mycophenolic-acid and Atrophy

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Autoantibodies; Autoimmune Diseases of the Nervous System; Brain; Disease Progression; Encephalomyelitis; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Myelin-Oligodendrocyte Glycoprotein

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is used in transplanted patients, with frequent gastrointestinal adverse effects. We report the case of a patient, under chronic therapy with mycophenolate mofetil , during a diagnostic workup for a chronic diarrhea, which presents a duodenal villous atrophy ( VA) with negative celiac serology, which is a diagnostic challenge. VA secondary to MMF is a very unusual adverse effect. Just a few cases have been reported in the literature.

Topics: Adult; Atrophy; Celiac Disease; Duodenum; Endoscopy, Gastrointestinal; Humans; Immunosuppressive Agents; Kidney; Mycophenolic Acid; Transplant Recipients

The widely used International Study of Kidney Disease in Children (ISKDC) classification for Henoch-Schönlein purpura nephritis (HSPN) does not completely correlate with the clinical presentation and long-term prognosis of this disease. Primary IgA nephropathy (IgAN) and HSPN share common features; thus, the Oxford classification of IgAN might be useful in predicting the long-term outcomes of HSPN. However, its value has not been confirmed in children with HSPN.. We selected children with HSPN diagnosed between 2003 and 2015, and reclassified their renal biopsies according to the Oxford classification scoring system. The primary outcome was impaired renal function, and remission of proteinuria and clinical remission were secondary outcomes.. We included 104 patients (58 males, 46 females) with a median age of 10 (4-17) years. Mesangial hypercellularity (M1) was strongly associated with proteinuria, and tubular atrophy/interstitial fibrosis (T1&2) and C2 (with crescents in > 25% of glomeruli) were associated with reduced estimated glomerular filtration rate (eGFR) at the time of biopsy. Patients with M1, endocapillary proliferation (E1), segmental glomerulosclerosis (S1), and crescents (C1&2) were more likely to have been treated with high-dose methylprednisolone. At univariate time-dependent analyses, S1 was strongly associated with the primary outcome (p = 0.025), whereas T1&2 was significantly negatively associated with proteinuria remission (p = 0.035) and clinical remission (p = 0.038).. Our findings suggest that the Oxford classification is valid for children with HSPN. S and T lesions, which are ignored in the ISKDC classification, can be used to assess renal outcomes of HSPN, and such assessments are not affected by currently available treatments. The value of M, E and C lesions in predicting response to therapy and renal outcome warrants further study.

Topics: Adolescent; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Atrophy; Biopsy; Child; Child, Preschool; Cyclophosphamide; Female; Fibrosis; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; IgA Vasculitis; Immunosuppressive Agents; Kidney Tubules; Leflunomide; Male; Methylprednisolone; Mycophenolic Acid; Proteinuria; Risk Factors

The potential diagnostic value of circulating free miRNAs in plasma compared to miRNA expression in blood cells for rejection processes after kidney transplantation is largely unknown, but offers the potential for better and timely diagnosis of acute rejection. Free microRNA expression of specific blood cell markers was measured in 160 plasma samples from kidney transplant patients under standard immunosuppressive therapy (steroids±mycophenolic acid±calcineurin inhibitor) with stable graft function, urinary tract infection, interstitial fibrosis and tubular atrophy, antibody-mediated rejection (ABMR), Borderline (Banff3), tubulo-interstitial (Banff4-I) and vascular rejection (Banff4-II/III) applying RT-PCR. The expression levels of specific microRNAs miR-15B, miR-103A and miR-106A discriminated patients with stable graft function significantly (p-values 0.001996, 0.0054 and 0.0019 resp.) from patients with T-cell mediated rejection (TCMR) and from patients with urinary tract infection (p-values 0.0001, <0.0001 and 0.0001, resp.). A combined measurement of several microRNAs after multivariate logistic regression improved the diagnostic value supported by subsequent cross-validation. In conclusion, the measurement of circulating microRNAs in plasma from patients with renal transplants distinguishes TCMR and urinary tract infection from stable graft function. In contrast to miRNA expression measurement in blood cells it does not allow a discrimination from ABMR or interstitial fibrosis and tubular atrophy.

Topics: Adult; Aged; Atrophy; Biomarkers; Calcineurin Inhibitors; Diagnosis, Differential; Female; Fibrosis; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; MicroRNAs; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Prognosis; Steroids; T-Lymphocytes; Transplantation Tolerance; Urinary Tract Infections

Cellular and antibody-mediated rejection processes and also interstitial fibrosis/tubular atrophy (IFTA) lead to allograft dysfunction and loss. The search for accurate, specific and non-invasive diagnostic tools is still ongoing and essential for successful treatment of renal transplanted patients. Molecular markers in blood cells and serum may serve as diagnostic tools but studies with high patient numbers and differential groups are rare. We validated the potential value of several markers on mRNA level in blood cells and serum protein level in 166 samples from kidney transplanted patients under standard immunosuppressive therapy (steroids±mycophenolic acid±calcineurin inhibitor) with stable graft function, urinary tract infection (UTI), IFTA, antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR) applying RT-PCR and ELISA. The mRNA expression of RANTES, granulysin, granzyme-B, IP-10, Mic-A and Interferon-γ in blood cells did not distinguish specifically between the different pathologies. We furthermore discovered that the mRNA expression of the chemokine IL-8 is significantly lower in samples from IFTA patients than in samples from patients with stable graft function (p<0.001), ABMR (p<0.001), Borderline (BL) TCMR (p<0.001), tubulo-interstitial TCMR (p<0.001) and vascular TCMR (p<0.01), but not with UTI. Serum protein concentrations of granzyme-B, Interferon-γ and IL-8 did not differ between the patient groups, RANTES concentration was significantly different when comparing UTI and ABMR (p<0.01), whereas granulysin, Mic-A and IP-10 measurement differentiated ongoing rejection or IFTA processes from stable graft function but not from each other. The measurement of IL-8 mRNA in blood cells distinguishes clearly between IFTA and other complication after kidney transplantation and could easily be used as diagnostic tool in the clinic.

Topics: Adult; Aged; Animals; Atrophy; Biomarkers; Blood Cells; Calcineurin Inhibitors; Diagnosis, Differential; Fibrosis; Graft Rejection; Humans; Immune Tolerance; Interleukin-8; Isoantibodies; Kidney; Kidney Transplantation; Mice; Middle Aged; Mycophenolic Acid; Steroids; T-Lymphocytes; Urinary Tract Infections

Chronic transplant dysfunction after kidney transplantation is a major reason of kidney graft loss and is caused by immunological and non-immunological factors. There is evidence that mycophenolate mofetil (MMF) may exert a positive effect on renal damage in addition to immunosuppression, by its direct antifibrotic properties. The aim of our study was to retrospectively investigate the role of MMF doses on progression of chronic allograft dysfunction and fibrosis and tubular atrophy (IF/TA).. Retrospective, cohort study.. Patients with kidney transplant in a tertiary care institution. This is a retrospective cohort study that included 79 patients with kidney and kidney-pancreas transplantation. Immunosuppression consisted of anti-interleukin 2 antibody induction, MMF, a calcineurin inhibitor±steroids.. An association of average MMF doses over 1 year post-transplant with progression of interstitial fibrosis (Δci), tubular atrophy (Δct) and estimated-creatinine clearance (eCrcl) at 1 year post-transplant was evaluated using univariate and multivariate analyses.. A higher average MMF dose was significantly independently associated with better eCrcl at 1 year post-transplant (b=0.21±0.1, p=0.04). In multiple regression analysis lower Δci (b=-0.2±0.09, p=0.05) and Δct (b=-0.29±0.1, p=0.02) were independently associated with a greater average MMF dose. There was no correlation between average MMF doses and incidence of acute rejection (p=0.68).. A higher average MMF dose over 1 year is associated with better renal function and slower progression of IF/TA, at least partly independent of its immunosuppressive effects.

Topics: Adult; Atrophy; Cohort Studies; Disease Progression; Female; Fibrosis; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Kidney Tubules; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation.. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil.. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001).. These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Topics: Adult; Aged; Atrophy; Biopsy; Drug Therapy, Combination; Female; Fibrosis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Linear Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Netherlands; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Biomarkers, Tumor; Carcinoma, Renal Cell; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Kidney Transplantation; Male; Mucin-1; Mycophenolic Acid; Nephrectomy; Postoperative Complications; Reoperation; Tacrolimus

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Topics: Adult; Aged; Atrophy; Diarrhea; Duodenum; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Treatment Outcome

We evaluated the role of renal tubular Nox-2 in the pathogenesis of epithelial-to-mesenchymal transition (EMT) in kidney allografts.. We examined this question in the human kidney allografts with interstitial fibrosis and tubular atrophy not otherwise specified (IFTANOS), in the Fisher to Lewis rat transplant model, and in the in vitro model of transforming growth factor-beta1-induced EMT in normal rat kidney epithelial cells (NRK52E).. We first demonstrated that Nox-2 and alpha-smooth muscle actin (SMA) were increased in renal tubules from kidney transplant recipients on calcineurin inhibitors, mycophenolic acid (MPA), and prednisone with IFTANOS, suggestive of EMT (n=6). Next, we examined Nox-2 expression and fibrogenesis in syngeneic transplants, allogeneic transplants treated with MPA 40 mg/kg per 24 hr, and untreated allogeneic transplants for 6 months (n=14 in each group). Immunofluorescent and immunohistochemical studies for Nox-2, alpha-SMA, and E-cadherin showed that similar to patients with IFTANOS, rat allografts had greater tubulointerstitial staining for Nox-2 and alpha-SMA. MPA therapy prevented these changes. Immunoblot analyses examining Nox-2 signaling (phospho-nuclear factor [NF]-kappaB), redox signaling (phospho-smad2), and fibrosis (alpha-SMA and fibronectin) demonstrated that MPA treatment prevented the up-regulation of Nox-2, inhibited p-NF-kappaB and p-smad2, and down-regulated alpha-SMA and fibronectin levels. Finally, we examined Nox-2 signaling in vitro and confirmed that MPA inhibited phospho-NF-kappaB, Nox-2, phospho-smad2, and alpha-SMA during transforming growth factor-beta1-induced EMT of NRK52E cells while reducing Nox-2, vimentin, and fibronectin mRNA levels.. MPA may down-regulate Nox-2 activation and EMT through the NF-kappaB pathway in the tubular epithelial cells, suggesting a novel role for this drug independent of its immunosuppressive properties.

Topics: Adult; Animals; Anti-Bacterial Agents; Atrophy; Biopsy; Creatinine; Disease Models, Animal; Fibrosis; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Mycophenolic Acid; NF-kappa B; Oxidative Stress; Rats; Rats, Inbred Lew; Reactive Oxygen Species; Transforming Growth Factor beta1; Transplantation, Homologous

Mycophenolate mofetil (MMF) is an immunosupressor agent frequently used in patients after bone marrow or solid organ transplants. The most common adverse reactions of the drug are gastrointestinal, specially diarrhea and vomiting. We report a 53-year-old male, that received a heart transplant receiving immunosuppression with cyclosporine, mycophenolate mofetil and prednisone. Six months after the transplant, the patient started with diarrhea, anorexia and weight loss. A duodenal biopsy showed villous atrophy. Celiac disease and the presence of parasites were discarded. Mycophenolate mofetil was discontinued and one week later, diarrhea subsided. Two months later the patient was asymptomatic and recovered weight. A new duodenal biopsy showed absence of villous atrophy.

Topics: Atrophy; Biopsy; Duodenum; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Microvilli; Middle Aged; Mycophenolic Acid

Leucopenia and diarrhoea are the main side effects observed after the use of mycophenolate mofetil (MMF) in renal-transplant patients. The mechanism of diarrhoea remains unknown. We report on four cases presenting with severe diarrhoea, which appeared, respectively, at 4, 10, 24, and 66 months after MMF therapy had been started. All patients presented with weight loss and biological signs of malabsorption syndrome. Oesophago-gastroduodenoscopy revealed duodenal villous atrophy, which was confirmed by pathology examination. Anti-endomysium antibodies were negative. In all patients, diarrhoea disappeared within 1 month of MMF withdrawal without a gluten-free diet. A control oesophago-gastroduodenoscopy was performed in one patient 6 months later and was considered normal. None of the patients showed evidence of cytomegalovirus in enterocytes or cytomegalovirus-positive viraemia. In conclusion, villous atrophy induced by MMF might be one of the mechanisms of diarrhoea. It is mandatory to differentiate coeliac disease from MMF-induced villous atrophy because, in the latter case, a gluten-free diet is not required.

Topics: Adult; Atrophy; Duodenum; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Male; Microvilli; Middle Aged; Mycophenolic Acid

Mycophenolate mofetil (MMF) is a new immunosuppressant developed for the prevention and treatment of acute renal rejection after transplantation. Diarrhea is the most frequent side effect observed during treatment with MMF. Its pathogenic mechanisms remain unknown. We describe a case of severe diarrhea due to villous atrophy in a renal transplant recipient during treatment with MMF. The patient was free of symptoms before MMF. Villous atrophy disappeared a few months after MMF withdrawal.

Topics: Adult; Atrophy; Female; Humans; Immunosuppressive Agents; Intestine, Small; Kidney Transplantation; Microvilli; Mycophenolic Acid