF-MMF group showed better relapse-free survival than MMF-AZA and MMF-CNI patients (76% vs 56% vs 43%, respectively at 5 years; 69% vs 32% vs 0%, respectively at 10 years; MMF-MMF vs MMF-AZA or MMF-CNI, P = 0.049 or 0.019, respectively; MMF-AZA vs MMF-CNI, P = 0.490). Patients treated with MMF for >24 months had better relapse-free survival than those treated for shorter durations (88% vs 48% at 5 years; 81% vs 28% at 10 years; P < 0.001). Renal function at 10 years was better in the MMF-MMF group. Anaemia was associated with MMF treatment. Other adverse events were comparable and relatively minor with MMF, AZA or CNI as maintenance. Long-term treatment with CSs and MMF from induction to maintenance phase is associated with relatively favourable long-term outcome in Chinese LN patients. Discontinuation of MMF before 24 months may increase the risk of flares.

Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate

Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ˜50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.

Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr−/− mice

RationaleRecent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is...

Mycophenolate mofetil reduces renal T cell numbers and prevents high fat induced hypertension in Dahl rats

Dahl salt-sensitive rats (SS) display fat-sensitive hypertension following 4 weeks of high fat diet (HF; 60% fat/0.4% NaCl) compared to SS on normal fat diet (NF; 14% fat/0.4% NaCl) (telemetry: 152 ± 5 vs 133 ± 6 mmHg; p<0.05; n=4). Recently, we showed that mycophenolate mofetil (MMF; 30 mg/kg/day) prevents fat-induced hypertension. The aims of this study were to determine if 1: HF increases renal T cell number vs NF SS; 2: MMF reduces renal T cell numbers in HF SS; 3: MMF reduces total cellular proliferation in kidneys from HF SS. Following magnetic-cell separation, renal T lymphocytes were not changed (p>0.05) with HF in SS (HF: 22 ± 2; NF: 33 ± 6 × 106/2 kidneys; n=3). With immunolocalization, CD3+ cell count was not altered (p>0.05) with HF in renal cortex (HF: 16 ± 3; NF: 17 ± 3 cells/400 μm2; n=6–8) or medulla (HF: 25 ± 2; NF: 20 ± 2 cells/400 μm2; n=6–8). MMF reduced renal cortical CD3+ cells in HF SS (28 ± 3 vs 16 ± 3 cells/400 μm2; n=5; p<0.05) but not medullary CD3+ counts (HF-MMF: 19 ± 2 vs HF+MMF: 16 ± 3; n=5; p>0.05). Total cellular proliferation status was assessed with Ki-67 immunhistochemistry. MMF treatment did not change (p>0.05) renal cortical Ki-67+ cells (HF-MMF: 16 ± 1; HF+MMF: 15 ± 2 Ki-67+ cells/400 μm2; n=5) or medullary Ki-67+ cells (HF-MMF: 19 ± 2; HF+MMF: 21 ± 6 Ki-67+ cells/400 μm2; n=5). These data suggest that immunosuppression prevents hypertension in HF SS by reducing renal T lymphocyte number.

Impact of maintenance immunosuppressive regimens - balance between graft protective suppression of immune functions and a near physiological immune response

The Symphony study showed superior 1-year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin-secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post-transplant. Tacr- compared with CsA-based immunosuppression was independently associated with increased IL-2 (P<0.0001, CD4 cells; P=0.014, CD8 cells) and CD4 cell IL-4 responses (P=0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL-10 responses (P=0.008), B-cell IL-6R expression (P<0.0001) and ISC formation [P=0.020, staphylococcus cowan strain I (SAC I); P=0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL-4 by Tacr, decreased CD4 cell IL-10 responses by MMF) and suppression of B-cell functions (MMF), whereas Tacr/Aza was associated with physiological IL-2 and IL-4 and stronger humoral responses which may reduce the risk of infectious disease complications.

Mycophenolate mophetil therapy for chronic immune thrombocytopenic purpura resistant to steroids, immunosuppressants, and/or splenectomy in adults

Treatment options are limited in patients with chronic immune thrombocytopenic purpura (ITP) which has been unresponsive to corticosteroids and/or splenectomy. Mycophenolate mophetil (MMF) is effective in many autoimmune disorders including severe and refractory ITP through its targeting of T-cell and B-cell lymphocytes. We report on the efficacy of MMF (1.5–2 g/day) in 16 adults with severe steroid-resistant ITP. MMF was administered for at least 12 weeks (median 37 weeks, range 14–64 weeks). Patients comprised of 10 females and six males, with median pre-treatment platelet counts of 8 × 109/L, median age of 55 years, median ITP duration of 58 months and a median of four prior treatments (range 3–8); nine had been previously splenectomized. Eleven patients (69%) responded after 12 weeks of MMF: 6 (55%) achieving complete remission (CR) and five (45%) achieved partial remission (PR). MMF therapeutic responses were better in those patients who had had fewer prior treatments (p < 0.05), and were independent of patient age, sex, disease duration, and splenectomy status (p > 0.05). Five of the 11 responders (45%; 3CR/2PR) had sustained remissions; however, six responders (55%; 3CR/3PR) relapsed after median of 14 weeks (range 9–20). Three of the six relapsing patients responded to MMF reinstitution achieving stabile PRs; three were left untreated as none had further bleeding and their platelets remained at “safe” levels (median 30 × 109/L). The MMF treatment was well tolerated; one heavily pretreated patient developed a bronchopneumonia and a second had an episode of diarrhea. MMF used as a second-line agent can produce a sustained response in severe ITP which has been unresponsive to steroid and/or splenectomy without major toxicity.

The influence of immunosuppressive drugs on vascular endothelial growth factor production in relation to VEGF -1154 g and -2578 C genotypes.

The pathogenesis of many diseases is correlated to irregularity in vascular endothelial growth factor (VEGF) expression. RESULTS from several association studies show that variation in the level of VEGF expression is related to polymorphic sequences within the VEGF gene. Additionally, there are many studies showing that some gene polymorphisms significantly influence the pharmacokinetics of immunosuppressive drugs. The aim of this study was to determine the influence of immunosuppressive drugs on VEGF production in individuals with different VEGF genotypes. ARMS-PCR was used to genotype VEGF polymorphisms at positions -1154 and -2578 within the promoter of VEGF gene. A VEGF-specific ELISA was used to determine the influence of immunosuppressive drugs on VEGF production in PBMCs of individuals with different VEGF genotypes. Suppressive effect of mycophenolic acid was observed just in individuals with GG -1154/CC -2578, GG -1154/CA -2578 and GA -1154/CC -2578 haplotypes. Additionally, VEGF was significantly suppressed in all individuals after treatment with rapamycin except those who had AA -1154/CA -2578 and AA -1154/AA -2578 VEGF genotype combinations. RESULTS of a recent study revealed that MMF treatment might be effective in preventing chronic renal rejection only in recipients with IL-10 high producer genotype. Additionally result of another study showed that CYP3A5 genotype markedly influences the pharmacokinetics of rapamycin in kidney transplant recipients. Therefore with regard to our results, different suppressive effect of mycophenolic acid and rapamycin on VEGF production might also be dependent on VEGF genotype.

Polyoma virus‐associated progressive multifocal leukoencephalopathy after renal transplantation: Regression following withdrawal of mycophenolate mofetil

The 2008-released FDA safety report described a potential association between use of MMF and progressive multifocal leukoencephalopathy. We here report the case of an 11-yr-old kidney transplanted boy suffering from PML who showed rapid improvement parallel to withdrawal of MMF. This case contributes to the increasing knowledge on side effects of MMF treatment in children.

Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant children

The aim of the study was to evaluate the efficacy and safety of the conversion of MMF to EC-MPS in pediatric renal transplant recipients. We included 12 patients with stable graft function who were receiving MMF treatment. In the first visit, a complete medical examination was performed, which included a GSRS, a nine-point pharmacokinetic profile, samples for renal, liver and hematological tests and evaluation of IMPDH2 gene expression. The patients were transferred to an equimolar dose of EC-MPS. Two wk later, a clinical evaluation and blood collection, as in the first visit were performed. There was no change in serum creatinine, leukocyte count, serum albumin, or transaminase levels, but we found a statistically significant reduction of hemoglobin after conversion (13.2 +/- 1.6 g/dL with MMF vs. 12.5 +/- 1.3 g/dL when receiving EC-MPS). The GSRS total mean score was 16 +/- 12 with MMF vs. 8 +/- 5 with EC-MPA (p < 0.05). There was no statistically significant difference between formulations in the gene expression of IMPDH 2, in the AUC(0-12h) or in C(max). However, peak concentration occurred later with EC-MPS.

Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate‐salt hypertensive rats

1. The interplay between the immune and renin-angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non-angiotensin II-dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)-salt-induced hypertension, in rats. 2. Male Sprague-Dawley rats underwent uninephrectomy and received either a sustained-release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA-salt- and placebo-treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA-salt rats compared with untreated DOCA-salt hypertensive rats (mean arterial pressure by telemetry on Day 18,146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF-treated DOCA-salt rats compared with untreated DOCA-salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA-salt-induced rise in renal cortical T-lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA-salt hypertension.