mycophenolic-acid and Neutropenia

Leukopenia and neutropenia (L/N) may affect treatment decisions, potentially resulting in poor clinical and economic outcomes among kidney transplant recipients (KTRs). The burden of L/N is poorly quantified systematically. This systematic literature review aimed to summarize the incidence of, risk factors for, and clinical and economic outcomes associated with L/N post-KT.. We systematically searched MEDLINE, Embase, and the Cochrane Library (from database inception-June 14, 2021) and conferences (past 3 years) to identify observational studies examining epidemiology, risk factors, or outcomes associated with L/N among adult KTRs.. Of 2081 records, 82 studies met inclusion criteria. Seventy-three studies reported the epidemiology of L/N post-KT. Pooled incidence of neutropenia, defined as absolute neutrophil counts (ANC) <1000/μl, ranged from 13% to 48% within 1-year post-transplant; ANC <500/μl ranged from 15% to 20%. Leukopenia, defined as white blood cell counts <3500/μl, was 19% to 83%. Eleven studies reported independent risk factors associated with L/N post-KT. D+/R- cytomegalovirus status, mycophenolic acid (MPA), and tacrolimus use were the most consistent risk factors across studies. Fourteen studies reported L/N-associated clinical outcomes. We noted a trend toward a positive association between neutropenia and acute rejection/opportunistic infections. Mixed findings were noted on the association between L/N and graft failure or mortality. Dosage modifications of valganciclovir, MPA, cotrimoxazole, and anti-thymoglobulin and the need for granulocyte colony-stimulating factor (G-CSF) use were common with L/N.. Findings suggest post-transplant L/N were common and associated with frequent modifications of immunosuppressive agents, requiring G-CSF use, and rejection or opportunistic infections. Findings highlight the need for interventions to reduce risk of L/N post-KT.

Topics: Adult; Anemia; Graft Rejection; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Neutropenia; Opportunistic Infections; Transplant Recipients; Valganciclovir

Whether the intensity of the conditioning regimen affects febrile neutropenia (FN) and severe bacterial infections (SBIs) is not well established. We analyzed the risk factors (RFs) for the development of FN and SBI in the first 100d post-transplant in 195 consecutive adult recipients of a reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-allo).. The RIC regimens consisted of fludarabine plus melphalan (62%) or busulphan (38%) (FluMel or FluBu). SBIs include pneumonia, urinary tract infections, and bacteremia.. FN occurred in 141 patients (72%), always in the first 30d post-allo-RIC. However, a SBI occurred in only 27 patients (14%) during this early post-transplant period (

Topics: Adult; Bacterial Infections; Busulfan; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Mucositis; Mycophenolic Acid; Myeloablative Agonists; Neutropenia; Retrospective Studies; Risk Factors; Time Factors; Transplantation Conditioning; Transplantation, Homologous

Secondary cytopenias are serious complications following hematopoietic cell transplantation. Etiologies include myelotoxic agents, viral infections, and possibly transplant-related factors such as the intensity of the conditioning regimen and the source of stem cells.. We retrospectively analyzed data from 2162 hematopoietic cell transplant recipients to examine the effect of these factors on overall cytopenias occurring after 28 days in hematopoietic cell transplantation.. Advanced age of the patient, recipient cytomegalovirus seropositivity, unrelated donor status, human leukocyte antigen mismatch and lower doses of transplanted CD34(+) cells (≤ 6.4×10(6)/kg) significantly increased the risk of cytopenias after day 28. Non-myeloablative hematopoietic cell transplantation had protective effects on anemia and thrombocytopenia after day 28 (adjusted odds ratio 0.76, probability value of 0.05 and adjusted odds ratio 0.31, probability value of <0.0001, respectively) but not on overall or ganciclovir-related neutropenia. This lack of protection appeared to be due to the use of mycophenolate mofetil in the majority of recipients of non-myeloablative hematopoietic cell transplants. Peripheral blood stem cells did not confer protection from cytopenias when compared to bone marrow.. Elderly patients appear to be more prone to cumulative toxicities of post-transplant drug regimens, but non-myeloablative conditioning, optimized human leukocyte antigen matching, and higher doses of CD34(+) cell infusions may reduce the risk of cytopenia after day 28.

Topics: Adult; Age Factors; Aged; Anemia; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Thrombocytopenia; Time Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.

Topics: Adolescent; Anemia, Hemolytic, Autoimmune; Autoimmune Diseases; Child; Child, Preschool; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Leukocyte Count; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Neutropenia; Pain; Prodrugs; Thrombocytopenia

We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple sclerosis. The patient also developed synchronous immune thrombocytopenia and immune neutropenia, but not aplastic anemia. This patient received high dose steroids, intravenous immunoglobulin (iv.Ig), rituximab, red cell transfusions, vincristine, G-CSF, cyclosporin and mycophenolate to treat the combination of cytopenias over a period of 6 months with subsequent improvement in bone marrow function. While alemtuzumab has several recognized autoimmune complications, little is known about the potential hematological side effects. The combination of red cell aplasia, immune thrombocytic purpura and autoimmune neutropenia has not previously been described in the literature following alemtuzumab immunotherapy and highlights the importance of monthly blood monitoring post alemtuzumab administration.. Lay abstract We report a case of 28-year-old women with relapsing remitting multiple sclerosis who was treated with alemtuzumab and subsequently developed a series of autoimmune complications. Several months after completing her second course of alemtuzumab the patient became breathless and noticed bruising on her legs. On investigation she was found to be anemic and had a low platelet level (which predisposed her to bruising). In addition, her immune system was also impaired meaning she was more prone to developing opportunistic infections. The patient was treated with a variety of different medications and required blood transfusions for several months before she recovered. Despite the multiple complications the patient developed from alemtuzumab her multiple sclerosis remains stable with no new relapses 3 years following treatment.

Topics: Adrenal Cortex Hormones; Adult; Alemtuzumab; Antineoplastic Agents, Immunological; Cyclosporine; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Mycophenolic Acid; Neutropenia; Purpura, Thrombocytopenic, Idiopathic; Red-Cell Aplasia, Pure; Rituximab; Treatment Outcome; Vincristine

Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS.. We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing.. A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients.. MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

Topics: Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; RNA, Ribosomal, 16S

Late-onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and recurrence.. We conducted a single-center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of <1,000 cells/µl during B cell depletion. Secondary outcome measures included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox proportional hazards regression models. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.. We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year of B cell depletion therapy was 6.6% (95% CI 5.0-8.7). The incidence rate during the first year was higher compared to thereafter (7.2 cases per 100 person-years [95% CI 5.4-9.6] versus 1.5 cases per 100 person-years [95% CI 1.0-2.3]). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted HR 2.96 [95% CI 1.10-8.01] and 1.98 [95% CI 1.06-3.71], respectively). LON was not observed in minimal change disease or focal segmental glomerulosclerosis. The majority of episodes (59.4%) were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON.. LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, LON can be associated with serious infections and thus warrants vigilant monitoring.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Asymptomatic Diseases; Autoimmune Diseases; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Fever; Filgrastim; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematologic Agents; Humans; Immunologic Factors; Incidence; Lupus Erythematosus, Systemic; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Nephrosis, Lipoid; Neutropenia; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Factors; Rituximab; Sepsis

Immunosuppressive drugs are necessary to avoid or reduce the risk of rejection of transplanted organs. The immunosuppression generated may result in these patients needing  antibiotics and antivirals to be prescribed to them in conjunction with their immunosuppressants to avoid the risk of infection. This has generated an increase in neutropenia in patients treated with mycophenolate mofetil in combination with valganciclovir. The purpose of this study is to estimate the risk of neutropenia attributable to combination treatment of mycophenolate mofetil with valganciclovir in patients with a transplanted liver.. This is a retrospective cohort study. It included patients who received a liver transplant between 2012 and 2017 and who were treated with mycophenolate mofetil or with a combination of mycophenolate mofetil and valganciclovir. Minimum follow-up was 100 days posttransplantation. Children under 16 years of age and patients who died during follow-up were excluded. Binary logistic regression analysis was used to determine the association of neutropenia with sex, age, diabetes, creatinine at baseline and at discharge, and concomitant treatment of mycophenolate mofetil with valganciclovir. Relative risk and 95% CI were calculated using logistic regression coefficients.. 144 patients were analyzed, 87 were treated with mycophenolate mofetil and 57 received mycophenolate mofetil and valganciclovir together. An overall risk of neutropenia of 37% [95% CI (29- 45)] was observed. The risk was significantly higher in patients who received the combination of mycophenolate mofetil and valganciclovir (56%) than in those treated with mycophenolate mofetil alone (24%), p = 0.001. Binarylogistic-regression analysis revealed that concomitant use of mycophenolate mofetil with valganciclovir was associated with an increased risk of neutropenia: Relative risk = 4.97, 95% CI [2.25-11.00].. Our study shows that concomitant use of mycophenolate mofetil and valganciclovir increases the risk of neutropenia in patients with a transplanted liver.. Objetivo: Los fármacos inmunosupresores son necesarios para evitar o reducir el riesgo de rechazo de órganos trasplantados. La inmunosupresión generada puede dar lugar a que estos pacientes necesiten recibir antibióticos y antivíricos con los inmunosupresores para evitar el riesgo de infecciones. Esto ha generado un incremento de neutropenia en pacientes tratados conjuntamente con micofenolato de mofetilo y valganciclovir. El objetivo de este estudio es estimar el riesgo de neutropenia atribuible al tratamiento concomitante de micofenolato de ofetilo y valganciclovir en pacientes trasplantados hepáticos.Método: Estudio de cohorte retrospectiva. Se incluyeron pacientes receptores de hígado entre 2012 y 2017 tratados con micofenolato de mofetilo o con la combinación de micofenolato de mofetilo y valganciclovir, con al menos 100 días de seguimiento postrasplante. Se excluyeron menores de 16 años y pacientes fallecidos durante el seguimiento. El análisis de regresión logística binaria se utilizó para determinar la asociación del riesgo de neutropenia con el sexo, edad, diabetes, creatinina basal y al alta, y tratamiento concomitante de micofenolato de mofetilo y valganciclovir. El riesgo relativo y los IC 95% se calcularon mediante los coeficientes de regresión logística.Resultados: Un total de 144 pacientes fueron analizados, 87 se trataron con micofenolato de mofetilo y 57 recibieron conjuntamente micofenolato de mofetilo y valganciclovir, observándose un riesgo de neutropenia del 37%, IC 95% [29-45]. Este riesgo fue significativamente mayor en pacientes que recibieron la combinación de micofenolato de mofetilo y valganciclovir (56%) respecto a los tratados solo con micofenolato de mofetilo (24%), p = 0,001. El análisis de regresión logística binaria reveló que el uso concomitante de micofenolato de mofetilo y valganciclovir se asociaba a un mayor riesgo de neutropenia: riesgo relativo = 4,97, IC 95% [2,25-11,00].Conclusiones: Nuestro estudio demuestra que el uso concomitante de micofenolato de mofetilo y valganciclovir aumenta el riesgo de neutropenia en pacientes trasplantados hepáticos.

Topics: Child; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Neutropenia; Retrospective Studies; Valganciclovir

Topics: Antineoplastic Agents, Immunological; Hepatitis; Humans; Immunologic Factors; Ipilimumab; Male; Melanoma; Middle Aged; Mycophenolic Acid; Neutropenia; Nivolumab

Neutropenia after kidney transplant is an adverse event usually treated with a dosage reduction of mycophenolic acid. We evaluated the efficacy and safety of substituting mycophenolic acid with everolimus in patients with persistent neutropenia after kidney transplant.. This study was a retrospective analysis. A total of 17 patients who were initially treated with mycophenolic acid (1912 ± 196 mg/d), calcineurin inhibitors, and methylprednisolone for kidney transplant were included.. In 15 patients, neutropenia occurred within the first 3 months (during valganciclovir administration), and in 2 patients between the fourth and sixth month after transplant. One hundred eighteen episodes of neutropenia were recorded, originally treated by reducing the dosage of mycophenolic acid (765 ± 390 mg/d) and administering granulocyte colony-stimulating factor. Three patients experienced acute rejection 5 to 10 days after reducing the dosage of mycophenolic acid, and they were successfully treated with pulse steroids. Five patients developed cytomegalovirus infection 108 ± 65 days after the onset of neutropenia. After replacing mycophenolic acid with everolimus, episodes of neutropenia were observed in 6 patients. In 1 patient, discontinuing everolimus was necessary after 1.5 months of treatment. In 5 patients with cytomegalovirus infection, neutropenia subsided after termination of valganciclovir treatment. In the remaining 11 patients, no episodes of neutropenia were observed. No episodes of acute rejection occurred, and renal function remained stable during a followup of 47 ± 30 months (estimated glomerular filtration rate [eGFRMDRD6]: 45 ± 14 mL/min/1.73 m2→47 ± 22 mL/min/1.73 m2].. Replacing mycophenolic acid with everolimus appears to be a safe and effective alternative treatment in neutropenic renal transplant recipients.

Topics: Adult; Cytomegalovirus Infections; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Ganciclovir; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Time Factors; Treatment Outcome; Valganciclovir

Using rituximab, we have performed successful ABO-incompatible kidney transplantations in recipients without splenectomy as well as in those with high pretransplant anti-A/B antibody titers. A common and increasingly recognized toxicity of rituximab is late-onset neutropenia (LON), defined as unexplained grades III to IV neutropenia occurring at least 4weeks after the last dose of rituximab in the absence of an alternative explanation.. Between May 2006 and December 2011, 25 patients who received rituximab underwent successful ABO-incompatible kidney transplantation and were enrolled as the subjects in this study. The incidence rate and clinical features of LON as well as the relationship between LON and acute rejection in these patients were studied.. Twelve recipients (48%) experienced LON 2 to 12months after transplantation. Five of the 12 patients (41.6%) who developed LON had an episode of biopsy-confirmed acute cellular rejection, as compared with one of the 13 patients (7.7%) who did not develop LON. Moreover, 3 patients who experienced LON developed steroid and deoxyspergualin-resistant acute cellular rejection requiring OKT-3 administration.. The frequency of acute cellular rejection was higher in ABO-incompatible kidney transplant recipients with LON than in those without LON. Our findings suggested that these recipients who developed LON after rituximab administration may be at an increased risk for acute cellular rejection.

Topics: ABO Blood-Group System; Adolescent; Adult; Aged; Allografts; Antibodies; Antibodies, Monoclonal, Murine-Derived; Antigens, CD19; Antigens, CD20; Blood Group Incompatibility; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Subsets; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Neutropenia; Rituximab; Transplant Recipients; Young Adult

To describe a patient in whom initiation of micronized fenofibrate precipitated mycophenolate induced neutropenia.. A 57-year-old man was admitted to the hospital because of febrile neutropenia. He had undergone kidney transplantation seventeen years ago. The patient's immunosuppressive maintenance regimen consisted of mycophenolate mofetil (MMF) 500 mg three times a day, and meprednisone 4 mg daily. His medical history included, hypertension treated with losartan 50mg daily, and dyslipidemia treated with ezetimibe 10mg /simvastatin 20mg for four years (until 2 weeks before admission when micronized fenofibrate 200 mg per day was started because of persistently elevated triglycerides levels. On presentation temperature was 37.8°C and initial laboratory tests showed 3130 White Blood Cell Count(WBC)/μL with neutropenia (absolute neutrophil count (ANC) 313/μL) Fenofibrate and mycophenolate mofetil were discontinued, piperacillin tazobactam 4.5gr three times a day and granulocyte stimulation factor 300 μg/day were started. Three days after admission WBC was 7280/μL, neutrophils: 22%, ANC: 1160/mm(3). Mycophenolate mofetil was restarted and granulocyte stimulation factor was discontinued. One month after discharge his WBC was 4480/μL and ANC 1926/μL.. The initiation of fenofibrate in a patient on stable and therapeutic doses of mycophenolate may have precipitated mycophenolate induced neutropenia, a well described, dose dependent phenomenon. Mycophenolic acid (MPA) displays a complex pharmacokinetic profile susceptible to potential significant interactions with fenofibrate. Since approximately 99% of MPA and fenofibrate bind to albumin, displacement may occur, leading to increased free MPA. Second competition of fenofibric acid for UGT1A9 an enzyme implicated in conjugation of MPA may have decreased its metabolism. The combination of these two effects may increase the risk of dose dependent neutropenia. Using the Interaction Probability Scale (DIPS), the interaction was designated as probable.. Until further evidence is available, when fenofibrate is started in a renal transplant patient on mycophenolate careful monitoring should be considered to avoid potentially fatal complications.

Topics: Dose-Response Relationship, Drug; Drug Interactions; Fenofibrate; Glucuronosyltransferase; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Protein Binding; Serum Albumin; Severity of Illness Index; UDP-Glucuronosyltransferase 1A9

Cytomegalovirus (CMV) infection remains a major problem in recipients with heart transplantation (HTx), because it may play a significant role in the development of cardiac allograft vasculopathy, which is one of the major causes of death after HTx. Valganciclovir (VGC) is effective for the treatment of CMV infection, but is often associated with neutropenia, especially when used with mycophenolate mophetil (MMF). We experienced an HTx recipient with positive CMV antigenemia who suffered progressive neutropenia after administration of VGC. We switched MMF to everolimus (EVL) and assay for CMV antigenemia was constantly negative even after discontinuation of VGC. In all other 14 HTx recipients who received EVL for any reason, we found that assay for CMV antigenemia remained negative throughout the period of EVL administration. Considering the prophylactic effect on CMV, EVL can not only be an alternative to rescue from comorbidity, but might also be indicated earlier especially in CMV-seronegative HTx recipients.

Topics: Adult; Antigens, Viral; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Drug Substitution; Drug Therapy, Combination; Everolimus; Ganciclovir; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Neutropenia; Opportunistic Infections; Sirolimus; Valganciclovir

Patients aged 60 years and older represent the fastest-growing population with end-stage renal disease worldwide, and the need for a kidney transplant among this population is increasing. Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved, and the rates of graft survival in these patients are currently similar to those in recipients of ABO-compatible grafts. However, the outcomes of ABO-incompatible kidney transplantation in elderly patients over 60 years of age have not been well studied yet.. We studied 4 elderly kidney transplant patients who received their grafts from ABO-incompatible living donors at our institution between December 2006 and December 2011, focusing on the immunosuppressive protocols, complications and graft survivals. The mean observation period was 21.5 months (range, 8 months to 62 months). Our immunosuppressive protocols were as follows: to remove the anti-A/B antibodies, the patients underwent 4-8 sessions of double-filtration plasmapheresis and/or plasma exchange prior to kidney transplantation until the anti-A/B titers were less than 1:16. For the patients with low anti-A/B titers (<1:512), the immunosuppressive protocol consisted of a single dose of rituximab (150 mg/m(2)). The patients with high anti-A/B antibody titers (≥1:512) underwent splenectomy and received 2 doses of rituximab. The pretransplant immunosuppressive protocol included B-lymphocyte suppression with 4 weeks of mycophenolate mofetil (0.5 g/day for low-titer protocol and 1 g/day for high-titer protocol).. All 4 patients underwent successful transplantation. At the end of follow-up, their mean serum creatinine was 1.18 mg/dl. No patient experienced antibody-mediated rejection or acute cellular rejection. Late-onset neutropenia occurred in two cases. Two cases experienced cytomegalovirus reactivation by cytomegalovirus antigenemia. In one patient, diffuse hemorrhage required surgical intervention. However, there were no severe complications.. Although a careful evaluation of patients is needed, ABO-incompatible kidney transplantation may become a viable treatment option for elderly patients with end-stage renal disease.

Topics: ABO Blood-Group System; Aged; Antibodies, Monoclonal, Murine-Derived; Blood Group Incompatibility; Cytomegalovirus; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Plasma Exchange; Plasmapheresis; Rituximab; Splenectomy; Transplants; Virus Activation

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bacteremia; Central Nervous System Neoplasms; Drug Administration Schedule; Female; Fever; Fungemia; Humans; Immunocompromised Host; Immunosuppressive Agents; Lupus Nephritis; Lymphoma; Methotrexate; Mycophenolic Acid; Neurotoxicity Syndromes; Neutropenia; Rituximab; Treatment Outcome; Young Adult

Mycophenolic acid is a commonly used immunosuppressant after organ transplantation and in autoimmune diseases; however, myelosuppression is a major complication despite its largely favorable side-effect profile. Mycophenolic acid targets inosine monophosphate dehydrogenase, which is essential for T-cell proliferation. The T-cell cytokine interleukin-17 (IL-17 or IL-17A) and its receptor maintain normal neutrophilic granulocyte numbers in mice by induction of granulocyte-colony-stimulating factor. To test whether mycophenolic acid induces neutropenia by inhibiting IL-17-producing T cells, we treated C57Bl/6 mice with mycophenolate-mofetil (the orally available pro-drug) and found a dose-dependent decrease in blood neutrophils. This myelosuppressive effect was completely abolished in mice that lack the IL-17 receptor. Mycophenolic acid delayed myeloid recovery after bone marrow transplantation and decreased the percentage of IL-17-producing T cells in the spleen and thymus, and inhibited IL-17 production in human and mouse T cells in vitro. Injection of IL-17 during mycophenolic acid treatment overcame the suppression of the circulating neutrophil levels. Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings.

Topics: Animals; Cell Differentiation; Colony-Stimulating Factors; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Interleukin-17; Leukopoiesis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycophenolic Acid; Neutropenia; Neutrophils; Receptors, Interleukin-17; T-Lymphocytes

A 27-year-old woman underwent living kidney transplantation from her mother. She received basiliximab, tacrolimus, mycophenolate mofetil (MMF), and a corticosteroid. Before transplantation, her complete blood count and white cell differential were normal. On about the 70th postoperative day (POD 70), her white blood cell (WBC) count began to decrease. On POD 113, her WBC count was 2800/μL. There was no evidence of viral infection, other systemic infection or malignancy. Drug-induced neutropenia, especially MMF-induced neutropenia, was suspected, and the dosage of MMF was reduced. However, the neutrophil count fell to 0/μL within 2 weeks. We further reduced the dosage of MMF and administered granulocyte-colony stimulating factor (G-CSF), which only temporarily increased the neutrophil count. Then, MMF was discontinued and switched to azathioprine, resulting in recovery of neutrophil count without subsequent rejection. MMF-induced neutropenia frequently occurs and should be monitored not only by WBC count but also by white cell differential count, since early discontinuation is the key to successful resolution of neutropenia. Switching from MMF to azathioprine or administration of G-CSF with or without MMF discontinuation might be options for treatment to avoid subsequent rejection.

Topics: Adult; Azathioprine; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Neutropenia

Topics: Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Middle Aged; Mycophenolic Acid; Neutropenia; Scleroderma, Systemic

An increased incidence and magnitude of leukopenia during concomitant treatment with valganciclovir (VGC) and mycophenolate mofetil (MMF) has been reported.. To evalute the incidence and severity of leukopenia and neutropenia among liver recipients treated with VGC and related factors.. Retrospective analysis of clinical and analytical data related to leukopenia (<3000 leukocytes/mm(3)) and neutropenia (<900 neutrophils/mm(3)) in liver transplant patients who were treated with VGC from 2003 to 2007. We examined the influence of concomitant administration of MMF and development of subsequent infections.. Among 209 liver transplants, 40 treatments with VGC were prescribed in 37 patients (17.7%), 12 of which (30%) were associated with MMF. The patients has an average age of 49.7 +/- 12.7, body mass index (BMI) of 27.28 +/- 5.17, and Model for End-stage Liver Disease Score (MELD) 12.45 +/- 7.5. The daily average dose of VGC was 1440 +/- 446.5 mg and MMF, 1454.5 +/- 350.3 mg. We observed a decrease of 30% in initial leukocyte count (5353.7 +/- 2706.6) and 40% in neutrophil count (3600 +/- 2182.1). With no relationship to total dose or BMI-adjusted dose of VGC nor concomitant administration of MMF. The initial leukocyte count was significantly lower (4411 +/- 1930 vs 6206 +/- 3053; P = .03) and underwent a main drop (2344.7 +/- 1974.3 vs 898.1 +/- 2435.6; P = .04) when leukopenia developed. In the induced neutropenia group, previous leukocyte count (3797.1 +/- 1223.9 vs 5683.9 +/- 2829.3; P = .01), MELD (18.7 +/- 8.8 vs 11.1 +/- 6.6; P = .01), and the creatinine pretreatment (1.44 +/- 0.4 vs 1.09 +/- 0.3; P = .01) were significantly different. Subsequent infections induced by the leukopenia were not observed.. In our series, the concomitant use of VGC and MMF was not associated with a greater incidence of leukopenia and/or neutropenia than VGC administration alone. Previous leukocyte count was associated with them. MELD and renal dysfunction are factors related to severe neutropenia. Leukopenia was not associated with a greater incidence of infections.

Topics: Adult; Antiviral Agents; Body Mass Index; Creatinine; Cytomegalovirus Infections; Female; Ganciclovir; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Leukocyte Count; Leukopenia; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Valganciclovir

Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02-1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/microL achieved in a mean of 1.5+/-0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.

Topics: Adult; Aged; Bacterial Infections; Drug Therapy, Combination; Female; Graft Rejection; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Tacrolimus

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 +/- 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 +/- 296 mg/d). Leukopenia was significantly associated with simultaneous liver-kidney transplantation and with second kidney transplantations (P < .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation (P = .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses (P < .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF-tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia.

Topics: Antiviral Agents; Cytomegalovirus Infections; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Neutropenia; Postoperative Complications; Valganciclovir

Mycophenolate mofetil (MMF) is a potent, safe immunosuppressive agent for rescue therapy of acute and chronic rejection in orthotopic liver transplant recipients. It helps to reduce the serious toxic side effects of calcineurin inhibitors (CNIs). The side effects of MMF, such as bone marrow toxicity, have been reported. Herein we report four patients who underwent liver transplantation and developed neutropenia while receiving MMF.. Between April 2002 and October 2003, we performed 24 liver transplants in 25 patients. Eighteen patients were given MMF for the following reasons: renal failure in nine (50%); treatment of acute rejection in three (16.6%); primary prophylaxis of rejection in five (27.7%); and CNI withdrawal in one (5.5%).. Of the 18 patients treated with MMF, there were 11 men (61.1%) and seven women (38.8%), with an overall mean age of 55.5 years. This therapy was ceased in four patients due to neutropenia (22%). Discontinuation of MMF was followed by a rapid and spontaneous rise in neutrophils in two patients. Granulocyte colony stimulating factor (GCSF) was administered to one patient and in another a bone marrow biopsy was performed due to persistent anemia, leukopenia, and thrombocytopenia. The mean time from starting MMF to the development of neutropenia was 4 months. Only the third patient showed elevated levels of MMF.. MMF is a potent immunosuppressive agent in liver transplantation. However, because serious hematologic toxicity has been reported, we recommend caution in administration and careful monitoring of blood levels.

Topics: Female; Graft Rejection; Humans; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Treatment Outcome

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

Topics: Adolescent; Adult; Aged; Chimerism; Cytomegalovirus; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Liver; Liver Function Tests; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Nausea; Neutropenia; Recurrence; Serum Albumin; Transplantation Conditioning; Transplantation, Homologous; Virus Activation

Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Area Under Curve; Child; Child, Preschool; Daclizumab; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Half-Life; Humans; Immunoglobulin G; Immunosuppressive Agents; IMP Dehydrogenase; Infant; Kidney Transplantation; Male; Mycophenolic Acid; Neutropenia; Prednisone; Receptors, Interleukin-2; Sirolimus

Aspergillus infection is a rare but devastating complication following organ transplantation with high mortality rate. Aspergillus fumigatus is the most common cause of invasive aspergillosis. This fungus is present in the environment worldwide. Aspergillus infection is mainly acquired by inhalation of spores and several nosocomial infections in transplant recipient have been associated with construction work at hospitals. Risk factors for invasive aspergillosis include administration of steroid boluses, history of cytomegalovirus infection, neutropenia and prolonged antibiotic use after transplantation. Successful treatment depends on three factors: early diagnosis, aggressive antifungal therapy and decrease or removal of immunosuppression. Amphotericin deoxycholate has been the standard treatment for many years but lipid preparations for amphotericin are now used due to their significantly fewer adverse effects. A number of new antifungal drugs are now being developed including new azoles such as voriconazol and echinocandin. Invasive aspergillosis has a high mortality rate more than 95% when cerebral dissemination is demonstrated. We report the case of a 47 years old woman who received a cadaveric renal graft and developed pulmonary aspergillosis with fulminant cerebral dissemination two months later. The diagnosis of pulmonary aspergillosis was by culture isolation obtained from bronchioalveolar lavage. Removal of immunosuppresive agents and liposomal amphotericin B therapy were started shortly after admission. Brain CT scan performed on the 12th day showed cerebral dissemination. The recipient died two days later. Our patient had several risk factors such as the administration of steroid boluses and cytomegalovirus infection. Invasive aspergillosis must be always included in the differential diagnosis of fever and pulmonary disease in the renal transplant recipient.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Cross Infection; Cyclosporine; Cytomegalovirus Infections; Fatal Outcome; Female; Fever; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Liposomes; Lung Diseases, Fungal; Middle Aged; Mycophenolic Acid; Neuroaspergillosis; Neutropenia; Polycystic Kidney, Autosomal Dominant; Prednisone; Risk Factors

Mycophenolate mofetil (MMF) is a drug which decreases the frequency of renal transplantation rejection. However, cytomegalovirus infections are a common feature of this treatment leading the physicians to prescribe antiviral prophylactic drugs like valacyclovir. During this association, neutropenia occur and the cause of this adverse effect is difficult to define. This report presents a case of neutropenia in a woman treated with MMF and valacyclovir. As the duration of the valacyclovir treatment exactly corresponds to the neutropenia duration, and the mycophenolate trough levels increased with the neutrophil count, the responsibility of this neutropenia was ascribed to valacyclovir. However, an examination of the literature for cases of neutropenia led to the suspicion of an interaction between MMF and valacyclovir. Mycophenolate may increase intracellular concentrations of valacyclovir up to haematotoxic levels. This mechanism may explain the interaction and further research is needed to confirm this interaction.

Topics: Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Drug Interactions; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Neutropenia; Valacyclovir; Valine

The pseudo-Pelger-Huet (PH) anomaly has been associated with a variety of primary haematological disorders, infections and drugs. Recently, the development of dysgranulopoiesis characterised by a pseudo-PH anomaly has been reported in two patients with the use of mycophenolate mofetil (MMF) in the setting of heart and/or lung transplantation. We present a further five cases of MMF-related dysgranulopoiesis characterised by a pseudo-PH anomaly occurring after renal transplantation.. All patients were receiving standard immunosuppression protocols for renal transplantation, including a combination of MMF, steroids and either cyclosporin or tacrolimus. Oral ganciclovir was also used for cytomegalovirus prophylaxis in each case.. Development of dysplastic granulopoiesis occurred a median of 96 days (range 66-196 days) after transplantation. Moderate or severe neutropaenia (<1.0 x 10(9)/l) developed in three cases, and appeared to be directly correlated with the percentage of circulating neutrophils present with dysplastic morphology. Resolution of dysgranulopoiesis occurred in all cases only after dose reduction and/ or cessation of both MMF and ganciclovir.. In our series, the observed dysplastic granulopoiesis appeared related to the combination of MMF and ganciclovir, rather than MMF alone. Further study is required to determine the exact incidence and pathogenesis of this pattern of bone marrow toxicity.

Topics: Antiviral Agents; Bone Marrow Cells; Cell Nucleus; Drug Therapy, Combination; Female; Ganciclovir; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Neutropenia; Neutrophils; Pelger-Huet Anomaly; Postoperative Complications

Two transplant recipients developed striking morphological abnormalities in their circulating neutrophils while receiving mycophenolate. The changes included nuclear hypolobulation and abnormal clumping of nuclear chromatin and were presumably related to inhibition of guanosine nucleoside synthesis. In both cases the neutrophil abnormalities preceded the development of neutropenia and were thus a sign of impending hematological toxicity. The hematological changes resolved after the drug was discontinued.

Topics: Adult; Antineoplastic Agents; Enzyme Inhibitors; Humans; Male; Mycophenolic Acid; Neutropenia; Neutrophils