mycophenolic-acid and Obesity

Focal segmental glomerulosclerosis (FSGS) is a pathologic condition that represents many disease entities. The goals of therapy are to cure the disease. When this is not possible, the secondary goals are to reduce proteinuria to avoid the complications of nephrotic syndrome and to delay progression of kidney disease. Proteinuria remission is one of the most important independent predictors of kidney survival. Children with FSGS who do not achieve partial or complete remission have a 50% risk of progression to ESRD within 5 years whereas those who enter complete remission have a 5-year kidney survival rate of 90%. Treatment of idiopathic FSGS commonly involves immune-based and nonimmunologic therapy options. This manuscript will review the current state of FSGS therapy for children.

Topics: Adrenal Cortex Hormones; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antihypertensive Agents; Child; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Obesity; Rituximab; Tacrolimus; Treatment Outcome; Vitamin D Deficiency

Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear.. We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF.. Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 < BMI < 35 kg/m2) was associated with a significant risk of acute rejection for the mTORi-Tac group [obesity class 1 hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.21-2.62, P = .003]. A similar trend was observed in the Tac-MMF group for advanced obesity HR 1.29; 95% CI 0.96-1.73, P = .087). For the Tac-MMF group, recipients with both overweight and obesity had significantly impaired survival due to cardiovascular events and also increased mortality due to infection in advanced obesity. Combination of mTORi and calcineurin inhibitor was associated with lower rejection rates and stable long-term kidney function while reducing cardiovascular side effects linked to calcineurin inhibitors in obese kidney graft recipients.. These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Obesity; Propensity Score; Sirolimus; Tacrolimus; Transplant Recipients

Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Inosine Monophosphate; Metabolomics; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Obesity; RNA, Messenger

Kidney transplant (KT) recipients are at an increased risk for severe COVID-19 because of their immunosuppressed state. A 42-year-old KT patient was diagnosed with COVID-19 three months after KT. Despite lymphopenia and several risk factors, he had a mild disease course. Nasopharyngeal real-time reverse transcriptase polymerase chain reaction for SARS-CoV-2 became negative 48 days after detection. SARS-CoV-2 IgG antibodies became negative after day 40. TTV DNA load increased with the onset COVID-19 and reduced after its resolution. This is the first report where TTV DNA load was measured during the course of COVID-19.

Topics: Adult; Antibodies, Viral; Comorbidity; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Serological Testing; Diabetes Mellitus; DNA Virus Infections; DNA, Viral; Glucocorticoids; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Lymphopenia; Male; Mycophenolic Acid; Obesity; Prednisolone; SARS-CoV-2; Severity of Illness Index; Tacrolimus; Torque teno virus; Viral Load

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS).. The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies.. 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine.. Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alemtuzumab; Azathioprine; Black or African American; Cladribine; Comorbidity; COVID-19; Crotonates; Cyclophosphamide; Cyclosporine; Databases, Factual; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Hospitalization; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Incidence; Interferon-beta; Logistic Models; Lupus Erythematosus, Systemic; Male; Methotrexate; Middle Aged; Mitoxantrone; Multiple Sclerosis; Mycophenolic Acid; Natalizumab; Nitriles; Obesity; Risk Factors; Rituximab; SARS-CoV-2; Toluidines; United States; White People; Young Adult

Topics: Abatacept; Adult; Antibodies; Female; Gastrectomy; Graft Rejection; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Obesity

Obesity has been reported as risk factor for reduced posttransplant graft and patient survival and increased delayed graft function (DGF).. The purpose of this work is to analyze the effect of body mass index (BMI) on defined transplant outcomes in patients transplanted under defined guidelines in a kidney transplant program.. Review of a prospectively collected database in renal transplant recipients receiving rabbit antithymocyte globulin induction, mycophenolate mofetil, tacrolimus, and early corticosteroid withdrawal between 2001 and 2011.. This review was conducted in a single abdominal transplant program in the United States.. Primary outcome was death-censored graft survival categorized by posttransplant body mass groups. Secondary outcomes included DGF as well as patient survival.. Four hundred sixty seven patients were identified. No difference was observed in graft survival or DGF between BMI groups. One-year, death-censored graft survival and patient survival rates ranged from 97.5% to 100% and 96.6% to 100%, respectively. Delayed graft function was uncommon across all BMI groups, ranging from 5.3% to 9.1%, with the lowest incidence in patients with a BMI ≥ 35 kg/m(2). Biopsy-proven acute rejection rates at 1 year were similar across all groups (10.1%-14%) as were estimated glomerular filtration rates were at 1, 3, and 5 years.. Our results do not show an effect of BMI on posttransplant outcomes, suggesting that relaxation of BMI criteria may be warranted for recipient selection.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Body Mass Index; Comorbidity; Databases, Factual; Delayed Graft Function; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Obesity; Overweight; Retrospective Studies; Survival Rate; Tacrolimus; Thinness; Treatment Outcome

Increased focus on the potential negative side effects of steroid usage in pediatric transplantation has led to steroid minimization or steroid-free transplantation. In this study, we report results after complete steroid avoidance in renal transplantation in the period 1994-2009. We evaluate the effects of complete steroid avoidance on allograft function, BMI, and linear growth. The majority of transplanted children were induced with antithymocyte globulin and immunosuppressed with a calcineurin inhibitor and mycophenolate mofetil. Steroids were given only when rejection occurred or due to comorbidities. Anthropometric data were collected from 65 transplantations in 60 children. Patient survival was 93%; graft survival was 81% after five yr (N = 42) and 63% after 10 yr (N = 16). Acute rejection within the first year of transplantation was 9%. The distribution of the children's BMI before transplantation was normal; the mean BMI-SDS was 0.21 before transplantation, and this value remained stable during the next five yr. Post-transplantation the children demonstrated significant improved growth as the mean height-SDS increased significantly from -1.7 to -1.1. Catch-up growth was most pronounced in the youngest (< six yr). Steroid-free immunosuppression in pediatric renal transplantation is safe and protects against steroid-induced obesity and short stature.

Topics: Adolescent; Anthropometry; Antilymphocyte Serum; Body Mass Index; Calcineurin Inhibitors; Child; Child, Preschool; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Mycophenolic Acid; Obesity; Renal Insufficiency; Retrospective Studies; Steroids; Treatment Outcome

Follicular carcinoma of the thyroid is a relatively rare malignancy in childhood even in paediatric solid organ transplant recipients. The risk of developing de novo malignancies after liver transplantation is higher compared to the general population. We report an 18-yr-old girl who had successfully undergone liver transplantation five yr earlier for neonatal sclerosing cholangitis complicated by the development of dysplastic nodules. Baseline immunosuppression was with tacrolimus and prednisolone. Mycophenolate mofetil was later added in view of steroid-resistant episodes of graft rejection. She subsequently suffered from marked obesity and essential hypertension needing antihypertensive medication. Five yr after liver transplantation, she presented with a right-sided thyroid swelling that was rapidly progressive with no associated lymphadenopathy and normal systemic examination. Ultrasound of her neck revealed a solid lesion in the right lobe of the thyroid gland with ill-defined margins, and a diagnostic right thyroid lobectomy confirmed the diagnosis of follicular carcinoma with focal capsular and vascular invasion. She underwent total thyroidectomy and currently remains well on thyroxine supplements. Our report highlights the need for high level of suspicion and prompt investigation into any abnormal lesion in the long-term follow-up of solid organ transplant recipients.

Topics: Adenocarcinoma, Follicular; Adolescent; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Obesity; Prednisolone; Tacrolimus; Thyroid Neoplasms; Treatment Outcome

We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Diet; Enzyme Inhibitors; Guanosine; IMP Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Obesity; Weight Loss

Anomalous inflammatory responses triggered by the metabolic syndrome cause renal injury. This discovery links renal lipid accumulation with lipotoxicity to inflammation and may explain the insidious fibrosis and cellular decay characteristic of nephropathy in the metabolic syndrome. However, it is not clear whether control of inflammation protects the kidney independently of lipid accumulation, which is a required step for lipotoxicity in hyperglycemia and dyslipidemia. We hypothesized that in rats with the metabolic syndrome, and overt nephropathy, treatment with mycophenolate mofetil (MMF; 10 mg.kg(-1).day(-1) ip for 14 wk) would reduce the abnormal renal lipid depots and limit renal inflammation and injury. We studied groups of lean and obese F1 hybrid Zucker fatty diabetic/spontaneous hypertensive heart failure (ZS) rats. MMF did not affect lean rats. In obese ZS rats, MMF did not change severe hyperglycemia or the higher kidney loads of unutilized lipid and peroxidation products. Nonetheless, MMF dramatically reduced diabetes/obesity-derived systemic and renal inflammation, limited renal size, hyperfiltration, and fibrosis. These data indicate that in rats, anti-inflammatory therapy presumably acting downstream, and independently of lipotoxicity, can effectively limit renal injury and fibrosis.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Cholesterol; Inflammation; Kidney; Kidney Diseases; Male; Metabolic Syndrome; Mycophenolic Acid; Obesity; Phenotype; Rats; Triglycerides

The obese Zucker rat has metabolic condition resembling type II diabetes, including hyperlipidemia, obesity, insulin resistance, and hyperglycemia. With advancing age, the obese Zucker rat develops glomerulosclerosis, proteinuria, and renal failure. Since immune cells play a central role in the development of chronic renal injury, we evaluated the potential benefit of mycophenolate mofetil (MMF), alone and in combination with angiotensin receptor type 1 blockade (ARB) in the obese Zucker rat.. Thirteen-week-old male obese Zucker rats (fa/fa) were randomly assigned to four experimental groups (five rats each) that received the following treatments for 3 months: (1) losartan (100 mg/L in the drinking water), (2) MMF (20 mg/kg/day), (3) MMF and losartan, and (4) placebo. Lean Zucker rats (N = 5) were included as normal controls. Renal function, biochemical parameters, renal histology, and immunohistology were evaluated.. The placebo-treated obese Zucker rats exhibited proteinuria and significant glomerular and tubulointerstitial injury in association with renal immune cell infiltration. Proteinuria, histologic damage, and renal immune cell infiltration were all reduced by MMF treatment alone or in combination with ARB. The improvement of proteinuria and structural damage was more pronounced in the group that received the combination of MMF and losartan.. MMF treatment alone, and especially in combination with ARB, improves nephropathy in the obese Zucker rat.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Immunosuppressive Agents; Losartan; Male; Mycophenolic Acid; Obesity; Rats; Rats, Zucker

We report a 20-year-old-male with severe aplastic anaemia who was treated with nonmyeloablative haematopoietic stem cell transplantation (NSCT) from a sibling donor. As the patient presented with complications consisting of mental retardation, severe obesity, a bone fracture, and recurrent infections, we selected NSCT instead of a myeloablative regimen, to reduce regimen-related toxicity (RRT). Conditioning therapy consisting of busulfan, fludarabine, antithymocyte globulin and FK506 was used to obtain immune suppression. RRT was limited and he is now in complete remission 19 months after NSCT. On day 91, he developed chronic graft-vs.-host disease; it was resolved by the combination of FK506, corticosteroids, and mycophenolate mofetil. Our experience contributes to the growing interest in NSCT as a modality for treating not only malignant haematological disorders associated with complications, but also nonmalignant haematological diseases.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Busulfan; Female; Fractures, Bone; Graft Rejection; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Intellectual Disability; Male; Methylprednisolone; Mycophenolic Acid; Obesity; Peripheral Blood Stem Cell Transplantation; Prednisolone; Remission Induction; Siblings; T-Lymphocytes; Tacrolimus; Tissue Donors; Transplantation Chimera; Transplantation Conditioning; Vidarabine

The impact of obesity on graft survival after renal transplantation continues to be controversial. We have reviewed our experiences with living donor and cadaver transplantation in the current decade, focusing specifically on the impact of obesity on transplant outcome. Preoperative body mass index (BMI, kg/m2) was calculated for all adult renal transplant recipients between January 1990 and December 1995 and was used to classify patients as non-obese, moderately obese or morbidly obese. The effect of the degree of obesity on early and late outcomes after renal transplantation was examined. Three hundred and thirty-three recipients had pre-transplant BMI < 30 (normal or mild obesity), 68 BMI 30-40 (moderate obesity), and 7 BMI over 40 (morbid obesity). There was no correlation between obesity and other demographic factors. Wound infections and delayed graft function occurred more commonly in moderately and morbidly obese than in other cadaver donor recipients. Obese patients gained more weight after surgery and were given lower doses per kilogram of cyclosporine. There was, however, no significant correlation between obesity and graft survival for either cadaver or living donor transplants. Although obese patients have an increased risk of delayed graft function with cadaver donor transplantation, obesity has no discernible impact on either immunologic or overall graft survival with cadaver or living donor transplantation. The impact of moderate obesity on transplant outcome is modest and should not prevent these patients from receiving a transplant.

Topics: Adult; Azathioprine; Body Mass Index; Cadaver; Cyclosporine; Diabetes Mellitus; Female; Glucocorticoids; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Obesity; Obesity, Morbid; Prednisone; Surgical Wound Infection; Survival Rate; Transplantation, Homologous; Treatment Outcome; Weight Gain