mycophenolic-acid and Kidney-Diseases

The management of immunosuppression utilized in glomerular diseases requires highly nuanced care. Timely recognition and management of these disorders is essential to mitigate the extent of kidney damage. This involves being cognizant of the various classes of immunosuppression, which includes alkylating agents, antimetabolites, calcineurin inhibitors, anti-CD20 therapy, complement inhibitors, corticosteroids, and intravenous immunoglobulin. The mechanisms of action of these drugs, along with associated pharmacokinetics and pharmacodynamics, facets of monitoring, and adverse effects are important aspects with which nephrologists are required to be well versed. In addition, an understanding of therapeutic decisions such as induction and maintenance regimens in the setting of glomerular disease and alteration based on trajectory of disease and subsequent response is imperative. The overarching principle of these strategies of immunosuppression is to achieve a balance of disease mitigation without exposure to inadvertent harm. Special groups such as pregnant women, elderly patients, and patients treated with dialysis are especially susceptible to immunosuppression and thus need highly weighed therapeutic strategies and enhanced surveillance of adverse effects.

Topics: Aged; Curriculum; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Pregnancy

Topics: Animals; Child; Drug Monitoring; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Organ Transplantation

Care of pregnant woman, including fertility and procreation counseling, has become a significant part of the nephrological practice in the last years. In this context, the management of immunosuppression assumes a primary role both for autoimmune diseases and for post-transplant follow up. The present review analyzes the latest evidence on immunosuppressive drugs of current use in nephrology and kidney transplantation. Although the placenta inactivates prednisone and prednisolone, it is advisable to limit the dose to the minimal effective one, to prevent side effects. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancies in autoimmune diseases because of the safety profile and its steroid-sparing property. In lupus nephropathy, hydroxychloroquine is a current indication in the prevention of flares. Cyclosporine and tacrolimus can also be used as steroid-sparing agents as well as in post-transplant maintenance therapy. Experience on mammalian target of rapamycin inhibitors is limited and its use during pregnancy is still controversial even if initial positive data are emerging. Intravenous immunoglobulins are safe and represent an important option for relapses of lupus and vasculitis. Mycophenolate mofetil and cyclophosphamide are to avoid. An important part is reserved to biologic agents, which are having a huge impact on therapy protocols for several pathologies. Data on the utilization of these molecules during pregnancy, however, are still scant and therefore they do not yet allow a definitive evaluation of their safety profile.

Topics: Azathioprine; Biological Products; Calcineurin Inhibitors; Cyclophosphamide; Directive Counseling; Female; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Pregnancy; Pregnancy Complications; TOR Serine-Threonine Kinases

The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication. Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone. Expert opinion: CNI sparing regimens are well-established. Complete CNI avoidance after kidney transplantation was often associated with impaired graft survival until the approval of the co-stimulation blocker belatacept for de novo immunosuppression after kidney transplantation. Concerns still exist with respect to severe T-cell-mediated rejection episodes in the early phase after transplantation. Thus, a triple drug regimen with CNI, mycophenolic acid and steroids still represents the gold-standard of immunosuppressive therapy. Alternative substances expand the possibilities of tailoring individual immunosuppression for different indications such as biopsy-proven CNI toxicity, polyoma virus BK nephropathy or CNI-triggered thrombotic microangiopathy. However, a change of the immunosuppressive therapy must always be balanced against each patient´s individual immunological risk in order to address the importance of chronic antibody-mediated rejection driven by donor specific antibodies (DSA).

Topics: Abatacept; Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Steroids; Transplantation, Homologous; Treatment Outcome

Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related.. The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers.. In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.

Topics: Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Tacrolimus

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimu

Topics: Adult; Calcineurin Inhibitors; Child; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; TOR Serine-Threonine Kinases

Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n = 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.

Topics: Azathioprine; Biopsy; Calcineurin Inhibitors; Chronic Disease; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

The idea of individualizing therapies to obtain optimal clinical results is not new but has only recently been applied to kidney diseases. Nonetheless, kidney disorders present a variety of opportunities to personalize medicine. Here, the heterogeneity of kidney disorders is reviewed to provide a rationale for pursuing personalized medicine. Data on adjusting therapy on the basis of pharmacogenetics/genomics and pharmacodynamics are summarized to demonstrate where the field is, and biomarker studies that reflect the future of personalized medicine are discussed. The goal of this review is to demonstrate that we can personalize therapy for kidney diseases but that considerable investment in new research will be required for personalized medicine to be routinely used in nephrology clinics.

Topics: Aryl Hydrocarbon Hydroxylases; Azathioprine; Calcineurin Inhibitors; Complement C3; Complement C4; Cyclophosphamide; Cytochrome P-450 CYP2C19; Humans; Kidney Diseases; Leukocytes, Mononuclear; Lupus Nephritis; Mycophenolic Acid; Peptidyl-Dipeptidase A; Precision Medicine; Receptors, Fc

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.

Topics: Biomarkers; Calcineurin Inhibitors; Diabetes Mellitus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Survival Rate

In the past two decades, new immunosuppressive drugs have emerged that have achieved a significantly reduction in acute rejection and short-term graft survival. This improvement, however, has not had the expected impact on long-term survival of the transplant. Paradoxically, the most used and effective drugs to prevent acute rejection are calcineurin inhibitors, but they contribute to delayed graft loss and patient death because they are nephrotoxic and also cause other adverse effects on blood pressure, lipid metabolism and glucose homeostasis. It was therefore necessary to develop new molecules free from these side effects that allow the use of low-dose or calcineurin inhibitor-free regimens without causing other adverse effects on patient and graft survival. Thus, the great development in the field of immunology has led to the discovery of important new pathways in the alloimmune response and subsequent development of molecules that act selectively against different points in the activation of the immune cascade. In this article we will review the most relevant clinical data published on immunosuppression and presented at different congresses over the year 2007, selecting those that we considered most relevant and that may have impact on the treatment of our patients in the future.

Topics: Antibodies, Monoclonal; Calcineurin Inhibitors; Drug Design; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Randomized Controlled Trials as Topic

We reviewed the literature in 2007 on 3 groups of systemic diseases affecting the kidney: lupic nephropathy (LN), small vessel vasculitis (SVV) and renal amyloidosis. A systematic review of 268 patients with LN pooled from 4 studies found that mycophenolic acid (MPA) in the induction phase caused more remissions and achieved greater renal survival than cyclophosphamide (CP), confirming it as a valid alternative to CP. Using a protocol including rituximab and MPA in the induction phase (14 days), MPA alone without corticoids is effective and safe in the maintenance phase. Rituximab has also been successfully used in CP-resistant forms of LN, where it reduces clinical activity and mesangial proliferation. Plasma exchanges achieve better results than bolus corticoids in SVS with severe renal failure. Complications are severe. Anti- TNF-alpha agents provide no benefit in this indication. Prolonged administration of low-dose corticoids reduces the incidence of relapses. MPA is an alternative to CP if this drug cannot be administered. Good results are achieved with rituximab in CP-resistant forms. According to a controlled trial, treatment of AL amyloidosis with dexamethasone and melphalan has equivalent results to highdose melphalan and rescue with hematopoietic stem cell transplant. In AA amyloidosis, eprosidate slows the rate of progression of renal failure.

Topics: Adrenal Cortex Hormones; Amyloidosis; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Melphalan; Mycophenolic Acid; Plasma Exchange; Randomized Controlled Trials as Topic; Recurrence; Rituximab; Vasculitis

Topics: Chronic Disease; Humans; Kidney Diseases; Kidney Glomerulus; Mycophenolic Acid; Remission Induction

Topics: Anti-Glomerular Basement Membrane Disease; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Mycophenolic Acid; Nephrosis, Lipoid; Vasculitis

Topics: Antibodies, Monoclonal; Azathioprine; Basiliximab; Cyclophosphamide; Cyclosporine; Fatty Acids, Monounsaturated; Fingolimod Hydrochloride; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Propylene Glycols; Recombinant Fusion Proteins; Ribonucleosides; Sphingosine

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.

Topics: Calcineurin Inhibitors; Child; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Organ Transplantation; Sirolimus; Tacrolimus

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

Progress in understanding the pathogenesis and treatment of rheumatologic and glomerular diseases such as systemic lupus erythematosus and particularly lupus nephritis has been closely linked with the development of newer immunosuppressive agents. With improved patient survival following the institution of cyclophosphamide and corticosteroid therapy, longer-term management issues came to the forefront, especially how to decrease adverse effects of the immunosuppressive regimen. Many of the immunosuppressive regimens used in lupus patients were first established as efficacious and safe through their use in solid organ transplantation. Mycophenolate mofetil (MMF) is now widely used in the field of transplantation. Following anecdotal reports describing benefits of MMF in lupus and lupus nephritis patients, small studies and finally large randomized, controlled trials have established the use of MMF in these patients, particularly those with lupus nephritis. MMF use in other rheumatologic and renal diseases has been evaluated in only smaller studies and very few randomized controlled trials. Nevertheless, many studies currently are ongoing with this immunosuppressive agent. This article will review the published data and the experience of two major New York medical centers with the use of MMF in autoimmune and renal diseases.

Topics: Acute Disease; Autoimmune Diseases; Clinical Trials as Topic; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Granulomatosis with Polyangiitis; Humans; Immunosuppression Therapy; Kidney Diseases; Lupus Nephritis; Mycophenolic Acid; Nephritis, Interstitial

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. Although short-term results are excellent, long-term graft survival has not improved substantially in recent times. Chronic allograft nephropathy (CAN) and death with a functioning graft are the most important causes of graft loss. Recent evidence shows that nephrotoxicity of calcineurin inhibitors contributes to CAN, and the introduction of non-nephrotoxic drugs such as mycophenolate mofetil (MMF) and mammalian target of rapamycin inhibitors may provide new immunosuppressive strategies to improve long-term results after renal transplantation. MMF decreases the risk of developing chronic allograft failure and is useful for treating established CAN, because it has a beneficial effect on allograft fibrosis. Treatment with sirolimus (SRL), a basic immunosuppressive drug given in association with MMF, may offer better renal function, decrease the prevalence of CAN, and downregulate expression of genes responsible for the progression of CAN than treatment with cyclosporine A (CsA). SRL also permits an early elimination of CsA from SRL-CsA-steroid regimens and shows better renal function and improved renal histology without risk of rejection. Notably, this approach improves graft survival at 4 years. Further multicenter studies are needed to determine whether both approaches produce similar results by comparing immunosuppression caused by SRL-based and tacrolimus (TAC)-based treatments. Because TAC is the most commonly used anticalcineurin drug, it is important to compare the effects of steroid-TAC-SRL treatment with and without elimination of TAC. Finally, although caution is needed, the use of non-nephrotoxic immunosuppressive treatment may change the natural history of CAN.

Topics: Animals; Cyclosporine; Disease Progression; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Sirolimus; Tacrolimus; Transplantation, Homologous

Glomerulonephritis is an important manifestation of small vessel vasculitides such as Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Renal involvement in these diseases is characterized by a pauci-immune segmental necrotizing and crescentic glomerulonephritis that is strongly associated with circulating antineutrophil cytoplasmic autoantibodies. We will review recent advances in understanding the pathogenesis of antineutrophil cytoplasmic autoantibody-related renal vasculitides and innovative approaches to their treatment.. An experimental milestone in antineutrophil cytoplasmic autoantibody research has been reached in the past year. Using an innovative mouse model, investigators from the University of North Carolina in Chapel Hill have recently acquired robust data supporting the pathogenic role of antineutrophil cytoplasmic autoantibodies in the glomerulonephritis and small vessel vasculitis, analogous to those seen in microscopic polyangiitis and Wegener granulomatosis. Novel immunosuppressive approaches have been examined including preliminary studies using biologic agents, such as antagonists of tumor necrosis factor and monoclonal antibodies to B lymphocytes.. Recent insights into the pathogenesis of antineutrophil cytoplasmic autoantibody-related vascular injury and the availability of new biologic, immune response modifiers to complement standard chemical immunosuppressive agents offer exciting new prospects for investigation in the management of patients with small vessel renal vasculitides.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Disease Models, Animal; Humans; Kidney; Kidney Diseases; Methotrexate; Mice; Mycophenolic Acid; Rituximab; Vasculitis

To evaluate the association of long-term continuous mycophenolate mofetil (MMF) versus azathioprine (AZA) therapy and renal allograft function, as measured by the slope of reciprocal creatinine, we analyzed 49,666 primary renal allograft recipients reported to the United States Renal Data System between October 31, 1988 and June 30, 1998.. The primary study endpoint was defined as a greater than 20% decrease below a 6-month baseline of 1/serum creatinine (SCr) (slope of reciprocal creatinine) at or beyond 1 year after transplantation. A secondary endpoint was defined as reaching an SCr value greater than 1.6 mg/dL. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. Multivariate analyses were corrected for potential confounding covariates.. According to the Cox proportional hazard model, 12-month continued therapy of MMF versus AZA was associated with a protective effect against declining renal function, as measured by the slope of reciprocal creatinine (relative risk [RR]=0.84, confidence interval 0.78-0.91, P<0.001). For 24-month continued therapy of MMF versus AZA, MMF was associated with a further decreased risk for a decline in renal function (RR=0.66, confidence interval=0.57-0.77, P<0.001). Furthermore, MMF was associated with a protective effect against reaching the SCr threshold of 1.6 mg/dL (RR=0.80, P<0.001) beyond 12 months posttransplantation.. Continuous use of MMF versus AZA was associated with a protective effect against declining renal function beyond 1 year after transplantation. Further study is needed to confirm that continued MMF therapy is protective against long-term deterioration in renal function.

Topics: Adult; Azathioprine; Creatinine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Survival Analysis; Transplantation, Homologous

The incidence of progressive nephropathies and, consequently, the population suffering from end-stage renal disease have increased steadily in recent years, posing an ever-growing cost, in both human and financial terms, to society. There is mounting evidence that, in both immune-mediated and nonimmune-mediated chronic nephropathies, renal inflammatory events are key to the propagation and perpetuation of renal injury. Mycophenolate mofetil (MMF) is an antilymphocyte agent recently introduced in clinical practice for the prevention of allograft rejection. The present review discusses clinical and experimental evidence that the anti-inflammatory action of MMF can be advantageously used to arrest immune- and nonimmune-mediated progressive injury of native kidneys as well.

Topics: Disease Progression; Drug Therapy, Combination; Humans; Immune System Diseases; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents, Non-Steroidal; Fibrosis; Humans; Inflammation; Inflammation Mediators; Kidney Diseases; Models, Biological; Mycophenolic Acid; Nephritis; Renin-Angiotensin System; Transforming Growth Factor beta

High-dose corticosteroids in combination with cytotoxic drugs are universally accepted as the initial approach in vasculitides that are associated with anti-neutrophil cytoplasmic antibodies. Cyclophosphamide is the most effective cytotoxic drug and is used in more severe cases. Because cyclophosphamide has more severe short- and long-term side-effects than methotrexate, methotrexate is used in less severe cases. New prospects for the treatment of vasculitis include novel immunosuppressive agents (e.g. mycophenolate, 15-deoxyspergualin, and leflunomide), sequential chemotherapy (e.g. cyclophosphamide followed by azathioprine or cyclophosphamide followed by methotrexate), intravenous immunoglobulin, tumour necrosis factor-alpha directed therapy, anti-lymphocyte directed therapy (e.g. antithymocyte globulin or anti CD52/anti CD4 antibodies), anti-adhesion molecule directed therapy (e.g. anti-CD18 or intercellular adhesion molecule-1 antisense) or immunoablation using high-dose cytotoxic medication with or without stem cell rescue.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antilymphocyte Serum; Cyclophosphamide; Guanidines; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Isoxazoles; Kidney Diseases; Leflunomide; Methotrexate; Mycophenolic Acid; Prednisone; Remission Induction; Trimethoprim, Sulfamethoxazole Drug Combination; Tumor Necrosis Factor-alpha; Vasculitis

Renal infiltration with macrophages and monocytes is a well-recognized feature of not only immune, but also nonimmune kidney disease. This review focuses on the investigations that have shown accumulation of immunocompetent cells in experimental models of acute and chronic ischemia, protein overload, hypercholesterolemia, renal ablation, obstructive uropathy, polycystic kidney disease, diabetes, aging, murine hypertension, and nephrotoxicity. We examine the mechanisms of infiltration of immunocompetent cells and their participation in the self-perpetuating cycle of activation of the angiotensin system, generation of reactive oxygen species, and further recruitment of monocytes and lymphocytes. We also discuss the possibility of antigen-dependent and antigen-independent mechanisms of immune cell activation in these animal models. Finally, we review the recent studies in which suppression of cellular immunity with mycophenolate mofetil has proven beneficial in attenuating or preventing the progression of renal functional and histologic damage in experimental conditions of nonimmune nature.

Topics: Animals; Antigens; Disease Models, Animal; Humans; Immunocompetence; Immunosuppressive Agents; Kidney Diseases; Lymphocyte Activation; Lymphocytes; Macrophage Activation; Macrophages; Models, Biological; Mycophenolic Acid

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Humans; Kidney Diseases; Kidney Glomerulus; Mycophenolic Acid

Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been available for almost 20 years. Although these drugs are highly effective and represent the mainstay of transplant immunosuppression, they are associated with acute and chronic nephrotoxicity. Acute nephrotoxicity, which occurs in the early period after transplantation, leads to a higher rate of dialysis, and chronic nephrotoxicity may eventually result in graft loss. Acute and chronic nephrotoxicity is becoming more common as the use of marginal kidneys for transplantation increases. Two recently available immunosuppressive agents, mycophenolate mofetil and sirolimus (rapamycin), have no nephrotoxicity. The use of these drugs in combination with other agents has led to the development of new paradigms of immunosuppressive therapy. This paper reviews the results of clinical trials that have investigated these new approaches to immunosuppression in renal transplant recipients.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Multicenter Studies as Topic; Mycophenolic Acid; Sirolimus; Treatment Outcome

Cyclosporine and tacrolimus reduce allograft rejection, improve allograft half-life and patient survival. Ironically, the nephrotoxicity of these agents may adversely affect allograft survival in renal transplant recipients or cause end-stage renal diseases in other solid organ and bone marrow transplant recipients. Acute dose-dependent and chronic non-dose-dependent nephrotoxicity has been reported in both transplant recipients and patients with autoimmune disorders. Preliminary evidence suggests that drug therapeutic monitoring has little value in the diagnosis or management of nephrotoxicity associated with calcineurin inhibitors. Although the exact mechanism of nephrotoxicity is not fully understood, several factors have been implicated in the pathogenesis of immunosuppressive-induced nephrotoxicity. Renal and systemic vasoconstriction, increased release of endothelin-1, decreased production of nitric acid and increased expression of TGF-beta are the major adverse pathophysiologic abnormalities of these agents. Reducing the dose of a calcineurin inhibitor, or using protocols without calcineurin inhibition may ultimately minimize the risk of drug toxicity and improve allograft and patient survival. New experiences with non-nephrotoxic agents and protocols including mycophenolate and sirolimus allow for early calcineurin inhibitor reduction or elimination without increasing the risk of allograft rejection.

Topics: Calcineurin Inhibitors; Cyclosporine; Endothelin-1; Graft Rejection; Immunosuppressive Agents; Kidney; Kidney Diseases; Mycophenolic Acid; Nitric Oxide; Sirolimus; Tacrolimus; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vasoconstriction

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

Topics: Area Under Curve; Drug Interactions; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Transplantation

Topics: Humans; Kidney Diseases; Kidney Glomerulus; Mycophenolic Acid; Nephrectomy; Purines

The immunosuppressive drug mycophenolate mofetil is a potential new treatment for autoimmune renal disease. In addition to its effects in modulating the autoimmune response, mycophenolate mofetil reduces adhesion molecule expression and delays the progression of renal failure. Data from experimental models of glomerulonephritis, especially of lupus nephritis, have demonstrated that mycophenolate mofetil reverses both inflammatory and autoimmune aspects of disease and influences outcome. As yet, clinical experience with mycophenolate mofetil remains anecdotal but provides a strong platform for the scientific evaluation of mycophenolate mofetil as a new therapeutic agent for these conditions in the future.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Mycophenolic Acid; Vasculitis

BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies.. Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47).. Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.

Topics: Adult; Aged; BK Virus; Drug Substitution; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Substance Withdrawal Syndrome; Tacrolimus; Tumor Virus Infections; Viremia

This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30-50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1-15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years.

Topics: Adult; BK Virus; DNA, Viral; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymerase Chain Reaction; Polyomavirus Infections; Survival Analysis; Tacrolimus; Transplant Recipients; Treatment Outcome; Urine; Viral Load; Viremia

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Research Design

Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open-label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent-to-treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy-proven acute rejection (BPAR), graft lost, death, and lost to follow-up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = -7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL-treated patients and in 8.3% of the MMF/CNI-treated patients (P = 0.04). Malignancy-related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL-treated patients and for 24.1% of the MMF/CNI-treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss).

Topics: Adult; Aged; Biopsy; Calcineurin Inhibitors; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephrons; Prospective Studies; Reproducibility of Results; Sirolimus; Time Factors; Treatment Outcome; Young Adult

Pediatric allogeneic stem cell transplant (AlloSCT) patients are at substantial risk of developing kidney injury (KI), and KI contributes to transplant-related morbidity and mortality. We compared the estimated creatinine clearance (eCrCl) at 1, 3, 6, 9, and 12 months post-AlloSCT in 170 patients following reduced toxicity conditioning (RTC) versus myeloablative conditioning (MAC) to baseline. eCrCl was calculated using the Schwartz equation. Patients with ≥ 50% drop in eCrCl from the baseline were considered to have KI. Patients received tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. The logistic regression model was used for assessing risk factors for KI. Seventy-six patients (median age = 10.6 years) received RTC AlloSCT; 94 patients (median age = 8.5 years) received MAC AlloSCT. The incidence of KI at 1 month post-AlloSCT was significantly higher in MAC versus RTC AlloSCT (43/94 [45.7%] versus 13/76 [17.1%] P < .0001). There was no statistical difference in KI at 3, 6, 9, and 12 months post-AlloSCT between the 2 conditioning groups. On multivariate analysis, only MAC was a significant risk factor for KI (odds radio [OR] 3.44, 95% confidence interval [CI] 1.59-7.42, P = .002). In multivariate analysis for risk factors affecting overall survival (OS), the following were statistically significant: MAC versus RTC (hazard ratio [HR] 2.66, P = .0008), average versus poor-risk disease status (HR 2.09, P = .004), matched sibling donor (MSD) and matched unrelated donor (MUD) versus umbilical cord blood (UCB) (HR 2.31, P = .013), no KI versus KI (HR 2.00, P = .005). In children, MAC is associated with significant risk of KI in the first month after transplant, and KI in the first month post-AlloSCT is associated with a significantly decreased OS.

Topics: Adolescent; Child; Child, Preschool; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Neoplasms; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Survival Rate; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous

The long-term use of cyclosporine always contributes to chronic renal allograft dysfunction. Converting from cyclosporine to sirolimus and reducing cyclosporine dosage under high mycophenolate mofetil levels are 2 common therapies. Their efficacy and safety have not been compared in Chinese patients.. In this prospective, open label, randomized study, 51 kidney recipients with an estimated glomerular filtration rate between 30 and 60 mL/min/1.73 m² were enrolled. Patients in the sirolimus group (n=22) initiated sirolimus 12 hours after cessation of cyclosporine. Patients in the cyclosporine group (n=29) significantly reduced cyclosporine dosage under high mycophenolate mofetil dosages. Both groups were followed-up for 4 years.. The baseline estimated glomerular filtration rate was 36.46 ± 6.22 mL/min/1.73 m² in sirolimus group and 36.07 ± 6.18 mL/min/1.73 m² in the cyclosporine group (P = NS). In cyclosporine group, the estimated glomerular filtration rate declined significantly at 12, 18, 24, 30, 36, 42, and 48 months after inclusion compared with baseline, and was lower than the sirolimus group at 30, 36, 42, and 48 months after inclusion (P < .05). As for the endpoints of graft loss and return to dialysis, the 4-year graft survival was 77.3% in the sirolimus group and 55.2% in the cyclosporine group (P = NS). As for the endpoint of serum creatinine doubling, 4-year survival was 77.3% in the sirolimus group and 41.4% in the cyclosporine group (P < .05). Three patients in sirolimus group (2 acute rejections, 1 pneumonia) and 2 patients in the cyclosporine group (owing to acute rejection) dropped out (P = NS).. Conversion from cyclosporine to sirolimus could improve long-term survival of renal grafts in Chinese patients.

Topics: Adult; Biomarkers; Chi-Square Distribution; China; Chronic Disease; Creatinine; Cyclosporine; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), often targeting myeloperoxidase (MPO). Cyclophosphamide (CYC) plus corticosteroids (CS) is considered standard therapy for patients with renal involvement, but treatment response is not satisfactory in all patients and CYC has well recognized toxicity. This prospective pilot trial explored whether mycophenolate mofetil (MMF) represents an effective alternative to CYC for induction and maintenance of remission in MPA with mild to moderate renal involvement.. Seventeen P-ANCA/MPO-ANCA-positive patients with MPA with mild to moderate renal involvement received MMF (1000 mg orally, twice daily) and CS (intravenous methylprednisolone, 1 to 3 g, followed by oral prednisone at 1 mg/kg per day). Oral CS were discontinued by month 6; MMF was continued through month 18. The primary outcome measure was remission by month 6 and stable renal function. Secondary endpoints included major relapses necessitating a switch to CYC plus CS, minor relapses requiring an increase in CS dosage, and adverse events.. Thirteen of 17 patients enrolled achieved the primary outcome, and 4 failed because of insufficient response, relapse, or MMF intolerance. Twelve patients remained in remission through month 18, renal function remained stable, and proteinuria improved. Side effects of MMF were mild, transient, and responsive to dose adjustments in all patients except one.. MMF represents an alternative to CYC for induction and maintenance of remission in patients with MPO-ANCA-associated MPA with mild to moderate renal disease.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Methylprednisolone; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Peroxidase; Pilot Projects; Prednisone; Prospective Studies; Recurrence; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome

Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable.. In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids+/-induction therapy.. In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5+/-27.9 and 76.8+/-32.1 mL/min at baseline, 65.4+/-24.7 and 72.2+/-26.2 mL/min at month 6, and 68.7+/-27.7 and 71.8+/-29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01).. Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.

Topics: Adrenal Cortex Hormones; Adult; Biopsy; Creatinine; Cyclosporine; Drug Therapy, Combination; Europe; Everolimus; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Time Factors; Treatment Outcome

Congenital uropathies account for nearly half the chronic kidney disease in children. Immune-mediated injury may contribute to progressive loss of kidney function in affected patients.. Open-label uncontrolled pilot study to determine the feasibility of treatment with the immunosuppressive drug mycophenolate mofetil (MMF) to prevent a decrease in kidney function in pediatric patients with congenital uropathies.. Children treated in an outpatient tertiary-care center were eligible if they had: (1) age of 3 to 16 years, (2) glomerular filtration rate (GFR) less than 50 mL/min/1.73 m(2), and (3) a congenital genitourinary tract abnormality.. After a 2-month run-in period, patients were prescribed MMF, 600 mg/m(2)/dose, twice daily for a 24-month treatment period.. The primary end point was feasibility based on the ability to recruit and retain subjects and lack of unanticipated adverse events. The secondary end point was change in GFR.. Patients were monitored by using standard clinical laboratory tests, and GFR was determined by means of iothalamate clearance.. 12 patients aged 8.9 +/- 4.8 years (10 boys, 2 girls) were treated with MMF for 18.6 +/- 8.0 months; 7 patients completed the entire treatment period. MMF dosage at the final study visit was 381 +/- 241 mg/m(2) twice daily. Gastrointestinal symptoms were the most common adverse effect. There was only 1 serious adverse event, an episode of fever and neutropenia requiring parenteral antibiotic therapy after 21 months of MMF therapy. GFR remained stable throughout the treatment period. Nutritional status, blood pressure, and serum calcium, phosphorus, and cholesterol levels were unchanged during this period.. Insufficient power to assess the safety or efficacy of MMF therapy for patients with congenital uropathies.. It is feasible to study MMF as an adjunctive therapy to retard the progression of kidney disease in children with congenital uropathies. A multicenter randomized clinical trial is warranted to determine the efficacy of this novel treatment strategy.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Pilot Projects; Urologic Diseases

We performed a single-centre non-blinded clinical trial to compare the clinical efficacies of mycophenolate mofetil (MMF) and intermittent cyclophosphamide (CTX) pulse therapy as induction treatments in patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis (AAV) and moderate renal involvement.. Patients with active AAV and serum creatinine <500 micromol/L received either MMF treatment (MMF group) or monthly CTX pulse therapy (CTX group) for 6 months. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). The disease activity, remission rate, renal function and adverse reactions were compared between the two groups.. A total of 35 patients (15 male, 20 female: aged 49.1 +/- 12.2 years) were enrolled, with 18 in the MMF group and 17 in the CTX group. Of the 35 patients, 28 were MPO-ANCA positive and 2 were PR3-ANCA positive. Four patients were lost to follow-up in the CTX group. At Month 6, BVAS scores were much lower in the MMF group than in the CTX group (0.2 +/- 0.89 versus 2.6 +/- 1.7, P < 0.05). In the intent-to-treatment analysis, 14 of 18 patients (77.8%) treated with MMF and 8 of 17 patients receiving CTX (47.1%) had complete remission with an absolute difference of 30.7%. Eight of 18 patients (44.4%) in the MMF group and 2 of 17 patients (15.4%) in the CTX group recovered renal function. Serum ANCA decreased to normal in 41.7% of patients in the MMF group and in 16.7% in the CTX group. Side effects in the MMF group were pneumonia (1), herpes zoster (1) and gastrointestinal symptoms (2), and in the CTX group were leukocytopenia (1), gastrointestinal distress (4) and pneumonia (1).. Our study suggests that MMF effectively ameliorates disease activity and considerably improves renal function in patients with AAV. Further large-scale multicentre prospective randomized controlled trials will be needed to confirm these findings.

Topics: Antibodies, Antineutrophil Cytoplasmic; Biopsy; Creatinine; Cyclophosphamide; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Direct; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Remission Induction; Retrospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Vasculitis

Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation.. A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12.. Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36).. We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

Topics: Acute Disease; Adrenal Cortex Hormones; Creatinine; Cytochrome P-450 CYP3A; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; International Agencies; Kidney Diseases; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors; Tacrolimus

Humoral alloresponses may contribute to chronic allograft nephropathy (CAN) in a subset of kidney transplant recipients. For chronic humoral rejection, the efficacy of rescue therapy with tacrolimus and mycophenolate mofetil has been suggested.. Eleven recipients with C4d-positive CAN (index biopsy performed after a median of 3 years posttransplantation), who had been on cyclosporine A-based immunosuppression, were converted to tacrolimus, and if not part of basal therapy, to mycophenolate mofetil. We evaluated the effect of this tacrolimus/mycophenolate mofetil rescue therapy on clinical outcomes and on alloantibody formation detected with flow cytometric testing of panel-reactive antibody.. Tacrolimus/mycophenolate mofetil rescue therapy (plus anti-rejection treatment in six recipients with additional signs of acute cellular rejection) failed to prevent progressive deterioration of graft function. Four patients returned to dialysis after 4 to 18 months. Serial post-transplant serology detected HLA class I and/or II reactivity in seven recipients. Tacrolimus/mycophenolate mofetil therapy did not affect the time course of alloantibody levels. One patient with C4d-positive transplant glomerulopathy, who did not respond to tacrolimus/mycophenolate mofetil rescue therapy, developed nephrotic-range proteinuria associated with a rapid decline of allograft function. Despite considerable reduction in alloantibody levels and nearly complete clearance of C4d deposits, immunoadsorption failed to prevent graft failure in this patient.. Our data argue against the efficacy of tacrolimus/mycophenolate mofetil rescue therapy in established C4d-positive chronic allograft dysfunction. Prospective trials are needed to evaluate whether early initiation of this or other antihumoral strategies are capable of effectively preventing alloantibody-mediated chronic graft injury.

Topics: Adult; Aged; CD4 Antigens; Chronic Disease; Drug Combinations; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recovery of Function; Severity of Illness Index; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil, but delays release of mycophenolic acid until it reaches the small intestine. De novo renal transplant patients taking part in a 12-month, multicenter, randomized study received cyclosporine microemulsion (CsA-ME, early or delayed to day 6), EC-MPS, steroids, and interleukin-2 antagonist induction. Tolerability data relating to EC-MPS are reported. Ninety-seven patients were randomized to early CsA-ME and 100 patients to delayed CsA-ME. Median daily dose of EC-MPS was 1440 mg at all time points throughout the 12-month period. The most frequently reported adverse events were constipation, anemia, urinary tract infection, abdominal pain, leukopenia, and cytomegalovirus infection; there were four malignancies. Fifty patients (24.6%) discontinued EC-MPS prematurely by 12 months, including 42 patients (84%) who discontinued owing to adverse events. No patient discontinued treatment because of gastrointestinal adverse events. Two-thirds of patients (137 [67.5%]) maintained full EC-MPS dose throughout the 12-month study and did not require any dose reduction or dose interruption. EC-MPS is well tolerated in de novo renal transplant recipients when administered in combination with CsA-ME and steroids, with low rates of dose reductions or interruptions. Gastrointestinal adverse events were responsible for dose reduction or interruption in only 5% of patients.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Drug Therapy, Combination; Drug Tolerance; Emulsions; Female; Histocompatibility Testing; Humans; Isoantibodies; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tablets, Enteric-Coated; Tissue Donors

Mycophenolat mofetil (MMF) is a new imunosuppressant without nephrotoxic adverse effects. The aim of this study was to evaluate feasibility and effect of MMF introduction in conjunction with stepwise reduction of calcineurin inhibitors (CNI) in stable liver transplant patients with chronic CNI-induced renal dysfunction (RDF). In the MMF-group (n=27) but not in the controls (n=16), mean serum level of creatinine fell from a baseline of 227.4+/-67.9 micromol/l to 159.2+/-48.2 micromol/l (P<0,001), while mean urea level declined significantly from a baseline of 18.5+/-8.7 mmol/l to 11.4+/-4.2 mmol/l 6 months after initiation of MMF. Additionally, systolic and diastolic blood pressure values improved. In 52% of patients, dose reduction (n=11) or withdrawal (n=3) of MMF was necessary due to gastrointestinal or hematologic adverse effects. But also in patients on low dose MMF, there was a significant improvement of renal function without increased immunological risk.

Topics: Adult; Aged; Blood Pressure; Calcineurin Inhibitors; Cardiovascular Diseases; Cholesterol; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Urea; Uric Acid

There has been a need for a prospective, randomized, controlled trial to determine whether the addition of mycophenolate mofetil (MMF) to a calcineurin inhibitor (CNI)-based regimen or MMF addition followed by CNI withdrawal is an effective treatment for chronic allograft nephropathy (CAN). We conducted the first randomized, prospective study to compare the introduction of MMF with or without CNI withdrawal in long-term transplant recipients with histologically proven CAN and deteriorating renal function. The primary endpoint was renal function as indicated by the slope of the inverse serum creatinine vs. time at 32 weeks after randomization. After an interim analysis found a greater-than-expected difference between groups in the slopes of the inverse serum-creatinine, the study was stopped for ethical reasons. There were 20 patients in the MMF/CNI continuation and 19 patients in the MMF/CNI withdrawal groups (mean time post-transplant 7 years). Renal function improved in the dual-therapy compared with the triple-therapy group (p=0.002). Blood pressure decreased in the dual-therapy group with a significant difference between groups at 35 weeks (p=0.04). No acute rejections occurred. Long-term patients with CAN experience a significant improvement in renal function and blood pressure when CNIs are replaced by MMF.

Topics: Adult; Blood Pressure; Body Mass Index; Creatinine; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Random Allocation; Tacrolimus; Time Factors

This study was conducted to assess the effect of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. Forty-two cyclosporin-treated renal transplant recipients were studied. Patients were included if they had a negatively sloping reciprocal of creatinine vs time (ROCT) plot for >6 months and biopsy-proven CAN. Patients were excluded if they had previously been treated with tacrolimus/mycophenolate mofetil (MMF) or their serum creatinine was >400 micromol/l. Subjects were randomly treated with either: (A) MMF/reduced dose cyclosporin [MMF for azathioprine 0.5-1.0 g bd; cyclosporin trough level (C(0)): 75-100 ng/ml]; (B) tacrolimus for cyclosporin (C(0): 5-10 ng/ml); or (C) continuation of standard therapy. Glomerular filtration rate (GFR) was measured at baseline and after 6 months.. Two patients started dialysis within 6 months (one each from groups A and B). One patient in group A was intolerant of MMF, six others reported gastrointestinal symptoms and three developed anaemia. Cyclosporin dose was reduced by 24% [interquartile range (IQR): 14-27%] in group A [end-of-study C(0): 99 ng/ml (IQR: 90-113 ng/ml)]. In group B, the end-of-study tacrolimus C(0) was 7 ng/ml (5-9 ng/ml). The end-of-study cyclosporin C(0) in group C was 163 ng/ml (145-215 ng/ml). Comparison of ROCT slopes before and after intervention revealed a treatment advantage for group A (P<0.05). The GFR analysis was supportive (P = 0.05). When patients with GFR <20 ml/min/1.73 m(2) at enrollment were excluded from the analysis, the treatment advantage for group A reached statistical significance (n = 27, P<0.05).. MMF/reduced dose cyclosporin is superior to tacrolimus-for-cyclosporin and standard dose cyclosporin in patients with CAN, at least in the short term. The cyclosporin dose reduction component is likely to be of particular importance. Other findings suggest that early intervention is beneficial.

Topics: Chronic Disease; Cyclosporine; Disease Progression; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous

Long-term survival after orthotopic liver transplantation (OLT) is mainly influenced by adverse events caused by immunosuppression. Several studies have shown the efficacy of mycophenolate mofetil (MMF) in improving calcineurin inhibitor (CI)-induced nephrotoxicity with concomitant reduction or withdrawal of CI. In this prospective study we assessed the long-term effect and safety of MMF. Thirty-two OLT recipients with significant renal impairment due to either cyclosporine A ( n=25) or tacrolimus ( n=7) were enrolled in this study. CIs were reduced stepwise by at least 70%. Mean serum creatinine had decreased from 2.63+/-0.39 to 1.74+/-0.34 mg/dl after 1 month, and this improvement was maintained within a follow-up period of 4.8+/-0.6 (range 3.1-6.0) years, without major immunological or non-immunological side effects. Of all participants, 88% showed a significant reduction, and 41% even a normalization, in their serum creatinine level. In addition, MMF conversion, within 6 months of OLT, appears to be crucial in order to improve or even normalize renal function. This study demonstrates the long-term efficacy and safety of MMF in OLT recipients with CI-induced nephropathy.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Creatinine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Topics: Adult; Azathioprine; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Time Factors

Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Therefore, we evaluated the use of mycophenolate mofetil (MMF) for empirical treatment of primary glomerulopathies.. Forty-six patients with biopsy-proven primary glomerulopathies received MMF for > or =3 months as adjunctive or primary treatment. Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared using the Wilcoxon signed-ranks test.. Overall, the median Up/c decreased from 4.7 (range <0.1, 20.3) to 1.1 (<0.1, 14.3; P < 0.001) at the end of MMF treatment with no significant change in median serum creatinine 1.3 (0.6 to 6.1) to 1.2 (0.5 to 6.5) mg/dL. Median serum albumin increased from 3.4 (1.4, 4.6) to 4.1 (1.7, 48) g/dL (P < 0.001) and the median serum cholesterol decreased from 270 (148, 795) to 220 (140, 309) mg/dL (P < 0.001) post-treatment. For those with minimal change disease, a complete steroid withdrawal was accomplished in 5/6 steroid dependent patients. Focal segmental glomerulosclerosis (FSGS) patients had a median Up/c that decreased from 2.7 (0.1, 20.3) to 0.8 (<0.1, 8.2; P = 0.001) in 18 patients. In membranous nephropathy (MN) patients, the median Up/c decreased from 7.3 (0.1, 18.5) to 1.5 (<0.1, 14.3) (P = 0.001) in 17 patients. No significant change in median serum creatinine was detected in FSGS or MN patient groups during treatment.. Empirical MMF therapy in the majority of patients with primary glomerulopathies was well tolerated and achieved the goals of steroid withdrawal, improvement of nephrotic syndrome, and stabilization of renal function.

Topics: Adolescent; Adult; Aged; Creatinine; Female; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Kidney Glomerulus; Male; Middle Aged; Mycophenolic Acid; Nephrosis, Lipoid; Proteinuria; Steroids

Topics: Adult; Biopsy; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Spain; Transplantation, Homologous

Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors (CNI) in liver-transplant recipients. We undertook a randomised study to assess the safety and efficacy of CNI withdrawal and replacement by mycophenolate mofetil.. 28 people who had had renal dysfunction attributable to suspected CNI toxicity after liver transplantation participated in the study. We replaced CNI with mycophenolate mofetil in a stepwise pattern in half the group (study patients); the other half (controls) stayed on CNI immunosuppression. Renal function, blood pressure, uric acid, and blood lipids were measured before and 6 months after study entry. Side-effects of medication and graft function were recorded throughout the study.. At the end of the study, mean (SD) serum creatinine had fallen by 44.4 (48.7) micromol/L in study patients compared with 3.1 (14.3) micromol/L in controls; a mean difference of 41.3 micromol/L (95% CI 12.4-70.2). Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the study group but not in the control group (mean [95% CI] between group differences 10.8 mm Hg [3.0-18.6], 5.0 mm Hg [0.9-9.2], and 83.1 micromol/L [12.7-153.6], respectively). There were no changes in cholesterol or triglyceride concentrations in either group. Side-effects were reported by eight of the study patients. Three reversible episodes of acute graft rejection occurred in study patients during mycophenolate mofetil monotherapy, whereas none occurred in the control group.. Substitution of CNI by mycophenolate mofetil can improve renal function, blood pressure, and uric acid concentration of liver-transplant patients, but there is an increased rejection risk with mycophenolate mofetil monotherapy.

Topics: Blood Pressure; Calcineurin Inhibitors; Cholesterol; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Lymphoma; Male; Muromonab-CD3; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Tacrolimus; Transplantation, Homologous

Topics: ABO Blood-Group System; Adult; Antilymphocyte Serum; Communicable Diseases; Dose-Response Relationship, Drug; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Japan; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Pilot Projects; Survival Analysis

C3 glomerulopathy (C3G) is a rare kidney disease that causes kidney dysfunction as a result of dysregulation of the complement system alternate pathway (AP). C3G encompasses 2 separate disorders, C3 glomerulonephritis and dense deposit disease. The presentation and natural history is variable and kidney biopsy is needed to confirm the diagnosis. The overall prognosis is poor with high recurrence rates after transplant. A better understanding of C3G is needed as is high-quality evidence to guide therapy, which currently includes mycophenolate mofetil and steroids for moderate to severe disease, and terminal complement blockade with anti-C5 therapy in unresponsive cases.

Topics: Humans; Kidney; Kidney Diseases; Mycophenolic Acid

There is no standard recommendation for IgA nephropathy treatment in children.. This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis.. The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P < 0.01). Complete renal remission at 6-month, 1-year and 3-year follow up is 50.25%, 70% and 87.5% respectively. Five-year complete renal remission calculated by Kaplan-Meier analysis is 58.4%. Although without significant difference, there is trend of better survival with complete renal remission in group of nephrotic range proteinuria onset. There is no severe adverse effect.. This study supports the use of glucocorticoids plus immunosuppressive in addition to ACEI in IgA nephrology pediatric patients with proteinuria. We suggest proactive immunosuppressive treatment in IgA nephropathy in children. This is from a single center in China as may not same results in other population.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biopsy; CD4-Positive T-Lymphocytes; Child; China; Cyclophosphamide; East Asian People; Female; Follow-Up Studies; Glomerulonephritis, IGA; Glucocorticoids; Hematuria; Humans; Immunosuppressive Agents; Intraocular Pressure; Kaplan-Meier Estimate; Kidney Diseases; Male; Mycophenolic Acid; Proteinuria; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

Objective The objective of this study was to estimate the humoral immune response evaluated by immunoglobulin G (IgG) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD-IgG) following the third mRNA coronavirus disease 2019 (COVID-19) vaccination in patients with kidney disease who received immunosuppressive treatment. Methods The primary outcome was RBD-IgG levels after the third SARS-CoV-2 vaccination. The primary comparison was the RBD-IgG levels between patients with kidney disease who received immunosuppressive treatment (n=124) and those who did not (n=33). Results The RBD-IgG levels were significantly lower in the patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. The RBD-IgG levels were lower in patients treated with glucocorticoid monotherapy than in those who did not receive immunosuppressive treatment. Even in patients who received ≤5 mg prednisolone, the RBD-IgG levels were significantly lower. Nine of the 10 patients who received rituximab within one year before the first vaccination did not experience seroconversion after the third vaccination. Meanwhile, all nine patients who received rituximab only after the second vaccination experienced seroconversion, even if B cell recovery was insufficient. Patients treated with mycophenolate mofetil plus glucocorticoid plus belimumab had significantly lower RBD-IgG levels than those treated with mycophenolate mofetil plus glucocorticoid. Conclusion The RBD-IgG levels were lower in patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. Low-dose glucocorticoid monotherapy affected the humoral immune response following the third mRNA COVID-19 vaccination.

Topics: Antibodies, Viral; COVID-19; COVID-19 Vaccines; Glucocorticoids; Humans; Immunity, Humoral; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Rituximab; RNA, Messenger; SARS-CoV-2; Vaccination

Modern pharmacotherapy requires an individual approach to patients, taking into account changes in pharmacokinetics in pathological states and between-subject variability. This procedure is of particular importance in immunosuppressive drug therapy. In recent years, the attention has been paid to the usefulness of calculating the kinetic parameters of the drug in the optimization of the immunosuppressive treatment.. To assess the possibility of using mycophenolic acid (MPA) concentration measurements in order to optimize pharmacotherapy in patients with kidney diseases or after kidney transplantation.. The study included 103 patients with renal diseases (group 1) and after kidney transplantation (group 2), treated at the Department of Nephrology and Transplantation Medicine at the University Clinical Hospital, Wrocław, Poland. The concentrations of MPA were measured using Enzyme Multiplied Immunoassay Technique (EMIT®) method. A total of 193 pharmacokinetic profiles were performed.. The median of initial (C0) concentration for all patients was 2.09 mg/L, in group 1 - 2.06 mg/L and in group 2 - 2.11 mg/L. The median concentration at 30 min after drug administration (C30) was 11.72 mg/L in the whole study group, in group 1 - 11.52 mg/L and in group 2 - 12.72 mg/L. The median concentration at 120 min after the drug administration (C120) was 4.73 mg/L, 4.45 mg/L and 5.57 mg/L, respectively. The median area under the curve from C0 to C120 (AUC)0-120 was 15.77 h × mg/L for the entire study group, in group 1 - 15.46 h × mg/L and in group 2 - 16.78 h × mg/L. Using the Spearman's rank correlation coefficient for both groups, statistically significant (p < 0.05) correlations were found between 1) C0 and C30, 2) C0 and C120, 3) C0 and AUC0-120, 4) C0 and the daily dose, 5) C30 and AUC0-120, and 6) C30 and the morning dose. There were also statistically significant correlations between C120 and AUC0-120. Moreover, in group 1, a statistically significant correlation (p < 0.05) was found between 1) C120 and the daily dose, 2) C120 and albumin, 3) C120 and C30, and 4) C120 and AUC0-120. In the group 2, a statistically significant correlation was found between C120 and the morning dose.. Measurements of MPA concentrations are useful for optimizing immunosuppression in patients requiring an individualized treatment.

Topics: Area Under Curve; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Kinetics; Mycophenolic Acid

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered.

Topics: Antibodies, Viral; COVID-19; COVID-19 Vaccines; Humans; Kidney Diseases; Mycophenolic Acid; Rituximab

Nocardiosis is a life-threatening infection in immunocompromised patients. The prevalence of the disease ranges from 2.3% to 5% in renal allograft recipients. Here, we describe a case of BK nephropathy associating with nocardiosis with successful recovery. The 54-year-old male patient had end-stage kidney disease due to diabetic nephropathy associated with diabetic retinopathy, hypertension, and dyslipidemia. He started hemodialysis in October 2017; 2 years later, he underwent a deceased donor kidney transplant with 2 HLA mismatches and high panel reactive antibodies. He received desensitization with intravenous immunoglobulin and rituximab, received thymoglobulin as induction, and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. His serum creatinine decreased to a nadir of 90 μmol/L. He developed graft dysfunction, which was proven to be due to BK nephropathy. Therefore, mycophenolate mofetil was replaced with leflunomide in addition to intravenous immunoglobulin therapy. Ten months later, he had an accidental fall and sought an orthopedic evaluation. Magnetic resonance imaging of the lumbar spine and pelvis revealed lumbar spondylosis, avascular necrosis of the femoral head, and obturator muscle abscess. He was explored surgically, but the surgeon found no abscess or avascular hip necrosis. The patient's blood grew Nocardia, and he was readmitted and started imipenem and linezolid empirically. Brain and chest computed tomography scans ruled out any central nervous system or pulmonary involvement, but a bone scan revealed osteomyelitis of the right superior pubic ramus and prepubic swelling, which was confirmed by computed tomography to be an abscess in both obturator externus and internus. He continued the same antibiotics for 6 months based on culture and sensitivity. At follow-up, the patient has shown stable graft function (creatinine 155 μmol/L) with improved BK viremia with immunosuppression minimization. In renal transplant recipients, successful management of combined BK nephropathy and nocardiosis was feasible with minimization of immunosuppression and proper antimicrobial therapy.

Topics: Abscess; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia Infections; Polyomavirus Infections; Treatment Outcome; Tumor Virus Infections

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Immunosuppression Therapy; Kidney; Kidney Diseases; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger

A 66-year-old Chinese man underwent a deceased donor kidney transplantation. Induction-immunosuppressive protocol consisted of basiliximab (BAS) and methyl prednisolone (MP), followed by maintenance immunosuppression with cyclosporin (CsA), mycophenolate mofetil (MMF), and prednisone (PED). The patient's post-transplantation course was almost uneventful, and the graft was functioning well [serum creatinine (Scr) 2.15 mg/dL]. The MMF and CsA doses were decreased 1-month post-operative as the BK virus activation was serologically positive. His Scr was elevated to 2.45 mg/dL 45 days after the transplant. A graft biopsy showed BKV nephropathy (BKVN) and acute T cell-mediated rejection (TCMR) Banff grade IIA (I2, t2, ptc2, v1, c4d1, g0, and SV40 positive). The conventional anti-rejection therapy could deteriorate his BKVN, therefore, we administered BAS to eliminate activated graft-infiltrating T cells and combined with low-dose steroid. He responded well to the therapy after two doses of BAS were given, and the kidney graft status has been stable (recent Scr 2.1 mg/dL).

Topics: Aged; Basiliximab; BK Virus; Creatinine; Cyclosporine; Graft Rejection; Humans; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Polyomavirus Infections; Prednisolone; Prednisone; T-Lymphocytes

Protocol kidney biopsy (PKB) in kidney transplant is a useful tool for graft monitoring because the subclinical detection of histologic lesions helps to modulate immunosuppression. We analyze our experience.. We performed a descriptive study that analyzed the PKB results at the fourth to sixth month and the first year post transplant of patients with kidney transplant followed in our hospital between January 2015 and June 2021.. A total of 100 patients and 134 biopsy results were included, of which 71 were obtained between the fourth and sixth month and 63 at the first year. The mean age was 57.8 years, and 66% were men. Unknown etiology was the most common underlying kidney disease (31%), followed by diabetes mellitus (15%) and polycystic kidney disease (14%). A total of 80% had panel-reactive antibody < 50%. Induction therapy consisted of thymoglobulin (51%) and basiliximab (49%), and maintenance therapy consisted of corticosteroids and tacrolimus (100%), mycophenolate mofetil (82%), and mammalian target of rapamycin inhibitor (18%). Of the total of the PKB results (n = 134), 19 episodes of subclinical rejection (14%) and 10 with borderline changes (7.4%) were observed. Regarding other findings, there were cases of nephrocalcinosis (4.4%), immunoglobulin A nephropathy (2.2%), and BK nephropathy (1.5%). The PKB brought about a change in the therapeutic attitude in 45 cases (33%) of the total number of biopsies, the most frequent change being the administration of boluses of methylprednisolone (12.6%) and the change to mammalian target of rapamycin inhibitor (8.9%).. In our experience, PKB is a useful tool for monitoring and evaluating histologic changes without clinical expression in the kidney graft, allowing us to adapt the treatment during the first year of kidney transplant.

Topics: Biopsy; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Acute calcineurin inhibitor (CNI) nephrotoxicity is a common complication associated with CNI exposure. However, it can be difficult to diagnose. Herein, we report a case of acute CNI nephrotoxicity after heart transplant that was visualized using kidney Doppler ultrasonography.. A 38-year-old female patient underwent heart transplant 5 years after the use of left ventricular assist device support because of advanced heart failure due to ischemic cardiomyopathy. Corticosteroids, tacrolimus, and mycophenolate mofetil were administered as immunosuppressive regimens postoperatively. The patient gradually developed kidney dysfunction despite a favorable perioperative clinical course and hemodynamics. Serum creatinine increased to 1.89 mg/dL on postoperative day (POD) 9, and the kidney Doppler ultrasonography examination showed severely reduced blood flow in the renal and renal segmental arteries, indicating acute CNI nephrotoxicity due to vasoconstriction of the renal arterioles. After the cessation of tacrolimus, kidney function returned to baseline levels within 2 days, and the kidney Doppler ultrasonography examination on POD 19 revealed a significant increase in blood flow in the renal and renal segmental arteries. Basiliximab followed by everolimus were administered as alternative immunosuppressants. No organic stenosis of the renal artery was detected on the kidney magnetic resonance angiography, and the patient was discharged on POD 51, without any other adverse events, including rejection.. Although CNIs are widely used after heart transplant, acute nephrotoxicity should always be considered. After heart transplant, a kidney Doppler ultrasonography should be performed routinely and promptly if there are any clinical manifestations related to kidney function.

Topics: Adult; Calcineurin Inhibitors; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Mycophenolic Acid; Renal Insufficiency; Tacrolimus; Ultrasonography, Doppler

Renal dysfunction is related to short- and long-term survival after liver transplantation. We present herein a retrospective analysis of our experience with liver transplantation in recipients with pretransplant renal dysfunction treated with induction therapy followed by delayed/reduced de novo once-daily tacrolimus.. Liver transplantations performed between April 2008 and August 2011 were included in this study. Pretransplant renal dysfunction was defined as estimated glomerular filtration rate <60 mL/min. Interleukin-2 receptor antagonists were used for induction therapy. Initial once-daily tacrolimus dose was 0.10 mg/kg/day or 0.07 mg/kg/day if combined with mycophenolate mofetil (MMF). Tacrolimus target trough levels were 4 to 6 ng/mL during the first post-transplant year and <4 ng/mL the rest of the follow-up.. Nineteen patients comprised the study cohort with a median follow-up of 56.4 months (range, 11-78). Median day of tacrolimus introduction was 7 (range, 3-12). Once-daily tacrolimus was withdrawn in 6 patients (31.6%) due to evolution of renal dysfunction in all cases. At 5 years, 30% of the patients were under MMF monotherapy. Mean tacrolimus trough levels were maintained under 5 ng/mL. Mean estimated glomerular filtration rate at 5 years was 55.3 ± 12.7 mL/min. No patient needed hemodialysis or renal transplantation over the follow-up. Patient survival at 5 years was 78.9%.. Induction therapy followed by delayed/reduced de novo once-daily tacrolimus and maintenance of low tacrolimus exposition during the follow-up is effective to maintain long-term renal function and to achieve favorable patient survival in liver transplant recipients with pretransplant renal dysfunction.

Topics: Aged; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Preoperative Period; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid

Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined.. We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively.. Thirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups.. A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.

Topics: Adult; Azathioprine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Male; Mycophenolic Acid; Prednisolone; Recurrence; Retrospective Studies; Survival Rate; Treatment Outcome

The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.. We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.. Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.. These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

Topics: Adult; Aged; Anemia; Diabetes Mellitus; Female; Genome-Wide Association Study; Genotype; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; Tacrolimus; United States; Young Adult

Thrombotic microangiopathy (TMA) is a pathologic condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to microvascular endothelial lesions and thrombosis. It occurs in a variety of diseases and, unless recognized and treated, leads to severe morbidity and mortality. We present the case of a 48-year-old woman who underwent lung transplantation, initially under tacrolimus, mycophenolate mofetil (MMF), and prednisolone. Several complications emerged in the following months, including abdominal aortic and left renal artery thrombosis and cutaneous infections, although her renal function remained normal. Six months after transplant, her renal function began to deteriorate, which was assumed to be due to elevated tacrolimus levels and doses were adjusted. Due to leukopenia, MMF was changed to everolimus. One year after, she was admitted with fatigue, anemia, and renal dysfunction. Complementary exams revealed only iron deficiency, leukopenia, normal platelets, and elevated lactate dehydrogenase; her renal ultrasound was normal. A renal biopsy was performed and thrombotic microangiopathy was subsequently identified as the main cause of the renal dysfunction. Tacrolimus was therefore discontinued and MMF restarted with slow improvement of renal function. Only when everolimus was stopped did the patient's renal function show incremental improvement. TMA may be a serious complication after lung transplantation and the risk is higher when a combination of tacrolimus and everolimus is used. Renal biopsy findings are essential to confirm the final diagnosis of TMA, allowing for a change in immunosuppression to prevent permanent and severe renal damage.

Topics: Everolimus; Female; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Lung Transplantation; Middle Aged; Mycophenolic Acid; Tacrolimus; Thrombotic Microangiopathies

Surveillance biopsies (SBs) are performed in some pediatric kidney transplant programs, based on data obtained in earlier immunosuppressive eras that the treatment of subclinical acute rejection results in better graft survival. The benefit of SBs for patients on modern immunosuppression regimens is unclear. We have therefore evaluated the clinical utility of SBs in a population of children receiving a kidney transplant.. We have performed SBs at 3, 6 and 12 months post-transplantation as standard of care at our institution since 2013 in patients on a regimen of rabbit anti-thymocyte globulin, tacrolimus, mycophenolate and rapid steroid taper (RST; steroids maintained in some exceptions). We reviewed pathology reports of 82 SBs from 34 transplants in 34 children for all abnormal findings and adequacy of specimens. Clinical records were reviewed for changes in management resulting from SB findings and for significant procedure complications.. Of the 82 biopsies, 41 (50%) had abnormal findings separate from fibrosis, including five Banff Grade I rejections, ten borderline rejections, six calcineurin-inhibitor nephrotoxicity, four BK-virus nephropathy, five recurrent disease and three acute pyelonephritis. Moderate or more fibrosis was present in nine of the 82 (11%) biopsies. Management changes due to SB findings occurred in nine cases (11.0%). The proportion of abnormal findings or management changes did not differ between the RST or steroid-based groups. Patients performing clean intermittent catheterization showed inflammatory changes often read as rejection, but were managed differently. Three biopsies were deemed inadequate. No significant complications occurred.. A high percentage of the SBs performed under modern immunosuppression showed abnormal findings even when fibrosis was excluded. However, management changes due to the SB findings were less frequent, although they occurred in a clinically meaningful percentage of cases. Complications or inadequate specimens were rare.

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Young Adult

There is a lack of agreement regarding treatment for many aspects of systemic sclerosis (SSc). We undertook this study to generate SSc treatment algorithms endorsed by a high percentage of SSc experts.. Experts from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research group (n = 170) were asked whether they agreed with SSc algorithms from 2012. Two consensus rounds refined agreement; 62, 54, and 48 experts (36%, 32%, and 28%, respectively) completed the first, second, and third surveys, respectively.. For treatment of scleroderma renal crisis, 81% of experts agreed (first-, second-, and third-line treatments were angiotensin-converting enzyme inhibitors, then adding calcium-channel blockers [CCBs], then adding angiotensin receptor blockers [ARBs], respectively). For pulmonary arterial hypertension (PAH), 81% of experts agreed (for mild PAH, treatments were phosphodiesterase 5 [PDE5] inhibitors, then endothelin receptor antagonists plus PDE5 inhibitors, then prostanoids, respectively; for severe PAH, prostanoids were first-line treatment). For mild Raynaud's phenomenon (RP), 79% of experts agreed (treatments were CCBs, then adding PDE5 inhibitors, then ARBs or switching to another CCB, respectively; after the third line of treatment, mild RP was deemed severe). For severe RP, the first- through fourth-line treatments were CCBs, then adding PDE5 inhibitors or prostanoids, then adding PDE5 inhibitors (if not added as second-line treatment) or prostanoids (if not added as second-line treatment), then switching to another CCB, respectively. For active treatment of digital ulcers, 66% of experts agreed (first- and second-line treatments were CCBs and PDE5 inhibitors, respectively). For interstitial lung disease, 69% of experts agreed (for induction therapy, treatments were mycophenolate mofetil [MMF], intravenous cyclophosphamide [IV CYC], and rituximab, respectively; for maintenance, first-line treatment was MMF). For skin involvement, 71% of experts agreed (for a modified Rodnan skin thickness score [MRSS] of 24, first- and second-line treatments were methotrexate [MTX] and MMF, respectively; for an MRSS of 32, first- through fourth-line treatments were MMF, MTX, IV CYC, and hematopoietic stem cell transplantation, respectively). For inflammatory arthritis, 79% of experts agreed (first- through fourth-line treatments were MTX, low-dose glucocorticoids, hydroxychloroquine, and rituximab or tocilizumab, respectively). Algorithms for cardiac and gastrointestinal involvement had ≥75% agreement.. Total agreement for SSc algorithms was considerable. These algorithms may guide treatment.

Topics: Algorithms; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis; Calcium Channels; Cyclophosphamide; Endothelin Receptor Antagonists; Glucocorticoids; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Immunosuppressive Agents; Kidney Diseases; Lung Diseases, Interstitial; Methotrexate; Mycophenolic Acid; Phosphodiesterase 5 Inhibitors; Prostaglandins; Raynaud Disease; Rituximab; Scleroderma, Systemic

To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV.. Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months.. In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months.. This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.

Topics: Adolescent; Adrenal Cortex Hormones; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Child; Cohort Studies; Cyclophosphamide; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Diseases; Male; Methotrexate; Mycophenolic Acid; Prospective Studies; Recurrence; Registries; Remission Induction; Retrospective Studies; Rituximab

The immunosuppressive agents mycophenolate acid (MPA) and tacrolimus (Tac) are associated with a higher incidence of BK polyomavirus nephropathy (BKPyVAN). In this observational retrospective cohort study, the frequency of BK polyomavirus (BKPyV) complications over a 24-month period was studied.. 358 renal transplant recipients (RTR) treated with MPA, with either cyclosporine A (CsA) (CsAM group) or Tac (TacM group) and mostly prednisolone, were included.. Incidence of BKPyV-viremia was not significantly different between the CsAM (n = 42/191) (22.0%) and the TacM (n = 36/167) (21.6%) group. Biopsy proven BKPyVAN occurred more often in the TacM group (6.6%) versus the CsAM group (2.1%) (p = 0.03). Longitudinal data analysis showed a significant earlier decline of viral load in plasma in the CsAM group compared to the TacM group (p = 0.005). The incidence of biopsy proven acute rejection (BPAR) was significantly higher in the CsAM (19.9%) compared to the TacM (10.8%) (p = 0.02) group. Graft loss, estimated glomerular filtration rate and mortality rate did not differ in both treatment groups.. In conclusion, this study shows that immunosuppressive treatment with Tac and MPA compared to CsA and MPA is associated with a lower incidence of BPAR, but at the cost of an increased risk of developing BKPyVAN in the first two years post-transplant.

Topics: Adult; BK Virus; Cyclosporine; Female; Genotype; Graft Rejection; Host-Pathogen Interactions; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Outcome Assessment, Health Care; Polyomavirus Infections; Retrospective Studies; Tacrolimus; Transplant Recipients; Tumor Virus Infections

This study investigates whether the toxicity in kidneys as well as oxidative stress varied according to the dosing time of an immunosuppressive agent "mycophenolate mofetil (MMF)" in Wistar Rat. 300mg/kg of MMF was injected by intraperitonal at four different circadian stages (1, 7, 13 and 19h after light onset, HALO). Rats were sacrificed after 3days, and the kidneys were removed for determination of oxidative stress and histological analysis. Biochemical variable (creatinine, urea) was performed. Statistical analysis showed that MMF administration at 7 HALO produced a renal toxicity assessed by the significant increase in both blood creatinine and urea and antioxidant activity assessed by malondialdehyde and protein carbonyl levels indicating an induction of lipid peroxidation in oxidative damage. Whereas, at this time MMF induced a decrease the enzyme activities of renal catalase and superoxide dismutase, with a renal histopathology alterations (glomerular atrophy and lesions within proximal tubules). However, when MMF was injected in the middle of the dark-activity phase it produced a very mild renal toxicity and low oxidative stress. The obtained data indicate that the maximum of renal toxicity is observed when MMF was injected in the middle of the light- rest span in rats.

Topics: Animals; Antioxidants; Catalase; Creatinine; Immunosuppressive Agents; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Mycophenolic Acid; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Urea

Limited access to tertiary-level health care, limited trained pediatric nephrologists and transplant physicians, lack of facilities for dialysis, lack of an effective deceased donor program, non-affordability, and non-adherence to immunosuppressant drugs poses a major challenge to universal availability of pediatric transplantation in developing countries. We present the results of a survey which, to the best of our knowledge, is the first such published attempt at understanding the current state of pediatric renal transplantation in India. A designed questionnaire formulated by a group of pediatric nephrologists with the aim of understanding the current practice of pediatric renal transplantation was circulated to all adult and pediatric nephrologists of the country. Of 26 adult nephrologists who responded, 16 (61.5%) were involved in pediatric transplantation, and 10 of 15 (66.6%) pediatric nephrologists were involved in pediatric transplantation. Most of the centers doing transplants were private/trust institution with only three government institutions undertaking it. Induction therapy was varied among pediatric and adult nephrologists. There were only a few centers (n=5) in the country routinely doing >5 transplants per year. Preemptive transplants and protocol biopsies were a rarity. The results demonstrate lower incidence of undertaking pediatric transplants in children below 6 years, paucity of active cadaveric programs and lack of availability of trained pediatric nephrologists and staff. In contrast to these dissimilarities, the immunosuppressant use seems to be quite similar to Western registry data with majority favoring induction agent and triple immunosuppressant (steroid, mycophenolate mofetil and tacrolimus) for maintenance. The survey also identifies major concerns in availability of this service to all regions of India as well as to all economic segments.

Topics: Adolescent; Adult; Child; Child, Preschool; Developing Countries; Female; Geography; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; India; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Nephrology; Registries; Surveys and Questionnaires; Tissue Donors; Young Adult

Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation.. Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups.. Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01).. The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Chronic Disease; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Liver Transplantation; Male; Multivariate Analysis; Mycophenolic Acid; Prognosis; Remission Induction; Survival Rate; Tacrolimus

This study aimed to retrospectively analyze the long-term outcome of mycophenolate mofetil (MMF) therapy for microscopic polyangiitis (MPA) with mild to moderate renal involvement in Chinese patients. Thirty-four MPA patients (24 females, 10 males, aged 44.7 ± 17 years, BVAS score 13.8 ± 3.2, SCr 2.2 ± 1.1 mg/dl) with SCr < 5 mg/dl and who received glucocorticoids plus MMF therapy for inducing and maintaining remission were included in this study. The remission and relapse rates, patient and renal survival rates and adverse events were retrospectively analyzed. We found that 31 (91.2 %) of 34 patients achieved remission and were continuously treated with glucocorticoids plus MMF for maintaining remission. The median duration of MMF treatment was 24 months (IQR 15-53 months) and follow-up time was 86 months (IQR 29-124 months). During the follow-up, 7 (22.6 %) patients relapsed, one patient died, and one patient progressed into end-stage renal disease. The 5-year patient and renal survival rates were 92.8 and 95.2 %, respectively. 11 (32.4 %) patients suffered 16 adverse events, 13 of which were pulmonary infection. In conclusion, glucocorticoids plus MMF regimen as induction and maintenance therapy could achieve high remission rate and good long-term renal survival in MPA patients with mild to moderate renal involvement. Prospective controlled trials with a large sample size are needed to confirm the efficacy of MMF in this population.

Topics: Adult; China; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunocompromised Host; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Remission Induction; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.

Topics: Animals; Antibodies, Monoclonal; Azo Compounds; Collagen; Dose-Response Relationship, Drug; Enalapril; Fibrosis; Kidney Diseases; Male; Mycophenolic Acid; Non-Fibrillar Collagens; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Ureteral Obstruction

BK polyomavirus (BKV) infection and BKV nephropathy (BKVN) are risk factors for allograft function and survival.. We retrospectively analyzed BK viremia and BKVN in 348 patients who received a kidney transplantation donated after brain death (n=232) or living donation (n=116) between 2008 and 2013. A total of 266 patients were treated with standard immunosuppression consisting of basiliximab induction, calcineurin inhibitor (CNI), and mycophenolic acid (MPA, n=219) or everolimus (n=47); 82 patients received more intense immunosuppression with lymphocyte depletion, CNI and MPA (n=38) or everolimus (n=44).. BK viremia occurred in 33 (9.5%) patients in the first year and in 7 (2.0%) recipients in the second year after transplantation. BKVN occurred in 4 (1.1%) patients in the first year. Donor and recipient age, diabetes, previous transplantation, and type of transplantation (donated after brain death vs living donation) were not risk factors (P>.05). BK incidence did not differ depending on induction or maintenance immunosuppression.. Incidence of BK viremia is independent of recipient characteristics, type of transplantation as well as induction and maintenance immunosuppression.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; BK Virus; Calcineurin Inhibitors; Everolimus; Female; Germany; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Induction Chemotherapy; Kidney Diseases; Kidney Transplantation; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Recombinant Fusion Proteins; Retrospective Studies; Risk Factors; Transplantation, Homologous; Tumor Virus Infections; Viremia

This report concerns a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with frequent treatment-dependent relapses. A 75-year-old male presented with a 2-month history of progressive weakness of the limbs with no sensory symptoms. Neurological examination revealed normal cranial nerves, MRC grade 4 power in the proximal and distal muscles of the limbs, and generalized areflexia. However, the sensory examination results, serum immunoelectrophoresis, anti-HIV antibody, and vitamins B1 and B12 levels were normal. Cervical MR imaging was unremarkable. Cerebrospinal fluid showed albuminocytologic dissociation. Nerve conduction studies demonstrated prolonged distal latencies in the bilateral median nerves and left ulnar nerve. Treatment with intravenous immunoglobulin (IVIg) infusion resulted in a marked improvement. Thereafter, the patient had been treated with repeated IVIg to maintain motor function. Subsequently, the patient fulfilled the EFNS/PNS diagnostic criteria for pure motor form of definite CIDP. Treatment with ciclosporin with the plasma trough level of 60-150 ng/ml reduced the frequency of IVIg. However, renal function began to deteriorate 94 months after the initiation of ciclosporin. The calcineurin inhibitor was replaced with mycophenolate mofetil 1,500 mg, which significantly increased the interval between infusions without further renal impairment. Therefore, mycophenolate may represent an effective alternative treatment for some IVIg-dependent CIDP patients.

Topics: Aged; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Guillain-Barre Syndrome; Humans; Immunoglobulins, Intravenous; Kidney Diseases; Male; Mycophenolic Acid; Recurrence; Secondary Prevention; Time Factors; Treatment Outcome

Calcineurin inhibitors (CNI) are the base of immunosuppressive regimens in liver transplantation but they are associated with significant side effects, namely nephrotoxicity, which leads to increased morbidity and mortality. Through time, mycophenolate mofetil (MMF) as monotherapy has been suggested as an alternative in patients with CNI-related toxicity, but still no consensus has been reached as to its efficacy. We have evaluated the safety, efficacy, and tolerability of MMF monotherapy in selected patients, developing CNI-associated events, focusing primarily on kidney dysfunction. Thirty patients were selected (60% men) with a mean age of 48.5 years. Four patients (13%) were initially on a multidrug regimen that included MMF ad initio due to increased risk of kidney dysfunction. CNI tapering was initiated 5.1 years after liver transplantation (5 months to 13.9 years). The mean time of follow-up after conversion to monotherapy with MMF was 5.6 years (14 months to 12 years). Kidney function analysis accessed by creatinine values and glomerular filtration rate measurement showed a gradual improvement (P < .01). Graft dysfunction after conversion to monotherapy was observed in three patients who required reintroduction of the previous immunosuppressive regimen. Four patients referred minor side effects that were managed with dose reduction. None required MMF withdrawal. Ten patients died during follow up, mainly due to disease progression, 6.8 years after MMF conversion. In conclusion, MMF monotherapy seems to be safe, effective, and well tolerated in selected patients.

Topics: Adult; Aged; Calcineurin Inhibitors; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies

Calcineurin inhibitor-associated chronic nephrotoxicity threatens the prognosis of liver transplant recipients. This study aimed to study the mechanisms involved by identifying the cytokine profiles in tacrolimus (Tac)-induced nephrotoxicity.. We enrolled 125 living-donor liver transplant recipients. All of the recipients had normal serum cystatin (Cys) C and urine microalbumin before transplantation. They received a Tac-based immunosuppressive regimen (Tac + mycophenolate mofetil + prednisone) thereafter. Patients were grouped according to Cys-C results (measured a mean 3.55 ± 1.89 years after transplantation) as a measure of renal injury: the early renal damage group was Cys-C >1 mg/L, and normal renal function was Cys-C ≤1 mg/L. Serum levels of 10 cytokines and chemokines, as well as urine proteins including α1 microglobulin, microalbumin, transferrin, and immunoglobulin G, were compared between groups.. In the early renal damage group, the concentration of interferon-γ-induced protein (IP) 10 was higher and monocyte chemotactic protein (MCP) 1 was lower compared with the group with normal renal function (P = .027 and .048, respectively). Multivariate logarithmic regression analysis showed that IP-10 and MCP-1 were independently correlated with renal damage.. High level of IP-10 and low level of MCP-1 may be involved in renal injury and therefore may indicate poor prognosis. IP-10 could be a target for renal injury treatment after liver transplantation. Further studies with larger sample sizes are recommended to validate the study results.

Topics: Calcineurin Inhibitors; Chemokine CCL2; Chemokine CXCL10; Cytokines; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Interferon-gamma; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

Steroids are the mainstay of treatment for renal sarcoidosis. Many patients with sarcoidosis are chronically dependent on steroids and there is limited data on the use of steroid-sparing agents. This is a case of a patient that has remained in remission using mycophenolate mofetil (MMF) as a steroid-sparing agent. The patient is a 56-year-old female with a history of sarcoidosis diagnosed by lymph node biopsy who developed 3 episodes of acute kidney injury (AKI) in the setting of exacerbations of her sarcoidosis, each responding to prednisone treatment. Due to possible lifelong need for prednisone, MMF was started as a steroid-sparing treatment. She tolerated the MMF well and has now been steroidfree for 22 months. There have been only a few case reports about the use of MMF as a steroid-sparing agent in sarcoid-associated renal disease, in which patients could be successfully weaned off steroids. This is the longest reported follow-up of a patient being off steroids while on MMF. It is also notable for the patient having a relapse on the MMF which responded to an increased dose. MMF should be studied further as a potential steroid-sparing agent in the treatment of sarcoid associated renal disease.

Topics: Acute Kidney Injury; Female; Humans; Kidney Diseases; Middle Aged; Mycophenolic Acid; Sarcoidosis

To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil.. Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine.. The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate-mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3.. Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolate-mofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic.

Topics: Animals; Calcineurin Inhibitors; Creatinine; Immunosuppression Therapy; Immunosuppressive Agents; Ischemia; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Nephrons; Random Allocation; Rats, Wistar; Reperfusion Injury; Tacrolimus; Time Factors; Urea

Microscopic polyangiitis (MPA) is one of the most common forms of antineutrophil cytoplasm autoantibodies (ANCA)-associated vasculitis in children. Cyclophospamide and glucocorticoid-based treatment protocols are still considered gold standard in managing this multi-system disorder. But treatment-related toxicity is a major cause of chronic morbidity and early mortality in MPA. Hence, the search for an effective and safe alternative immunosuppressant is essential.. A retrospective analysis of baseline clinico-pathological presentation and treatment-outcome was performed among 11 paediatric MPA patients. All of whom were treated with a pre-specified cyclophosphamide free, rituximab- and mycophenolate mofetil (MMF)-based management protocol as per centre practice.. We describe the clinical course of 11 children with MPA over a median follow-up period of 20.9 months. Both patient survival and renal survival at 1 year follow-up were 100%. In spite of the varying degree of renal involvement at presentation, kidney function was recovered in all patients with a median estimated glomerular filtration rate (eGFR) of 79.5 mL/min/1.73 m(2). At last follow-up, 91% (10/11) of patients were in complete remission and one (9%) child continued partial remission state. There was no treatment failure. In total, 73% (8/11) of patients were off steroids at last follow-up and 82% (9/11) of patients never relapsed during follow-up period.. Efficacy and medium-term safety of rituximab- and MMF-based protocol in managing children with MPA was evident in this study.

Topics: Algorithms; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Microscopic Polyangiitis; Mycophenolic Acid; Remission Induction; Retrospective Studies; Rituximab; Survival Rate; Treatment Outcome

Standard therapy with corticosteroids (CS) and cyclophosphamide (CYC) followed by azathioprine has been shown to improve renal and patient survival in ANCA-associated renal vasculitis (rAAV). Mycophenolate mofetil (MF) has been progressively introduced for the treatment of rAAV in the last years because of its immunosuppressive efficacy combined with a lower toxicity profile. In this study, we retrospectively analyse the results of the introduction of MF for maintenance and induction therapy in rAAV in our institution from 2001 to 2013.. We reported 67 patients treated with MF as a maintenance treatment, divided by baseline serum creatinine (>500 µmol/L: Group 1 and <500 µmol/L: Group 2) and treatment schedule. Twenty-nine of the 67 patients were also treated with MF as induction treatment, mostly in Group 2. During the follow-up (2 years after the diagnosis) creatinine levels for serum glomerular filtration rate, ANCA titres, C-reactive protein and percentage of haematuria decreased in all groups. In Group 2, parameters and also relapse rates were similar at 24 months in patients treated with CYC or MF as an induction treatment (Subgroups 2a and 2b, respectively). Median dose of MF in maintenance treatment was 1000 mg daily and prednisone dose was tapered to 10 mg daily from Month 3. After 24 months, 82% of patients remained on MF therapy, 18% had discontinued the treatment, seven of them due to medical indication and two because of gastrointestinal intolerance. The percentage of patients that started renal replacement therapy was irregular in Group 1 depending on the subgroup (25-100%), and 10% in Group 2. Adverse effects, such as neutropenia, infections and neoplasia, were more prevalent in groups treated with CYC.. In conclusion, in our patients with rAAV, MF demonstrated to be an effective and well-tolerated option for maintenance treatment. As an induction treatment, MF seems to be similar to CYC for patients with moderate renal failure in the diagnosis.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; C-Reactive Protein; Female; Glomerular Filtration Rate; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus; Polyomavirus Infections; Pulmonary Fibrosis; Tacrolimus

To analyze the risk factors affecting BK virus associated nephropathy (BKVAN) after kidney transplantation.. Three screening methods for BKVAN including quantitative PCR assay for BK virus (BKV) DNA load in urine and plasma and quantitative assay of urine cytology concurrently with renal transplant biopsies for the evaluation of 615 patients from January 2006 to December 2014 were used. The renal allograft biopsy specimens were analyzed by routine histologic examination, immunohistochemistry and classified into three categories of BKVAN. Potential variables were analyzed by Logistic regression model multivariate analysis to assess and rank BKVAN related risk factors.. The positive rate of urine decoy cell , BKV viruria and viremia in 615 renal recipients were 13.7% (84/615), 29.3% (180/615), and 8.8% (54/615), respectively. BKVAN were diagnosed in 49 recipients. The incidence and the median level of the number of the decoy cell, BK viral load in urine and plasma were higher in the BKVAN group than those in non-BKVAN group (all P<0.05). Tacrolimus (Tac) combined with mycophenolic acid (MPA) protocol (OR=12.4, P=0.001) and severe pneumonia post-transplant (OR=3.7, P=0.001) were the independent risk factors impacting on BKVAN in renal recipients.. The renal recipients with high level of BKV replication, whose immunosuppressant protocol include Tac and MPA, should be suspected the diagnosis of BKVAN.

Topics: Biopsy; BK Virus; DNA, Viral; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Risk Factors; Tacrolimus; Transplant Recipients; Transplantation, Homologous; Viral Load; Viremia

Topics: Adult; Chronic Disease; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Treatment Outcome; Urticaria

BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood.. Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy.. Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk.. Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

Topics: Adult; Aged; Allografts; Antibodies, Monoclonal; Azathioprine; Basiliximab; BK Virus; Cohort Studies; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Polyomavirus Infections; Proteinuria; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Tacrolimus; Tumor Virus Infections; Viremia

Cytomegalovirus (CMV) infection is an important complication in organ and bone marrow recipients as well as patients infected with HIV. Although screening and prophylaxis have been defined in these patients, there are few data about the frequency of CMV disease in glomerular diseases treated by immunosuppression.. We recruited 133 patients with glomerular diseases treated by immunosuppression between 2006 and 2013. Patients who had any symptoms suggestive of CMV disease were screened for viral DNA. Immunosuppressive treatments were as follows: Group 1, steroid only; Group 2, steroid with cyclophosphamide (CP); Group 3, steroid with cyclosporine A; and Group 4, steroid with mycophenolate mofetil or azathioprine.. Patients developing CMV and non-CMV disease were compared for age, sex, renal pathology, hypertension, diabetes, baseline creatinine, and estimated glomerular filtration rate, and immunosuppressive regimen. At follow-up, 55 patients were tested for CMV disease during immunosuppressive treatment. Twenty-six patients had CMV DNA positivity of 1,112-205,500 copies/mL. Patients with CMV disease were all seen within the first 5 months of immunosuppressive treatment, and the disease was observed most commonly (14 patients, 53 %) in the first 2 months of treatment. Multiple regression analysis revealed that high baseline creatinine levels, older age, and use of steroids with CP were independent risk factors for development of CMV disease.. CMV disease is not an uncommon complication in patients with glomerular diseases treated by immunosuppression. Further prospective studies and prophylaxis should be addressed in future studies, including particular groups of patients.

Topics: Adult; Azathioprine; Biopsy; Cyclophosphamide; Cyclosporine; Cytomegalovirus Infections; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Real-Time Polymerase Chain Reaction; Retrospective Studies; Risk Factors; Turkey

The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry, and only 13% of their genomes arise from different ancestors.. We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk, and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines, and in the F2 progeny, we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio) from 6.6 to 1.2 mg/mg (P<0.001) in SHR-A3. Glomerular injury scores were reduced in MMF-treated SHR-A3 from 1.6 to 1.4 (P<0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 (P=0.001). MMF treatment also reduced renal fibrosis in SHR-A3 (3.9 versus 2.0; P<0.001).. Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.

Topics: Albuminuria; Alleles; Animals; Blood Pressure; Genetic Predisposition to Disease; Genetic Variation; Glomerular Filtration Rate; Haplotypes; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Lymphocytes; Mycophenolic Acid; Rats; Rats, Inbred SHR; Receptors, Immunologic; Sequence Analysis, DNA; Signal Transduction

To investigate the protective effects of rhein lysinate (RHL), a major bioactive constituent of the rhizome of rhubarb (Rheum palmatum Linn or Rheum tanguticum Maxim), against kidney impairment in senescence-prone inbred strain 10 (SAMP10) mice.. SAMP10 mice were orally administered RHL (25 or 50 mg/kg) daily until 50% of the mice died. Senescence-resistant inbred strain 1 (SAMR1) mice administered no drug were taken as control. The kidneys were harvested after animal death, and examined morphologically and with immunochemical assays. The levels of MAD, SOD and GSH-px in the kidneys were measured with a photometric method. The expression of inflammatory factors and related proteins in the kidneys was analyzed using Western blotting.. Treatment of SAMP10 mice with RHL had no effect on the body weight or phenotype. However, RHL significantly prolonged the median survival time of SAMP10 mice by approximately 25%, as compared to untreated SAMP10 mice. Compared SAMR1 mice, SAMP10 mice had a significantly lower level of SOD in the kidneys, but had no significant difference in the MDA or GSH-px levels. Treatment of SAMP10 mice with RHL significantly reduced the MAD level, and increased the SOD and GSH-px levels in the kidneys. Glomerulonephritis was observed in SAMP10 mice but not in SAMR1 mice. RHL decreased the incidence of glomerulonephritis, and significantly decreased the levels of TNF-α, IL-6, NF-κB, collagen types I and III in the kidneys.. Accelerated senescence is associated with glomerulonephritis in SAMP10 mice, and RHL prolongs their median survival time by reducing the severity of glomerulonephritis.

Topics: Adenine Nucleotides; Animals; Anthraquinones; Body Weight; Collagen Type I; Collagen Type III; Glomerulonephritis; Glutathione; Interleukin-6; Kidney Diseases; Macrophages; Male; Mice; Mycophenolic Acid; NF-kappa B; Rhizome; Superoxide Dismutase; Survival Rate; Tumor Necrosis Factor-alpha

We prospectively screened 609 consecutive kidney (538) and kidney-pancreas (71) transplant recipients for BK viremia over a 4-year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥ 10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥ 10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30-50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22-744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Immunosuppression Therapy; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Tumor Virus Infections; Viral Load

Topics: Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Mycophenolic Acid; Nephrons; Sirolimus

Calcineurin inhibitor-induced nephrotoxicity reduces long-term patient survival after heart transplant. Proliferation signal inhibitors, in combination with or replacing calcineurin inhibitors, may preserve or improve renal function. We evaluated the effect of calcineurin inhibitor-reduction and withdrawal in everolimus-based immunosuppression on renal function after a heart transplant.. Twenty-four patients with creatinine clearance < 1 mL/s (60 mL/min) were switched from tacrolimus and mycophenolate mofetil to low-dose tacrolimus/everolimus if their heart transplant was ≤ 1 year ago (group 1, n=13) and to everolimus/mycophenolate mofetil if their heart transplant was > 1 year ago (group 2, n=11). Serum creatinine levels and calculated creatinine clearance were analyzed up to 12 months after conversion.. The switch in immunosuppression was associated with a significant decrease/increase of serum creatinine/creatinine clearance in both groups between baseline and month 12 (group 1, creatinine, 221.0 ± 70.7 to 159.1 ± 44.2 μmol/L (2.5 ± 0.8 to 1.8 ± 0.5 mg/dL); creatinine clearance, 0.75 ± 0.45 to 1.01 ± 0.50 mL/s (45.1 ± 26.7 to 60.5 ± 29.7 mL/min) (P < .01 each); group 2, creatinine, 247.5 ± 79.6 to 159.1 ± 44.2 μmol/L (2.8 ± 0.9 to 1.8 ± 0.5 mg/dL), creatinine clearance, 0.57 ± 0.23 to 0.93 ± 0.33 mL/s (34.1 ± 13.8 to 55.7 ± 19.6 mL/min) [P < .05 each]) with no significant group difference in the creatinine and the creatinine clearance levels after switching. No acute rejections or deaths occurred during the 12-month follow-up. Four patients (36.4%) from group 2 and 1 patient (7.7%) from group 1 discontinued everolimus because of adverse events.. Everolimus allows calcineurin inhibitor-reduction and withdrawal after a heart transplant, resulting in improved renal function. However, adverse effects are common and lead to a high reconversion rate.

Topics: Adult; Aged; Biomarkers; Creatinine; Drug Substitution; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Recovery of Function; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Acquired pure red-cell aplasia is a rare disorder that can be either idiopathic or associated with certain autoimmune diseases, pregnancy, lymphoproliferative disorders, nutritional deficiencies, or medicines. We present a deceased-donor renal transplant patient who developed pure red-cell aplasia associated with mycophenolate mofetil or tacrolimus and was treated with cyclosporine. A 20-year-old woman was transplanted from a deceased donor 1 month earlier and presented to us with symptoms of fatigue, prostration, and palpitation. The results of a laboratory examination revealed anemia. A diagnostic work-up resulted in a diagnosis of pure red-cell aplasia. Mycophenolate mofetil was discontinued. Tacrolimus also was replaced with cyclosporine 2 months after mycophenolate mofetil was halted because of a lack of improvement in anemia. Three months later, her anemia improved with cyclosporine. Starting cyclosporine instead of tacrolimus or mycophenolate mofetil showed good improvement in our patient within 6 months of therapy.

Topics: Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Red-Cell Aplasia, Pure; Tacrolimus; Treatment Outcome; Withholding Treatment; Young Adult

In late 2009 transplant organizations recommended that kidney recipients be vaccinated for pandemic H1N1 influenza (pH1N1); however, the vaccine efficacy was unknown. We had offered a monovalent non-adjuvanted pH1N1 vaccine to transplant recipients. Here we compared the pre- and post-vaccination seroresponses of 151 transplant recipients to that of 71 hemodialysis patients and 30 healthy controls. Baseline seroprotection was similar between groups but was significantly different at 1 month (44, 56, and 87%, respectively). Seroconversion was significantly less common for transplant recipients (32%) than dialysis patients (45%) and healthy controls (77%). After adjusting for age and gender, dialysis patients were significantly more likely (2.7-fold) to achieve new seroprotection than transplant recipients. The likelihood of seroprotection in transplant recipients was significantly reduced by mycophenolate use (adjusted odds ratio 0.24), in a dose-dependent manner, and by reduced eGFR (adjusted odds ratio 0.16 for worst to best). Seroprotection and geometric mean antibody titers increased substantially in 49 transplant recipients who subsequently received the 2010 seasonal influenza vaccine. Thus, patients requiring renal replacement therapy had reduced seroresponses to vaccination with the monovalent vaccine compared with healthy controls. Transplant recipient responses were further reduced if they were receiving mycophenolate or had significantly lower graft function.

Topics: Adult; Aged; Antibodies, Viral; Case-Control Studies; Chi-Square Distribution; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Kidney; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Odds Ratio; Pandemics; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vaccination; Victoria; Young Adult

Tacrolimus (FK506) is associated with renal fibrosis in long-term use. Mycophenolatemofetil (MMF) can also inhibit or attenuate the progression of renal fibrosis. This study aimed to determine the different effects of FK506 and MMF on fibrosis-associated genes in the kidney in rats that underwent chronic allograft nephropathy (CAN).. Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. All recipients were given Cyclosporin A (CsA) 10 mg/kg-1.d-1 × 10 day and were then randomly divided into three oral treatment groups (n = 9 in each group): (1) the vehicle group was given vehicle orally; (2) the FK506 group was given 0.15 mg/kg-1.d-1 FK506; and (3) the MMF group was given 20 mg/kg-1.d-1 MMF. At 4, 8, and 12 weeks post-transplantation, serum creatinine (SCr), collagen deposition, Connective tissue growth factor (CTGF), alpha smooth muscle actin (α-SMA) and E-cadherin expressions were determined and hematoxylin-eosin (HE) and Periodic acid-Schiff (PAS) stains were performed.. Renal function progressively deteriorated and showed typical CAN morphology in the vehicle and FK506 groups, while SCr and inflammatory infiltration (Banff score) showed a significant decrease in the MMF group after 8 weeks post-transplantation compared with those in the other groups (p < 0.05). Furthermore, expression levels of CTGF and α-SMA in the MMF group were significantly reduced, and the down-regulated expression of E-cadherin was abated (p < 0.05).. MMF showed favorable effects on renal interstitial fibrosis, thus efficiently retarding the progression of CAN.

Topics: Animals; Chronic Disease; Drug Interactions; Fibrosis; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Rats; Rats, Inbred F344; Rats, Inbred Lew; Tacrolimus; Treatment Outcome

Organ transplants in elderly recipients have increased over the past few years. This situation poses specific problems both in terms of organs and recipients; therefore, immunosuppressant regimens must be adapted accordingly. A previous study demonstrated good initial results in kidney transplant cases in which older donors and recipients (average ages of 64.4 years and 61.3 years) had received initial immunosuppressant therapy with daclizumab and mycophenolate mofetil as well as delayed introduction of reduced-dose tacrolimus. In this study we reviewed the long-term results in the same group of patients.. An observational, retrospective multi-centre study carried out at a national level to determine survival rates and renal function in 126 patients included in the initial study (127 patients who survived the first year with a functioning graft, 123 treated according to protocol). We gathered data from the 2nd to the 6th year for 120, 118, 113, 102 and 62 patients, respectively. The evolution of renal function, relevant clinical data, and safety profiles were also analysed.. After five years, most patients continued with the initial immunosuppressant regimen: 92% tacrolimus and 80% mycophenolate mofetil; 48% had abandoned steroids and proliferation signal inhibitors had been introduced in 3%. Patient and graft survival (adjusted for patient death) after five years was 93.1% and 93.8%, respectively. The main cause of death was neoplasia (in 7 out of 10 cases) whilst graft loss was mainly due to death with a functioning graft. The other causes of death were 2 acute myocardial infarctions and a gastrointestinal haemorrhage. Renal function was moderately but significantly reduced with the passing of time (P<.001): average creatinine levels in the overall group of patients rose from 1.60 ± 0.50mg/dl after the 1st year to 1.63 ± 0.70 mg/dl at the end of study. MDRD dropped from 46.28 ± 15.64 ml/min after the 1st year to 45.69 ± 15.44 ml/min at the end of study (P<.01). Only two acute rejections were observed after the 1st year. There were 19 cardiovascular events registered in 12 patients.. The regimen used in our study was useful and appropriate for elderly donor-recipient pairs as demonstrated by the good long-term survival results, continued optimum renal function, and acceptable safety profile.

Topics: Age Factors; Aged; Antibodies, Monoclonal, Humanized; Cause of Death; Creatinine; Daclizumab; Donor Selection; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Rate; Tacrolimus; Tissue Donors; Treatment Outcome

The aim of this trial was to evaluate the impact of conversion from a calcineurin-inhibitor (CNI)-based immunosuppressive regimen to mycophenolate mofetil (MMF) and reduced-dose CNI on long-term renal function and survival in a series of 63 liver transplant patients with CNI-induced renal dysfunction.. CNI dosage was significantly tapered after introduction of 2,000 mg MMF per day. Renal function was assessed by determination of serum creatinine levels and calculated creatinine clearance (CCl). The impact of relevant clinical parameters on renal function and survival post-conversion was analyzed by univariate and multivariate analysis.. At 60 months post-conversion, mean creatinine level had significantly declined from 197.2±58.3 μmol/l at baseline to 160.0±76.5 μmol/l, and mean CCl has significantly increased from 38.4±13.4 ml/min at baseline to 47.9±21.1 ml/min (p<0.001), respectively. Forty-six patients (73.1%) demonstrated sustained renal response to modified immunosuppression. Full-dose MMF medication (p=0.006) and the early conversion (p=0.02) were identified as independent predictors of persistent renal function improvement. Sustained renal response to MMF plus reduced-dose CNI was identified as the most relevant independent promoter of long-term survival (hazard ratio 6.9). Five-year survival rate post-conversion was 93.9% in renal responders and 64.3% in renal non-responders (log rank<0.001).. Sustained renal response to MMF and CNI dose reduction promotes long-term survival in liver transplant patients with CNI-induced renal dysfunction.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Retrospective Studies; Survival Rate; Tacrolimus

Topics: Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus

The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153 ± 7 mm Hg and 8.0 ± 2.4, respectively) compared to rats fed normal protein (132 ± 3 mm Hg, 1.2 ± 0.3) or low-protein (132 ± 6 mm Hg, 0.3 ± 0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9 ± 3 × 10⁵ cells) than in rats fed the low-protein diet (9.1 ± 3 × 10⁵ cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9 ± 2.7 to 10.6 ± 2.0 × 10⁵ cells) while decreasing blood pressure (from 133 ± 3 to 113 ± 4 mm Hg) and the albumin/creatinine ratio (from 10.9 ± 2.3 to 5.4 ± 1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Creatinine; Dietary Proteins; Hypertension; Kidney; Kidney Diseases; Mycophenolic Acid; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; T-Lymphocytes; Time Factors

The aim was to report our experience of BK viremia surveillance after kidney transplant during a period of change from cyclosporine (CyA)-to lower-dose tacrolimus (Tac)-based primary immunosuppression regimens.. In a prospective single-center observational cohort study, 68 consecutive patients received renal transplant during the period when we used a CyA-based primary immunosuppression regimen and 66 after we changed to a lower-dose Tac-based regimen. Testing for BK viremia by quantitative polymerase chain reaction assay was performed at least monthly for a minimum of 1 year.. Thirty-nine (29.1%) patients developed BK viremia and 2 (1.5%) developed BK nephropathy. The actuarial time to BK viremia was shorter in patients receiving CyA/mycophenolate mofetil (MMF)/prednisolone (Pred) compared with Tac/MMF/Pred (P=0.04) and primary immunosuppression with CyA/MMF/Pred was the only independent predictor of BK viremia (hazard ratio 1.95; P=0.047). Comparing patients who experienced BK viremia and those who did not, there was no difference in incidence of acute rejection (20.5% vs. 25.3%; P=0.56) or estimated glomerular filtration rate at 12 months (48.8 vs. 49.9 mL/min/1.73 m(2)), but the incidence of ureteric stenosis was higher (10.3% vs. 1.1%; P=0.01).. Our data demonstrate a lower incidence of BK viremia in patients on lower-dose Tac compared with CyA-based primary immunosuppression in contrast to previous studies, and provide further support for the association between BK virus and ureteric complications.

Topics: BK Virus; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Prednisolone; Tacrolimus; Time Factors; Tumor Virus Infections; Viremia

The aim of this study was to investigate the effect of mycophenolate mofetil (MMF) using differential kidney proteome profiling of COL4A3-deficient mice as a model of progressive renal disease.. Histological evaluation of kidney sections was performed. Total protein lysate from kidneys of placebo- and MMF-treated COL4A3-deficient mice was studied for significant differences in protein abundance using 2-dimensional electrophoresis and mass spectrometry.. While tubulointerstitial fibrosis in COL4A3-deficient mice was inhibited by MMF, 19 proteins in the kidneys were regulated: 12 with lower (ATPO, TAGL2, CAH1, TPD52, VA0D1, SERPH, GNAL, PSB6, EF1D, OTUB1, NDUS8, and NAPSA) and 7 with higher (ACADM, ACY3, CK054, ACTB/G, ACTB, UBP5, and ACY1) spot intensity. Nine differentially expressed proteins showed interaction potential (ATPO, TPD52, PSB6, EF1D, OTUB1, NAPSA, ACTB, ACTG, and UBP5).. The identified proteins take part in different signaling pathways. With the highest probability, the VEGF signaling pathway (TAGL2, EF1D, and ACTB) and hypoxia (CAH1, PSB6, and ACTG) were influenced by MMF in fibrotic conditions. Moreover, MMF may modulate antifibrotic and apoptotic pathways as well as epithelial-mesenchymal transition (EMT). Different signaling pathways may be influenced by MMF therapy. These results suggest an inhibitory effect of MMF on renal EMT in COL4A3-deficient mice. Further studies are necessary to validate these findings.

Topics: Animals; Autoantigens; Collagen Type IV; Databases, Protein; Disease Models, Animal; Disease Progression; Down-Regulation; Electrophoresis, Gel, Two-Dimensional; Epithelial-Mesenchymal Transition; Fibrosis; Kidney; Kidney Diseases; Mice; Mice, Knockout; Mycophenolic Acid; Proteomics; Random Allocation; Signal Transduction; Up-Regulation

Topics: Adenocarcinoma; Adult; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Murine-Derived; Autoantigens; Cyclophosphamide; Disease Susceptibility; Drug Resistance; Granulomatosis with Polyangiitis; Hemoptysis; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Male; Methylprednisolone; Mycophenolic Acid; Myeloblastin; Prednisone; Rectal Neoplasms; Recurrence; Rituximab

BK polyomavirus (BKV) infection and BKV-associated nephropathy (BKVAN) are among the most important problems in renal transplantation. We aimed to determine the incidence of BK viruria, viremia, and BKVAN in renal transplant recipients in the northeastern part of Poland.. Urine and blood samples from 126 cadaveric renal transplant recipients were analyzed for BK viruria and viremia using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The diagnosis of BKVAN was established on the allograft biopsy.. Based on the BKV DNA analysis, the patients were divided into three groups: group 1 (n=89; 70.6%) without viruria or viremia, group 2 (n=24; 19.1%) with isolated viruria, and group 3 (n=13; 10.3%) with both viruria and viremia. The presence of BK viremia negatively correlated with time after the transplantation. BK viruria was associated with mycophenolate mofetil daily dose. In group 3 there were four patients (3.2%) with high viremia (>10(4) genome equivalents [gEq]/mL) and viruria (>10(7) gEq/mL) loads. Only one patient from this group developed clinical symptoms and had BKVAN in allograft biopsy. In all four cases, the maintenance immunosuppression therapy was based on tacrolimus and steroids.. Prevalence of BKV infection in renal transplant recipients in the northeastern part of Poland is similar to that reported by studies from other countries. We confirm that BK viremia could be predicted by the presence of intense viruria. Time after transplantation and the type of immunosuppression strategy are the most important predictors of BK viremia and viruria in patients after renal transplantation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; BK Virus; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Poland; Polyomavirus Infections; Risk Factors; Tumor Virus Infections; Viremia; Virus Replication; Young Adult

Within the scope of this study, the potential antifibrotic effect of mycophenolate mofetil (MMF) on COL4A3-deficient mice as an animal model for progressive renal fibrosis was investigated regarding kidney function and survival. Thirty-five animals were randomly assigned to one of five groups and treated with doses of 0, 10, 50, 100, or 150 mg/kg MMF per day, respectively. When increasing somnolence was observed, indicating end-stage renal disease, the mice were euthanized and blood was obtained. Serum concentrations of creatinine, urea nitrogen, total protein, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were quantified. The kidney histology was examined using hematoxylin and eosin as well as trichrome staining. The mean overall survival was 65.9 (+/-6.1) days with no significant difference between the treatment groups (P > 0.05, Mantel-Cox test). Serum predose concentrations of MPA and MPAG showed considerable interindividual variability. There was no correlation between survival time and MPA or MPAG concentrations (P > 0.05, Spearman rank correlation). However, an apparent decrease in serum creatinine and urea nitrogen concentrations was observed at higher doses of MMF, eg, -54% for creatinine in the 150-mg/kg/day group compared with placebo. A highly significant reciprocal correlation between MPA concentrations and serum creatinine was demonstrated (P < 0.01, r = -0.655, Spearman rank correlation). In conclusion, MMF may be a candidate drug for preserving kidney function in progressive renal fibrosis.

Topics: Animals; Autoantigens; Collagen Type IV; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Fibrosis; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Mice; Mice, Knockout; Mycophenolic Acid; Survival Rate

Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African-American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to > or =500 mg/g in 65% of AAs versus 14% of non-AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Risk Factors; Sirolimus; Steroids; Tacrolimus

In the present study the effect of mycophenolate mofetil (MMF), an immunosuppressant, on mercuric chloride (HgCl(2))-induced nephrotoxicity in male Wistar rats was investigated. Animals (200-250 g) were divided into five groups and were subjected to a 6-day treatment schedule. The first (control) group received only vehicle without any active drug. The second to fifth groups were administered HgCl(2) challenge (single dose of 5 mg/kg, s.c.) on the fourth day. Additionally, the second group received distilled water (DW) on all 6 days and the third group was administered DW the initial 3 days and MMF (10 mg/kg b.i.d. by oral gavage) on days 4-6. The fourth group was given DW the initial 2 days and MMF on days 3-6 and the fifth group received MMF all 6 days. All animals were euthanized on the sixth day. It was found that HgCl(2) administration caused significant nephrotoxicity, as indicated by a rise in serum creatinine, blood urea and soluble intercellular adhesion molecule 1 (sICAM-1) concentrations, histopathological injury and increased oxidative stress (altered malondialdehyde and glutathione levels) as compared to the control group. Administration of MMF significantly ameliorated HgCl(2)-induced nephrotoxicity. The results suggest the potential of MMF in preventing the acute nephrotoxicity of HgCl(2).

Topics: Animals; Creatinine; Glutathione; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney Diseases; Male; Malondialdehyde; Mercuric Chloride; Mycophenolic Acid; Oxidative Stress; Rats; Rats, Wistar; Urea

In large-scale clinical trials, the proliferation signal inhibitor (PSI) everolimus (EVL) combined with cyclosporine (CsA) and steroids, has been shown to be efficacious among de novo renal transplant recipients. Development of proteinuria has been shown to be an important predictor of renal dysfunction after conversion from CsA to a PSI-based regimen, and a key marker of allograft disease progression. Whether EVL de novo treatment is associated with a similar proteinuric effect is still under investigation.. We compared the development of proteinuria among a cohort of 24 renal transplant recipients who were prescribed EVL (3 mg/d; n = 12; high-dose group) or 1.5 mg/d (n = 12; standard-dose group), in association with CsA, versus third control cohort of 12 patients who received mycophenolate mofetil (control group). EVL doses were adjusted to achieve trough blood levels of 3-8 ng/mL and 8-12 ng/mL among the standard and high-dose groups, respectively. We assessed renal function and protein excretion over a 2-year observation.. The high-dose group showed a trend toward greater proteinuria than the standard-dose on control groups. They showed significantly greater proteinuria from 9 months until 2 years; 0.86 +/- 0.5, 0.5 +/- 0.3, 0.47 +/- 0.2 g/24 h (P = .03 and P = .02, respectively, at 24 months). Mean proteinuria significantly correlated with mean EVL doses (n = .73; P = .0001). Concomitantly, the estimated glomerular filtration rate (eGFR) was significantly lower among patients treated with EVL 3.0 versus 1.5 mg/d (53.7 +/- 24 vs 73.04 +/- 17.6 mL/min; P = .037). Among patients in the standard-dose, the eGFR was consistently higher than the control group (62.6 +/- 29 mL/min).. EVL/CsA therapy is a safe alternative regimen for de novo renal transplant recipients. Higher EVL doses are correlated with greater increases in proteinuria. The standard EVL dose seems to be useful treatment strategy to prevent acute rejection episodes, with a better renal prognosis in the long term.

Topics: Adult; Cohort Studies; Dose-Response Relationship, Drug; Everolimus; Female; Follow-Up Studies; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prognosis; Proteinuria; Sample Size; Sirolimus

Inflammatory events antecede established renal injury in rats with 5/6 renal ablation (Nx), as indicated by the beneficial effects of early, uninterrupted treatment with mycophenolate mofetil (MMF). Angiotensin II also exerts a major pathogenic role at this initial phase. We investigated whether losartan (L) or L+MMF treatment, started early, and L+MMF treatment, started late, would exert lasting renoprotection in Nx even after being discontinued.. Adult male Munich-Wistar rats underwent Nx and were divided into three groups: Nx (untreated), Nx(L) (given L), and Nx(LMMF) (given L and MMF). Protocol 1: treatments began on day 1, and ceased on day 30, after Nx. Protocol 2: L+MMF treatment began on day 30 and ceased on day 60.. Protocol 1: on day 30, hypertension, albuminuria and renal injury were strongly attenuated in Groups Nx(L) and Nx(LMMF). On day 120, these abnormalities were still attenuated in group Nx(LMMF). Protocol 2: on day 120, all parameters were similar between this late Nx(LMMF) group and untreated Nx.. In Nx, temporary suppression of early, transitory hemodynamic/inflammatory phenomena affords relatively durable renoprotection even after treatment discontinuation. This effect is not obtained with similar temporary treatment initiated later in the course of renal disease.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Blood Pressure; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Kidney Diseases; Losartan; Macrophages; Male; Mycophenolic Acid; Nephrectomy; Protective Agents; Rats; Rats, Inbred Strains; Time Factors

Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to attenuate the progression of renal interstitial fibrosis. However, the question of whether the newly synthesized IMPDH inhibitors with structures different from MMF have an antifibrotic effect remains unanswered. We evaluated the antifibrotic effects of BMS-566419, a chemically synthesized IMPDH inhibitor, using an experimental rat model, unilateral ureteral obstruction (UUO), in comparison with those of MMF. Expression levels of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-β1), which play important roles in UUO-induced renal fibrosis, were also investigated to determine the mechanism by which BMS-566419 affects the progression of renal fibrosis. After 14 days of UUO, interstitial fibrosis was frequently observed in the renal cortex of rats administered vehicle control. BMS-566419 by oral administration showed a significant and dose-dependent suppressive effect on UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment also decreased collagen content, as indicated by hydroxyproline concentration, and the expression of collagen type 1 mRNA. BMS-566419 also decreased the expression of mRNA for both MCP-1 and TGF-β1. The antifibrotic effects of treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 mg/kg. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN.

Topics: Acridines; Animals; Chemokine CCL2; Chronic Disease; Collagen; Fibrosis; Hydroxyproline; IMP Dehydrogenase; Kidney Cortex; Kidney Diseases; Male; Mycophenolic Acid; Piperazines; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Ureteral Obstruction

Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.

Topics: Adult; Aged; Cidofovir; Cytosine; Female; Humans; Isoxazoles; Kidney Diseases; Leflunomide; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Organophosphonates; Polyomavirus Infections; Prednisone; Renal Insufficiency; Tacrolimus; TOR Serine-Threonine Kinases

Mycophenolate mofetil (MMF) is included in the basic immunosuppression regimen in heart transplantation (HTx). Classically, the mycophenolic acid (MPA) concentration has not been considered to provide clinical information.. To perform a comparative analysis of MMF dosage and MPA concentration and their effect on post-HTx renal function.. Sixty patients underwent HTx between January 2007 and April 2009, and were followed up at 4 scheduled visits in 6 months. The standard MMF dose was 1000 mg/12 h, with adjustment according to clinical criteria. The MPA concentration was determined using an enzyme-multiplied immunoassay (EMIT 2000; Siemens Healthcare Diagnostics Inc, Deerfield, Illinois), without change in dosage. The correlation between mean MMF dosage and MPA concentrations at all visits vs renal function values was analyzed using serum creatinine concentration, creatinine clearance (CrCl; Modification of Diet in Renal Disease), and glomerular filtration rate (GFR; Cockcroft-Gault formula).. Mean (SD) patient age was 50 (13) years, and 45 of 60 (75.4%) were men. Pre-HTx values were as follows: creatinine concentration, 1.13 (0.47) mg/dL; CrCl, 81.59 (36.84) mL/min/1.73 m2; and GFR, 77.46 (30.60) mL/min. In the first 6 months post-HTx, significant negative correlations were observed between mean MPA concentration and creatinine concentration (r=.42; P=.001), CrCl (r=-.36; P=.01), and GFR (r=-.45; P=.001). No correlation was observed with mean MMF dosage.. There are important differences in the relationship of MPA concentration vs MMF dosage and post-HTx renal function. Although studies with a larger number of patients are needed, treatment guided by MPA concentration seems reliable for evaluation of renal function.

Topics: Adult; Female; Glomerular Filtration Rate; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid

This retrospective study was conducted to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. One-hundred and seventy-four cyclosporin (CsA)-treated renal transplant recipients were studied. Patients were included if they had a biopsy-proven CAN (mild to moderate) with serum creatinine < or =3.5 mg/dL. Patient treatment was switched to either: (A) MMF/reduced dose CsA (MMF for azathioprine (Aza); n = 132); or (B) Aza/Tac for CsA (n = 42). Patient records were checked for graft function and survival, and for co-morbidities after conversion.. Mean follow-up before conversion was 52.2 +/- 31.1 and 47.9 +/- 27.4 months for groups A and B, respectively. There was significant deterioration of graft function in group B after five years (P < 0.5). Ten-year actuarial graft survival was 38% in group A and 19% in group B (P = 0.04). Nine patients (five patients and four patients in groups A and B, respectively) started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P = 0.05), but a significantly higher incidence of diabetes mellitus (P = 0.04).There was no significant change or difference in blood pressure between groups.. Our results suggest that in patients with CAN and deteriorating allograft function, CsA minimization and addition of MMF achieved favorable efficacies in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Chronic Disease; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Based on case history and clinical and electrophysiological examinations, the authors report on a case of an 8-year-old girl who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy. The disease was complicated by deafness and kidney fibrosis. During treatment with methylprednisolone and intravenous immunoglobulin, followed by mycophenolate mofetil, prompt improvement of neurological findings occurred. The improvement of hearing was poor. Because the pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy has still not been clear, and on the grounds of several cases of chronic inflammatory demyelinating polyradiculoneuropathy conjoined with the kidney disease described in literature (glomerulopathy, interstitial nephritis), every patient with chronic inflammatory demyelinating polyradiculoneuropathy needs to undergo the urinalyses.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child; Deafness; Female; Fibrosis; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Kidney Diseases; Methylprednisolone; Mycophenolic Acid; Neural Conduction; Neuroprotective Agents; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Treatment Outcome

Anti-mTOR may induce proteinuria when utilized after renal transplantation. Little is known about the pathogenesis and composition of proteinuria. To clarify this unresolved aspect, we analyzed urinary protein composition utilizing an integrated proteomics approach, including quantitative assays, 2-dimensional electrophoresis, MALDI-TOF, and Western blots among 48 renal transplant recipients treated with everolimus (EVL; n = 31) or enteric-coated mycophenolic acid (EC-MPA; n = 17). High (>3 g/d) or intermediate levels of proteinuria (1-3 g) developed in 12 EVL patients (39%) compared with 4 subjects (23%) in the EC-MPA group. Proteinuria, which started during the first 2 days after EVL, tended to reduce during the follow-up. Quantitative proteomics showed an increase in low molecular proteins beta2 microglobulin (P < .001) and alpha1 microglobulin (P < .025). Qualitative proteomics showed a marked increase among all urinary components in EVL and EC-MPA patients. Major changes involved typical components of glomerular damage: albumin, Zn-alpha1 glycoprotein, alpha2HS glycoprotein, and leucine-rich alpha2 glycoprotein. In addition, we observed specific biomarkers for EVL: clusters of alpha1-antitrypsin fragments and monoclonal lambda chains. In conclusion, EVL induced proteinuria of a mixed glomerular and tubular origin that correlated with the start of treatment and reached nephrotic ranges in few cases. The specific urinary markers may reflect renal alterations related to the transplant or specific alterations associated with the drug.

Topics: Adult; Everolimus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus

The specific role of different immunosuppressive agents as risk factors for BK virus nephropathy (BKN) has not been well studied.. In this case-control study, we examined the association of tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone with BKN in renal allograft recipients transplanted between 1997 and 2004 at our center who underwent biopsies for allograft dysfunction. Drug levels or doses were recorded during the 3 months before the index biopsy. Random effects logistic modeling was used for data analysis.. There were 33 cases with BKN, biopsied at 16.4+/-2.8 months and 66 matched controls with biopsies at 21.5+/-2.1 months posttransplant (P=0.16). After adjusting for sex, race, retransplant status, diabetes, donor source, and induction agent, TAC blood level was associated with increased risk of BKN (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.02-1.7, P=0.03), whereas MMF dose was not (OR 1.0, 95% CI 0.99-1.0, P=0.2). Moreover, prednisone dose was also found to be a significant risk factor for BKN (OR 1.22, 95% CI 1.04-1.4, P=0.02).. The results of this study show that BKN is associated with TAC level and prednisone dose and not with MMF dose. This suggests that reducing TAC and prednisone dose and maintaining MMF may be a more appropriate initial approach for the treatment of BKN. Further studies are needed to compare the efficacy and safety of this approach with the currently recommended one.

Topics: Biopsy; BK Virus; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Transplantation, Homologous; Virus Activation

Cytotoxic drugs have reduced the mortality in patients with ANCA-associated vasculitis (AASV) but their use carries a substantial risk of toxicity. Efforts are made to switch from cytotoxic drugs to less toxic maintenance regimens. In this study we aimed to assess the efficacy of mycophenolate mofetil (MMF) as maintenance therapy in patients with AASV and renal involvement.. 22 patients with newly diagnosed AASV, microscopic polyangiitis (MPA) (n = 16), Wegener's granulomatosis (WG, n = 4), renal limited vasculitis (RLV, n = 1) and Churg-Strauss syndrome (CSS, n = 1) and renal involvement were followed for a median of 42 months (range 24 - 101). After 6 months of standard induction therapy, patients were switched to MMF monotherapy for 18 months. Renal parameters i.e. serum creatinine, proteinuria and urine sediment, BVAS scores and ANCA titers were assessed at baseline, after induction and after 18 months with MMF.. After the end of induction, 3 of the 4 patients who were initially hemodialysis (HD) dependent, remained on HD and were withdrawn from further analysis. In the remaining 19 patients, the improvement in renal function (p < 0.001), hematuria (p = 0.011), proteinuria (p = 0.007) and BVAS scores (p < 0.001) after induction was sustained after 18 months maintenance with MMF and no patient relapsing during this period. Until the end of the follow up, 31.58% of patients relapsed, at a median of 21.5 months (range: 18 - 60). Side effects were transient and infrequent.. In patients with AASV and renal involvement, MMF seems to be an effective and well tolerated option in sustaining short- and medium-term remission.

Topics: Antibodies, Antineutrophil Cytoplasmic; Chi-Square Distribution; Cyclophosphamide; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Mycophenolic Acid; Statistics, Nonparametric; Treatment Outcome; Vasculitis

Chronic kidney disease is common after heart transplantation, and is related to ciclosporin (CsA) therapy. We compared the safety and efficacy of two ciclosporin withdrawal regimens.. CsA was stopped and sirolimus (SRL) commenced immediately and the transfer was covered with prednisolone. Those on azathioprine (AZA) were transferred to MMF. In protocol A, the SRL target concentration was 16 (12-20) ng/ml; in protocol B, the target concentration was 7(5-10) ng/ml, but mycophenolate (MMF) and steroids were commenced prior to the transfer.. Baseline characteristics were similar in both groups except that group B were switched later after transplantation. Renal function improved significantly in both groups; this was maintained up to 1 year. Two patients in group A experienced acute rejection (ISHLT grade 3A or 2R); none was seen in group B. Six patients (46%) remained on protocol A and 22 (85%) remained on protocol B at 1 year.. MMF-SRL substitution resulted in a rapid but partial improvement in renal function; the lower dose SRL regimen was better tolerated.

Topics: Chronic Disease; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Sirolimus

Pulmonary-renal syndrome (PRS) associated with antineutrophil cytoplasmic antibodies (ANCA)-negative microscopic polyangiitis (MPA) is relatively rare, and the effects of plasmapheresis on these patients remain unclear. Here, we report the case of a 66-year-old man who presented with fever, acute renal failure, thrombocytopenia, and sudden onset of diffuse pulmonary hemorrhage. Prompt plasmapheresis and concurrent pulse therapy with methylprednisolone effectively rescued his pulmonary-renal syndrome. The patient was then diagnosed with MPA on the basis of typical histological findings and the absence of surrogate markers of Wegener's granulomatosis and Churg-Strauss syndrome. This case demonstrates the therapeutic effects of plasmapheresis on ANCA-negative MPA and highlights the necessity of prompt plasmapheresis for not only resolving pulmonary hemorrhage but also increasing the likelihood of renal function restoration in patients with PRS.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Antineutrophil Cytoplasmic; Glucocorticoids; Humans; Kidney Diseases; Lung Diseases; Male; Microscopic Polyangiitis; Mycophenolic Acid; Plasmapheresis; Prednisolone; Pulse Therapy, Drug; Radiography, Thoracic; Syndrome; Treatment Outcome

Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function.. We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids.. Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 +/- 1.22 mg/dL and 19 +/- 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 +/- 0.3 mg/dL and 107 +/- 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 +/- 0.45 mg/dL and 86 +/- 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]).. Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Length of Stay; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies

Standard therapy with corticosteroids and cyclophosphamide followed by azathioprine has improved renal and patient survival in renal vasculitis. However, this regimen is associated with high toxicity. Mycophenolate mofetil (MMF), a less toxic immunosuppressive drug, has been proposed as a therapeutic alternative.. We report 12 patients (4 males, 8 females, aged 65.6 A+/- 12.1 years) with anti-MPO renal vasculitis who were switched from standard therapy to MMF because of drug-related adverse effects: leukopenia, toxic hepatitis, nausea, hair loss or appearance of carcinoma. MMF was introduced at a dose of 500 mg/8 h, after 83 A+/- 56 days under standard therapy.. After 354 A+/- 195 days of MMF therapy, all patients maintained clinical remission. Mean values of serum anti-MPO, disease activity markers and serum creatinine decreased when these values were compared from pre-therapy to the time of switching to MMF, and then to the end of the study anti-MPO: 204 A+/- 144 U, 54 A+/- 85 U and 12 A+/- 5 U. Serum-reactive C protein 97 A+/- 82 mg/l, 13 A+/- 10 mg/l and 4 A+/- 2 mg/l. Erythrocyte sedimentation rate 88 A+/- 40, 41 A+/- 28 and 26 A+/- 15 mm. Serum creatinine 415 A+/- 238, 202 A+/- 93 and 169 A+/- 104 micromol/l. In one case there was a relapse of vasculitis under MMF and a low dose of prednisone after 9 months of therapy. Side effects were herpes infection in four cases and chickenpox in one. Neither leukopenia nor anemia was observed.. These results indicate that MMF could be an alternative therapy for anti-MPO renal vasculitis associated with cyclophosphamide or azathioprine-related toxicity.

Topics: Aged; Autoantibodies; Azathioprine; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Peroxidase; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Peroxidase; Vasculitis

Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is a transplantation approach that enables patients with comorbid conditions to undergo allogeneic HSCT. We investigated the outcome of patients with reduced renal function as a single comorbidity before HSCT. Thirteen patients with a glomerular filtration rate (GFR) of <60 mL/min/1.73 m2 were matched on sex, age, and type of transplant to 26 controls with normal renal function. All patients received a nonmyeloablative HSCT with fludarabine and/or total body irradiation conditioning (TBI). Graft-versus-host disease (GVHD) prophylaxis consisted of mycophenolate mofetil and cyclosporine. Data on renal function, cyclosporine dose, cyclosporine trough levels, hypertension, and GVHD were collected. Of the 13 patients with impaired renal function, 7 patients (54%) improved or stabilized to a GFR>or=60 mL/min/1.73 m2 at last follow-up. Four patients (31%) developed chronic kidney disease stage 3 (GFR <60 mL/min/1.73 m2) compared to 3 patients (12%) in the control group (P=.039). There was no difference in survival between cases and controls. Furthermore, there were no differences in complications after HSCT, and cyclosporine dose and trough levels were similar between cases and controls. Nonmyeloablative HSCT can be safely offered to patients with mildly reduced renal function. Cyclosporine can be administered at the same dose as patients without renal dysfunction, as long as cyclosporine trough levels and creatinine are monitored and dose adjustments are made if necessary.

Topics: Adult; Aged; Antineoplastic Agents; Cyclosporine; Disease-Free Survival; Female; Glomerular Filtration Rate; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

To evaluate cardiovascular disease (CVD) after renal transplantation we established a CVD database (no-intervention) including all patients transplanted among 2000-2002 in 14 hospitals from Spain (Renal Forum Group) (n=2600). They were prospective followed annually thereafter and we present herein the most important results concerning survival figures and CVD at four years. Mean recipient age was 49.7+/-13.7 years: 16% retransplanted and 12.5% hyperimmunized. Tacrolimus, mycophenolate mofetil, and steroids was used in 63%. Acute rejection (AR) rate at 1 year was 14.8%. Graft and patient survival at 48 months were 85.6% (death censored) and 91.7% respectively. The first cause of graft loss was vascular in the first year, death with function during the 2-3 years, and chronic allograft nephropathy at the 4th year. Donor age, time on dialysis, acute tubular necrosis (ATN), AR, SCr at 6 months, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in the first year, and systolic blood pressure at 24 months were independent risk factors for graft loss at 4th year. The first cause of death was CVD (predominantly ischemic heart disease (IHD) in the first year). Recipient age, ATN, and SCr at 6 months were independent predictors of mortality. Despite worsening of donor age, comorbidity, and advanced age of recipients, survival figures at four years are considered good in our Spanish non-selected population. Cardiovascular mortality is the most important cause of death and graft loss particularly, IHD in the first year. Therefore, to decrease post-transplant mortality a careful cardiovascular evaluation and treatment in the waiting list and a close follow-up of patients after transplantation is mandatory.

Topics: Adult; Cardiovascular Diseases; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors; Spain; Tacrolimus

Experience with sirolimus (SRL)-based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long-term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL-based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end-stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post-OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Child's class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI-treated group. Overall survival at 1 and 5 years post-OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL-based therapy in patients undergoing OLT for end-stage liver disease and concomitant malignancy.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy.. This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy.. At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205-1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1-9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2-2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0-3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function.. Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.

Topics: Acute Disease; Adult; Aged; BK Virus; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Postoperative Complications; Prednisone; Tacrolimus; Tumor Virus Infections

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Topics: Albuminuria; Angiotensin II; Animals; Cardiomegaly; Cell Proliferation; Cytoskeleton; Disease Models, Animal; Hypertension; Immunosuppressive Agents; Interferon-gamma; Kidney Diseases; Male; Mice; Mice, Knockout; Mycophenolic Acid; Sodium Chloride, Dietary; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

A selective and highly accurate HPLC-UV method is described to determine plasma concentrations of mycophenolic acid (MPA), the active metabolite of the prodrugs Cellcept and Myfortic. The method is simple and utilizes acidification of plasma and protein precipitation step using a mixture of acetonitrile and phosphate buffer (pH 3). Following vortex mixing and centrifugation, the supernatant (50 microL) was injected onto a Zorbax Eclipse XDB C(18) column (150 mm x 4.6 mm I.D., 5 microm particle size). A mobile phase composed of acetonitrile and 0.1 M phosphate buffer, pH 3 (43:57) delivered at 1.0 mL/min produced peaks for MPA and the internal standard (Naproxen) in <7 min. Calibration curves were linear (r(2)>0.994) from 1.0-40 microg/mL with intra- and inter-day precision <15% and accuracy >95%. The method's improved sensitivity (LOQ=1.0 microg/mL) and minimal sample processing allowed rapid monitoring of MPA in human plasma.

Topics: Acetonitriles; Buffers; Calibration; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Kidney Transplantation; Linear Models; Mycophenolic Acid; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-kappaB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg.kg(-1).day(-1)), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-kappaB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-kappaB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 +/- 5 mmHg, and MMF reduced this arterial pressure to 124 +/- 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-kappaB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Glutathione; Heart Rate; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; NF-kappa B; Proteinuria; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride, Dietary; Superoxide Dismutase; Superoxides; Time Factors; Vascular Resistance

Severe autoimmune myasthenia gravis is difficult to manage and may require immunosuppression with cyclosporine. However, cyclosporine dependency is associated with the risk of nephrotoxicity. Mycophenolate mofetil is a non-nephrotoxic alternative which should be considered to rescue cyclosporine-dependent, severe myasthenia gravis sufferers with renal impairment from progression to end-stage renal failure. However, the evidence is limited and studies have not assessed the outcome of a direct substitution in these cyclosporine-dependent patients. We study three such patients who successfully converted to mycophenolate mofetil, and briefly examine the evidence behind this option. We believe that total cyclosporine withdrawal is feasible, but strongly recommend overlapping mycophenolate mofetil treatment with cyclosporine.

Topics: Adult; Cyclosporine; Diabetic Nephropathies; Drug Evaluation; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Myasthenia Gravis; Mycophenolic Acid; Plasma Exchange; Prednisolone; Recurrence; Thymectomy

C-reactive protein (CRP) is a strong predictor of cardiovascular disease, all-cause mortality, and renal allograft loss. Little is known about the effects of immunosuppressive and cardiovascular risk-modifying drugs on CRP in renal transplant recipients.. We retrospectively identified stable patients with > or =1 highly sensitive CRP measurements between January 1 and August 31, 2005. Variables collected included patient demographics; transplant, dialysis, and cardiovascular disease-related variables; and medication profiles. Univariate correlations with CRP were assessed by unpaired Student t testing, analysis of variance, or chi analysis and followed by multivariate linear regression with stepwise backward elimination until a final stable model was attained.. CRP levels were obtained in 298 recipients. In univariate analysis, body mass index (P<0.0001) and systolic blood pressure (P=0.009) showed a positive correlation, whereas number of immunosuppressive drugs (P=0.05) and use of mycophenolate mofetil (MMF) (P=0.003) were negatively correlated with CRP levels. By multivariate analysis, only body mass index (P<0.0001) and MMF dose (P<0.0001) were independently and opposingly correlated with CRP. Mean CRP level was 5.18+/-5.7 mg/L in patients not taking MMF compared with 3.13+/-3.5 mg/L in those on 2000 mg per day (P=0.002).. MMF use correlates inversely with CRP levels in renal transplant recipients, suggesting that immunosuppressive regime design may alter allograft and cardiovascular disease risk in these patients. Prospective study of the effects of MMF on novel cardiovascular disease risk factors such as CRP is warranted.

Topics: Adult; Aged; Analysis of Variance; C-Reactive Protein; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies

Few studies have evaluated the long-term use of MMF in liver transplanted children with renal dysfunction. The aim of this study is to report the experience of a pediatric transplantation center on the efficacy and security of long-term use of a MMF immunosuppressant protocol with reduced doses of CNIs in stable liver transplanted children with renal dysfunction secondary to prolonged use of CsA or Tac. Between 1988 and 2003, 191 children underwent OLT and 11 patients developed renal dysfunction secondary to CNIs toxicity as evaluated by biochemical renal function parameters. The interval between liver transplantation and the introduction of the protocol varied from one to 12 yr. Renal function was evaluated by biochemical parameters in five phases: immediately prior to MMF administration; 3, 6, 12 and 24 months after the introduction of MMF. Among the patients, nine of them (82%) showed improvement of renal function parameters in comparison with the pretreatment values. The two patients that did not show any improvement were patients in whom the interval of time between OLT and the introduction of MMF was longer. All parameters of liver function remained unchanged. No episodes of acute or chronic rejection or increases in infection rates during the period were detected. Two patients developed transitory diarrhea and leukopenia that were reverted with reduction of MMF dosage. In conclusion, in liver transplanted pediatric patients with CNI-induced chronic renal dysfunction, the administration of MMF in addition to reduced doses of CNIs promotes long-term improvement in renal function parameters with no additional risks.

Topics: Adolescent; Blood Urea Nitrogen; Child; Child, Preschool; Creatinine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Failure; Liver Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Uric Acid; Vaccination

Persistent proteinuria in patients with quiescent lupus can result from membranous lupus nephritis and/or glomerular scarring following previous flares. This pilot study examined the effects of tacrolimus over two years in six patients with membranous/inactive lupus nephritis and persistent proteinuria despite angiotensin inhibition/blockade. Tacrolimus treatment reduced proteinuria and increased serum albumin (time effect, P = 0.047 and 0.032 respectively). Compared with baseline levels, proteinuria improved by more than 50% in five patients (83.3%) and hypoalbuminaemia was corrected in four patients. The efficacy was most prominent in four patients with biopsy-proven membranous lupus nephritis, whose protienuria improved by over 80%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment, despite non-excessive blood levels. These data suggest that tacrolimus is an effective treatment for proteinuria due to membranous lupus nephritis, but should probably be reserved for patients who are refractory to other non-nephrotoxic treatments, in view of the potential risk of subclinical nephrotoxicity.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Antinuclear; Autoantigens; Blood Glucose; Blood Pressure; Complement C3; Creatinine; DNA; Drug Evaluation; Drug Resistance; Female; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Diseases; Lipids; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prednisolone; Proteinuria; Retrospective Studies; Serum Albumin; Tacrolimus; Treatment Outcome

Post-renal transplant anaemia is a potentially reversible cardiovascular risk factor. Graft function, immunosuppressive agents and inhibition of the renin-angiotensin system have been implicated in its aetiology. The evaluation of erythropoietin (EPO) levels may contribute to understanding the relative contributions of these factors.. Two-hundred and seven renal transplant recipients attending the Belfast City Hospital were studied. Clinical and laboratory data were extracted from the medical records and laboratory systems.. Of the 207 patients (126 male), 47 (22.7%) were found to be anaemic (males, haemoglobin (Hb)<12 g/dl, females Hb<11 g/dl). The anaemic group had a significantly higher mean serum creatinine level (162.8 micromol/l vs 131.0 micromol/l, P<0.001) and lower mean estimated glomerular filtration rate (eGFR) (41.5 ml/min vs 54.9 ml/min, P<0.001) than the non-anaemic group. Individual immunosuppressive regimens were comparable between those with and those without anaemia. Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) administration was not more prevalent in those with anaemia compared with those without (36.2 vs 38.8%, P=0.88). There was a significant inverse correlation between Hb levels and serum EPO levels (R=-0.29, P<0.001), but not between EPO levels and eGFR (R=0.02, P=0.74). Higher EPO levels were predictive of anaemia, independent of eGFR in multivariate analysis.. Anaemia is common in post-renal transplant patients. The levels of renal function and serum EPO and not immunosuppressive regimens or ACE-I/ARB use, are strong and independent predictors of anaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Azathioprine; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Predictive Value of Tests

Topics: Cell Proliferation; Disease Progression; Extracellular Matrix; Fibrosis; Glyburide; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Prodrugs; Prognosis

Mammalian Target-of-Rapamycin inhibitors (mTOR inhibitors) can be used to replace the calcineurin inhibitors (CNIs) to prevent progression in chronic kidney disease (CKD) following organ transplantation. Discontinuation of tacrolimus in 136 recipients of kidney transplants with progressive renal dysfunction significantly decreased the rate of loss of estimated glomerular filtration rate (eGFR, mL/min/1.73 m(2)) (pre-intervention vs. post-intervention slopes, -0.013 vs. -0.002, p < 0.0001). Discontinuation of tacrolimus was associated with a sustained and significant improvement in graft function (pre-eGFR vs. post-eGFR; 26.0 +/- 1.1 vs. 47.4 +/- 2.1, p < 0.0001) in 74% of patients. This intervention was ineffective if the mean and (median) values of creatinine (mg/dL) and eGFR were 3.8 +/- 0.2 (3.4) and 18.4 +/- 1.9 (22.4), respectively, at the time of conversion therapy. During the follow-up (range, 1.5-34.6, months), a total of 13 patients had their first acute rejection following the conversion therapy, an annual incidence of less than 10% and none of these episodes resulted in graft loss. The salutary effects of sirolimus therapy following discontinuation of tacrolimus in patients with moderate to severe graft dysfunction due to allograft nephropathy even in high-risk patients improves kidney function and prevents acute rejection.

Topics: Biopsy; Calcineurin Inhibitors; Chronic Disease; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Transplantation, Homologous

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Creatinine; Hypertension; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lead; Lymphocytes; Macrophages; Male; Malondialdehyde; Mycophenolic Acid; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Superoxides; Transcription Factor RelA

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

This study is aiming to investigate the mechanism and drug intervention of chronic allograft nephropathy (CAN) induced by renal ischemia-reperfusion injury.. The closed colony strain Sprague-Dawley (SD) and Wistar Rats were used as donor and recipient, respectively. Orthotopic kidney transplantation was performed following the procedure of our previous study. The rats were divided into five groups: Group A only received CsA with 10 mg/(kg x d); except CsA, Group B,C,D received Yi Sheng injection with 4 mg/(kg x d), 8 mg/(kg x d), and MMF (20 mg/(kg x d)], respectively. Group E was control group. According to Banff standard, the serum creatinine (SCr) level and pathological change of rat grafted kidney were observed at the 4th, 8th and 12th weeks post-transplantation. The immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction were used to comprehend the localization and expression of TGFbeta1 and Smad2, 7 in the transplant kidney.. Compared with the lower dosage group, the differences of SCr level and pathological changes of CAN at all the time points after 8th week were statistically significant in the high dosage Yi Sheng group. It was showed that the Yi Sheng injection had the protective effect on CAN with a dose-dependent fashion. After transplantation, the rat kidney-sclerosis model showed that the up-regulated expressions of TGF-P, and Smad2 and the down-regulated expression of Smad7 in Group A and Group B were statistically significant, which meant that the difference was obvious when Group A compared with the other 4 groups. The expressions of TGF-beta1, and Smad2 were strongly positive in tubular epithelial cell, interstitial cell and glomerulus, while the expression of Smad7 was weak. Thickening of endovascular could significantly be inhibited in high dosage of Yi Sheng and MMF group.. The up-regulated expressions of TGF-beta1 and Smad2 and the down-regulated expression of Smad7 may accelerate the progression of CAN alone or with immune factors. The traditional Chinese medicine Yi Sheng injection and MMF can down-regulate the expression of TGF-beta1 and Smad2 and block the down-regulated expression of Smad7, which may postpone and lessen the progression of CAN.

Topics: Animals; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Gene Expression Regulation; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Smad2 Protein; Smad7 Protein; Transforming Growth Factor beta1; Transplantation, Homologous

Sarcoidosis is a multi-system disorder characterized by non-caseating epithelioid granulomas in multiple organs. The disease usually presents in young adults and is uncommon in children. Renal involvement can usually occur due to granulomatous interstitial nephritis, but renal failure is uncommon. Corticosteroids are the mainstay of therapy. We present the report of a child with severe renal failure secondary to renal limited sarcoidosis who was successfully treated with corticosteroid induction therapy. Because of the severe side effects of corticosteroids, mycophenolate mofetil was added and corticosteroids were tapered off. The child has been in sustained remission for over a year with mycophenolate mofetil monotherapy.

Topics: Adolescent; Adrenal Cortex Hormones; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Mycophenolic Acid; Remission Induction; Sarcoidosis

Cyclosporine (CyA) has positively impacted on the outcome of cardiac transplantation; however, the nephrotoxicity associated with CyA has been a major drawback.. In an effort to reduce exposure to CyA and possibly alleviate its nephrotoxic effects, we undertook a therapeutic strategy to switch cardiac transplant patients with biopsy-proven CyA nephrotoxicity from azathioprine (AZA) to mycophenolate mofetil (MMF) with subsequent CyA dose reduction or elimination.. MMF was substituted for AZA in five cardiac transplant patients (four males; mean age, 60 +/- 6 years old; average time from transplant was 7 +/- 3 years) who had biopsy proven evidence of CyA nephrotoxicity, and in whom CyA dose was reduced (3/5) or discontinued (2/5). At the time of the therapeutic intervention, four patients had an average serum creatinine of 230 +/- 62 micromol/L and one patient had just been started on haemodialysis (HD). During an average follow-up period of 42 months, the slope of the inverse serum creatinine significantly improved in three patients and continued to deteriorate in one patient. The patient on HD could be transiently taken off HD. However, he developed a severe episode of cardiac rejection requiring antirejection therapy and increase in the dose of CyA. The patient was subsequently returned back on HD.. In this preliminary report, we show that AZA to MMF switch with subsequent CyA dose reduction or discontinuation may slow down the progression of kidney disease in some patients. However, the patients should be followed closely for evidence of cardiac rejection.

Topics: Aged; Azathioprine; Chronic Disease; Creatinine; Cyclosporine; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Treatment Outcome

Experiments were performed to determine the importance of activation or infiltration of immune cells in the kidney during the development of hypertension and renal disease in Dahl salt-sensitive rats (SS/Mcw) fed a 4.0% NaCl diet. Compared with vehicle-treated rats, chronic administration of mycophenolate mofetil ([MMF] 30 mg/kg per day, IP), an immunosuppressive agent that has cytostatic effects on T and B cells, decreased cell-specific markers of T and B cells by 50% to 60% in the kidneys of SS/Mcw rats (n=5 per group). Further studies were performed on Dahl SS/Mcw rats, which were instrumented with chronic indwelling catheters and studied after 3 weeks on the 4.0% NaCl diet. Rats were administered MMF or 5% dextrose vehicle daily during the 3-week period of high NaCl intake. Mean arterial blood pressure in the rats administered MMF (122+/-2 mm Hg; n=11) was significantly decreased compared with vehicle-treated rats (139+/-4 mm Hg; n=9). Furthermore, the rate of protein (112+/-13 mg per day) and albumin excretion (15+/-3 mg per day) in the MMF-treated rats was significantly lower than the protein and albumin excretion rate in vehicle-treated rats (167+/-25 and 31+/-7 mg per day, respectively). Creatinine clearance and body weight were not different between the groups, averaging 0.52+/-0.08 mL/min per gram kidney weight and 322+/-10 g, respectively, in the MMF-treated group. These experiments indicate that the activation of the immune system or renal infiltration of immune cells plays an important role in the development of hypertension and renal disease in Dahl SS/Mcw rats consuming an elevated NaCl diet.

Topics: Albumins; Animals; Blood Pressure; Creatinine; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Proteins; Rats; Rats, Inbred Dahl; Sodium Chloride

Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity.. Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically.. Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft.. Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

Topics: Animals; Aorta; Aortic Diseases; Arterial Occlusive Diseases; Blood Cell Count; Cyclosporine; Drug Therapy, Combination; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Inbred Strains; Receptors, Lysosphingolipid; Retreatment; Sulfhydryl Compounds; T-Lymphocytes; Transplantation, Homologous; Tunica Intima

Because calcineurin inhibitor (CNI)-induced nephrotoxicity contributes significantly to late renal allograft loss, sirolimus (SRL)-based, CNI-free maintenance immunosuppression has been advocated, but data in the pediatric population are scarce. We therefore analyzed the efficacy and safety of an SRL-based immunosuppressive regimen plus mycophenolate mofetil (MMF) and corticosteroids vs. CNI minimization (mean dose reduction by 39%) plus MMF and corticosteroids in 19 pediatric recipients with biopsy-proven CNI-induced nephrotoxicity in a single-center case-control study. In the SRL group, we observed, one yr after study entry, an improvement of glomerular filtration rate (GFR) by 10.3 +/- 3.0 mL/min/1.73 m2 (p < 0.05 vs. baseline) in seven of 10 patients and a stabilization in the remaining three, while in the CNI minimization group GFR improved by 17.7 +/- 7.1 mL/min/1.73 m2 (p < 0.05) in six of nine recipients and stabilized in the remaining three. No patient in either group experienced an acute rejection episode. The main adverse event under SRL therapy was a transient hyperlipidemia in 70% of patients. In pediatric renal transplant recipients with declining graft function because of CNI-induced nephrotoxicity, CNI withdrawal and switch to SRL-based therapy or CNI minimization are associated with a comparable improvement of GFR after 12 months of observation.

Topics: Adolescent; Adrenal Cortex Hormones; Analysis of Variance; Case-Control Studies; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Sirolimus; Statistics, Nonparametric; Treatment Outcome

Mycophenolic acid (MPA) is glucuronidated by uridine diphosphate-glucuronosyltransferases (UGTs) to its pharmacologically inactive 7-O-glucuronide metabolite (MPAG). MPAG is excreted into the bile via the multidrug resistance-associated protein 2 (MRP2/ABCC2), which is essential for enterohepatic (re)circulation (EHC) of MPA(G).. The objective of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) in the MRP2 (G-1549A, G-1023A, A-1019G, C-24, G1249A, C3972T and G4544A) and UGT1A9 (C-2152T, T-275AandT98C) genes and MPA pharmacokinetics in 95 renal allograft recipients at days 7, 42, 90, and 360 after transplantation. In addition to mycophenolate mofetil, all patients received tacrolimus and corticosteroids as immunosuppression.. At day seven after transplantation, in the absence of the MRP2 C-24T SNP, mild liver dysfunction was associated with significantly lower MPA dose-interval exposure and higher MPA oral clearance, while liver dysfunction did not affect MPA pharmacokinetics in patients with the MRP2 C-24T variant. A similar effect is noted for the C-3972T variant, which is in linkage disequilibrium with C-24T. At later time points after transplantation the MRP2 C-24T SNP was associated with significantly higher dose-corrected MPA trough levels. Patients with the MRP2 C-24T variant had significantly more diarrhea in the first year after transplantation.. The MRP2 C-24T and C-3972T polymorphisms protect renal transplant recipients from a decrease in MPA exposure associated with mild liver dysfunction. Furthermore, this study suggests that the C-24T SNP is associated with a lower oral clearance of MPA in steady-state conditions.

Topics: Adrenal Cortex Hormones; Cohort Studies; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Linkage Disequilibrium; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mycophenolic Acid; Polymorphism, Single Nucleotide; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Prednisolone; Research Design; Tacrolimus; Time Factors; Treatment Outcome

Corticosteroids have been a component of maintenance immunosuppression for renal transplant since the 1960s and have helped to reduce the rate of acute rejection. Corticosteroids, however, have many adverse effects, and with the development of new immunosuppressive medications, many transplant centers have adopted protocols that eliminate or completely avoid the use of corticosteroids. Despite promising short-term results, the impact of corticosteroid elimination on long-term kidney function still is unclear. This single-center, retrospective, sequential study analyzed 212 renal transplant patients with a median follow-up of 5 yr. All patients received induction with IL-2 receptor antagonist and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. Ninety-six patients were maintained on chronic prednisone, and 116 were maintained without chronic prednisone (rapid steroid elimination). Kaplan-Meier patient and graft survival at 7 yr after transplantation were not statistically different between the two groups. Rate and severity of acute cellular rejection were similar. Furthermore, the slope of GFR decline per month at 5 yr after transplantation was not statistically different between the two groups. Prednisone-treated patients had a significantly higher incidence of hyperlipidemia and posttransplantation diabetes when compared with patients with rapid steroid elimination. It was concluded that with the current immunosuppressive medications, the use of chronic prednisone to maintain long-term kidney function and prevent acute cellular rejection is not justified.

Topics: Adult; Case-Control Studies; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

Sirolimus has been used in heart transplant recipients for treatment of rejection, alternative immunosuppression (IS) and promotion of regression and prevention of graft vasculopathy (coronary artery disease [CAD]). This study reports on our center's experience with 16 children who underwent heart transplantation.. Data were obtained by retrospective review.. Median age at time of review was 12.3 years (n = 16, 5.1 to 18.0 years; 9 boys, 7 girls), and at time of transplant 7.5 years (6 months to 18.0 years). Median time of sirolimus introduction was 2.7 years (1 month to 8.2 years) post-transplant. Fifteen patients were on steroids, 10 on tacrolimus (FK) and mycophenolate mofetil (MMF), 5 on FK and 1 on MMF with no calcineurin inhibitors (CNIs). The average dose of sirolimus was 0.25 mg/kg or 7.0 mg/m(2) to maintain a target level of 5 to 15 mug/liter. Sirolimus was started for CAD in 6 patients (38%), rejection in 5 (31%), and in 5 with combinations of CNI intolerance, CAD, renal dysfunction and rejection. All 6 who received sirolimus for rejection (International Society for Heart and Lung Transplantation [ISHLT] Grade 3A) showed improvement on follow-up biopsies. Two of 3 who received sirolimus for renal dysfunction showed improvement (glomerular filtration rate [GFR] 43 to 67 and 32 to 106 ml/min per 1.73 m(2), respectively). Side effects included hyperlipidemia (38%), abdominal pain (31%), mouth ulcers (26%), anemia or neutropenia (12.5%), persistent pericardial effusion (6%) and interstitial lung disease (6%). Sirolimus therapy was discontinued in 3 patients due to side effects.. In this study sirolimus was found to be a valuable IS agent for the management of rejection, significant renal dysfunction and CNI side effects. These results support the need for prospective studies of the role of sirolimus in primary rejection prophylaxis, primary CAD prophylaxis and CAD regression. There also exists a need to establish an adverse event profile for this drug.

Topics: Adolescent; Age Factors; Child; Child Welfare; Child, Preschool; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

In order to evaluate whether immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine would differently influence the outcome of the renal transplants, we prospectively analyzed the incidence of acute rejection episodes, cytomegalovirus infection within the first 6 months following renal transplantation and 5 yr graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. There was no significant difference in sex, HLA mismatch, cold ischemic time, and patients' weight between the two groups. Contrary to the previous studies which demonstrated that MMF could lower the incidence of acute rejection episodes and improved graft survival rate, the two groups showed no significant difference in the incidence of acute rejection episodes and 5-yr graft survival rate as well. This discrepancy in these results might explain that donor factors could be important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical studies of cadaveric renal transplantation.

Topics: ABO Blood-Group System; Adult; Azathioprine; Body Weight; Cadaver; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunophenotyping; Immunosuppressive Agents; Ischemia; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Tissue Donors; Treatment Outcome

Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined.. Retrospective analysis of 33 post-transplant patients with creatinine clearance (CrCl) below 50 mL/min who were changed from CNI to either MMF or AZA. Following CNI withdrawal patients were divided into two groups: those with improved CrCl after switching and those without, to identify the variables associated with improved renal function.. Variables associated with improved CrCl were: absence of hypertension or diabetes, shorter time between transplantation and switch, deterioration in CrCl in months prior to switch and treatment with MMF (compared with AZA).. Our findings suggest CNI withdrawal should be targeted to a subgroup of patients whose renal function is most likely to improve.

Topics: Azathioprine; Calcineurin Inhibitors; Creatinine; Diabetes Complications; Enzyme Inhibitors; Female; Follow-Up Studies; Forecasting; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; IMP Dehydrogenase; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Safety; Time Factors; Treatment Outcome

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Body Weight; Disease Progression; Drug Interactions; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Mycophenolic Acid; Nephrectomy; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1

Alternative to nephrotoxic calcineurin inhibitors regimens are feasible in renal transplantation. Sirolimus is an effective immunosuppressive drug with less drug-induced nephrotoxicity. Enteric-coated mycophenolate sodium provides a safety and efficacy alternative to mycophenolate mofetil. In peritoneal effluent, cancer antigen 125 (Ca 125) is a mesothelial cell marker and of in vivo biocompatibility of the new dialysis solutions. Longterm PD and peritoneal sclerosis are associated with a low number of mesothelial cells and a low concentration of dialysate Ca 125. Exposure to glucose and degradation products (GDPs) is important in the genesis of mesothelial damage. Short results of the more biocompatible solutions are promising (increasing of Ca 125). In the future, exposure to glucose can be reduced by using combinations of various osmotic agents, each in a low concentration (glycerol and amino acid solution).

Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Peritoneal Dialysis; Sirolimus

Discontinuation of steroids has long been a goal of transplant teams. However, whether this strategy is associated or not with a higher risk of long-term graft loss has not been resolved.. The authors analyzed a cohort of 91 renal allograft recipients who underwent transplantation between 1993 and 1997. They were treated with cyclosporine and mycophenolate mofetil (MMF) and then had steroids withdrawn. Inclusion criteria were as follows: serum creatinine lower than 133 microM, first or second renal transplants, no or only one acute rejection episode (borderline or Ia grade), and a peak of panel reactive antibodies under 50%. Prednisone was gradually tapered off and then discontinued over a period of 2 to 4 months.. There were no episodes of acute rejection after steroid withdrawal. Whether steroids were withdrawn before (early) or after (late) 6 months of renal transplantation did not influence outcome. By Kaplan-Meier analysis, patient survival was 93.6% and 100% at 5 years and 93.6% and 97.6% at 10 years in the early and late steroid withdrawal groups, respectively. Graft survival was 94.3% and 98.1% at 5 years and 87.6% and 82.4% at 10 years in the early and late steroid-withdrawal groups, respectively. Risk factors for graft loss in multivariate analysis were peak of panel reactive antibodies (relative risk, 1.074; 95% confidence interval, 1.017-1.134; P=0.01) and acute rejection (relative risk, 16.5; 95% confidence interval, 1.8-147; P=0.01).. Early and late steroid withdrawal in low-immunologic-risk renal allografts treated with cyclosporine and MMF can be achieved without risk of acute rejection and with excellent long-term results.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Drug Administration Schedule; Female; Graft Rejection; Histocompatibility Testing; Humans; Isoantibodies; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Reoperation; Retrospective Studies

Mycophenolate mofetil (MMF) introduction with concurrent reduction in calcineurin inhibitors has been shown to be beneficial in chronic allograft nephropathy (CAN) in adults. MMF was introduced to 19 children with CAN 26.3+/-5.8 (range 3.1-82.6) months after transplantation. Patients were followed up for a mean of 13.2+/-2.9 (range 1.2-51.1) months. The mean initial MMF dose was 660+/-56 mg/m2 per day, increased to 1,042+/-73 mg/m2 per day a year later. Cyclosporin was reduced from 138+/-10 mg/m2 per day at MMF introduction, to 116+/-15 mg/m2 per day at 6 months and 107+/-24 mg/m2 per day at 1 year. Six months prior to MMF introduction GFR deteriorated by -32.7+/-7.3 ml/min per 1.73 m2 per year. Six months after the introduction of MMF, GFR improved by +26.2+/-7.1 ml/min per 1.73 m2 per year (P <0.001). The introduction of MMF significantly reduced both the graft rejection rate (P=0.01) and systolic blood pressure (P=0.01), without a significant change in antihypertensive treatment. Haematological parameters did not significantly differ before and after MMF introduction. The introduction of MMF in paediatric renal transplant recipients with CAN may cause a significant improvement in GFR in both the short-term and the long-term and may well have a beneficial effect on systolic blood pressure. MMF has the potential to enable CNI-sparing protocols to be adopted.

Topics: Blood Pressure; Calcineurin Inhibitors; Child; Chronic Disease; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid

Polyoma virus nephropathy is recognized as an emerging clinical problem in renal transplantation; however, polyoma in native kidneys is unusual. We report a patient who developed polyoma nephropathy in his native kidneys 15 months after successful lung transplantation. His immunosuppression consisted of tacrolimus, mycophenolate mofetil, and large doses of steroids because of three rejection episodes. When the condition was recognized, cidofovir was an effective treatment (3 doses of 2-3mg/kg); however, his renal function deteriorated nonetheless. Tubulitis and interstitial cell infiltration in his native kidneys were evidence that the changes were in response to viral injury. Polyoma nephropathy of native kidneys is unusual. An earlier course of cisplatin treatment because of metastatic seminoma prior to lung transplantation may have been contributory to pre-existing renal injury. After cidofovir was begun, the polyoma viral load in serum and urine decreased substantially; however, after high-dose steroid treatment of two rejection episodes, each time a significant increase in viral load was seen. We stained biopsies of native kidneys from 30 recipients of other organs. The biopsies were done for various reasons but not because polymoma virus was suspected. We found no additional cases.

Topics: Adult; Antiviral Agents; Biopsy; BK Virus; Cidofovir; Cisplatin; Cytosine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Lung Transplantation; Male; Mycophenolic Acid; Neoplasm Metastasis; Organophosphonates; Polyomavirus; Polyomavirus Infections; Seminoma; Steroids; Tacrolimus

In end-stage cardiomyopathy where concomitant chronic renal failure is a contraindication for cardiac transplantation (HTx), simultaneous heart and kidney transplantation (HKTx) may be the only feasible therapeutic option. Due to the increased donor shortage, the clinical outcome of combined HKTx patients on tacrolimus-based immunosuppression was assessed and compared with a group of HTx patients.. Three hundred forty-nine HTxs, including 13 (4%) combined HKTxs, were performed since 1995. Two hundred twenty-one HTx and all HKTx recipients received tacrolimus-based immunosuppression. Acute rejection episodes (AREs), infections, renal function and clinical outcome were evaluated. Pre-operative renal diagnoses for HKTx patients included cystic nephropathy (n = 4), glomerulonephritis (n = 4), cytostatica-induced nephropathy (n = 1), chronic rejection after renal transplant (n = 1), reflux nephropathy (n = 2) and chronic calcineurin-inhibitor -induced nephropathy after HTx (n = 1). Twelve patients (92%) were on hemodialysis pre-operatively, 1 underwent implantation of a left ventricular assist device (LVAD) before HKTx.. After 4.7 +/- 2 years, 92% of HKTx compared with 85% of HTx patients had survived (p = 0.42). Acute cardiac rejection episodes were more frequent in HTx than in HKTx patients (0.04 +/- 0.09 vs 0.02 +/- 0.04 ARE/100 patient-days; p = 0.07). Incidence of infection was comparable (0.3 +/- 0.2 vs 0.5 +/- 0.4 infection/100 patient-days). Freedom from transplant vasculopathy was 100% in the HKTx group compared with 71% in the HTx group after 4 years (p = 0.04).. Tacrolimus-based immunosuppression yields promising long-term results in HKTx and HTx. The incidence of transplant vasculopathy seems to be lower after HKTx than after HTx. If these results are secondary to a protective effect of tacrolimus-induced tolerance or of tolerance-associated co-transplantation they will need to be investigated in prospective multicenter trials.

Topics: Cardiomyopathy, Dilated; Comorbidity; Coronary Disease; Creatinine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

The increasing shortage of cadaver donor kidneys has prompted the use of expanded or marginal donor kidneys, ie, from older donors or those with a history of hypertension or diabetes. These marginal kidneys may be especially susceptible to calcineurin inhibitor (CNI)-mediated vasoconstriction and nephrotoxicity. Recipients of renal transplants from marginal donors therefore require non-nephrotoxic immunosuppression. Some investigators have proposed using sirolimus, a novel and potent immunosuppressant, instead of CNIs. Moreover, another complication of solid-organ transplantation is thrombotic microangiopathy (TMA), which affects 3% to 14% of patients on immunosuppression therapy treated with CNIs. Therefore, it was suggested that CNIs may be substituted by sirolimus in patients with posttransplantation CNI-induced TMA. We report 3 patients who received marginal cadaveric kidneys and were administered maintenance immunosuppression with sirolimus, prednisone, and mycophenolate mofetil. They each developed de novo TMA despite never having been previously administered a CNI. In these cases, TMA occurred in marginal kidneys with possible endothelial injury before transplantation. Sirolimus may have prevented recovery from these injuries and thus may have promoted TMA in these marginal kidneys. The risk for such a vascular complication should be kept in mind in patients who receive marginal kidneys and are administered sirolimus, even when sirolimus is used without CNIs.

Topics: Aged; Arterioles; Biopsy; Drug Therapy, Combination; Endothelium, Vascular; Female; Fibrin; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Microcirculation; Middle Aged; Mycophenolic Acid; Organ Preservation; Prednisone; Sirolimus; Thrombosis; Tissue and Organ Harvesting; Transplants

Topics: Adult; Cord Blood Stem Cell Transplantation; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Mycophenolic Acid; Sepsis; Transplantation, Homologous

Mycophenolate mofetil (MMF) is used in liver transplantation (LTx) to reduce rejection, nephrotoxicity, neurotoxicity, and the need for steroids. Lower trough concentrations and bioavailability have been reported with oral MMF in first week after LTx. These parameters improve after the first month postoperatively. Previously published studies have used oral formulations of MMF. In this study, we sought to examine survival, rejection, and nephrotoxicity rates using IV MMF in live donor liver transplantation (LDLT).. Twenty-eight patients (mean age, 50.1 years; 15 men, 13 women) were examined between January 2000 and January 2004 with a mean follow-up of 17 months for survival, rejection, and renal function.. Four patients died at 2, 5, 8, and 18 months after LDLT from sepsis (n = 3) and recurrent hepatocellular carcinoma (n = 1). There were no retransplants; hence, patient and graft survival rates were the same (82.4%). Three patients (10.7%) experienced acute cellular rejection requiring treatment. The mean serum creatinine level prior to LDLT was 0.9 +/- 0.4 mg/dL, which remained stable throughout the study. One patient required hemodialysis during the perioperative period for 8 days.. In the current study, we demonstrate a new strategy of IV MMF administration with low-dose tacrolimus that provides for lower rates of acute rejection, better preservation of renal function, and one that is better tolerated compared with historical treatments after LTx.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Survival Analysis; Tacrolimus

Locally generated angiotensin II (AngII) may be involved in the pathogenic mechanisms of chronic renal diseases. Renal expression of AngII and other components of the renin-angiotensin system (RAS) were analyzed by immunohistochemistry and Western blot in a model of chronic progressive nephropathy induced by inhibition of nitric oxide synthesis. Renal injury was evaluated by histology and albumin excretion. Systemic RAS status was evaluated through plasma renin activity (PRA) and plasma AngII concentration. In addition, the effects of enalapril, losartan, and mycophenolate mofetil (MMF) on AngII expression in animals with chronic renal disease was also analyzed. Plasma renin activity and plasma AngII were not different between rats with nephropathy and controls (2.08 +/- 0.7 versus 2.03 +/- 0.5 ng/ml/h and 94.3 +/- 18 versus 78.9 +/- 16 fmol/ml, respectively). However, rats with chronic progressive nephropathy showed augmented renal content of angiotensinogen protein (13.5 +/- 3.5 versus 2.2 +/- 0.4 pixels in control rats; P < 0.05), enhanced expression of cathepsin D-a renin-like enzyme-in cortical collecting tubules (103.5 +/- 27.0 versus 66.2 +/- 3.6 cells/mm2 in controls; P < 0.01), and increased expression of AT1 receptor in interstitium (54.7 +/- 7.8 versus 1.3 +/- 0.4 cells/mm2 in controls; P < 0.001). Kidney angiotensin-converting enzyme content did not differ among the groups. Notably, an increased number of interstitial cells expressing AngII was detected in the renal interstitium (9.5 +/- 1.6 versus 1.7 +/- 0.6 cells/mm2 in controls; P < 0.05). Rats treated with Nomega-nitro-L-arginine-methyl-esther and losartan presented a decreased local AngII formation, in contrast to its known effect on plasma AngII. Moreover, mycophenolate mofetil lowered interstitial AngII expression, suggesting that inflammatory signaling may be involved in interstitial AngII generation. This study demonstrates the upregulation of local RAS in the kidney in a model of chronic progressive nephropathy.

Topics: Albumins; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Cathepsin D; Enalapril; Enzyme Inhibitors; Glomerulonephritis; Immunohistochemistry; Kidney; Kidney Diseases; Losartan; Male; Mycophenolic Acid; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Time Factors; Up-Regulation

Calcineurin inhibitors are one of the most common drugs used for prevention of acute rejection in recipients of renal allografts. New immunosuppressors have reduced the incidence of acute renal allograft rejection. There have been numerous recent attempts to develop alternative patterns of immunosuppressors for prevention of chronic renal allograft failure, and enhancing its survival. We described a patient who developed numerous complications after the initial postransplant period. He was treated with a calcineurin inhibitors-free immunosuppression in order to avoid nephrotoxicity, but had over 30 ng/ml of sirolimus. Renal function was impaired after cyclosponne withdrawal. Sirolimus was used in association with mycofenolate mofetil and prednisone.

Topics: Adult; Calcineurin Inhibitors; Comorbidity; Cyclosporine; Drug Therapy, Combination; Fever; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Pyelonephritis; Recurrence; Sirolimus; Ureteral Diseases; Urinary Bladder Fistula; Urinary Fistula

The authors evaluated the efficacy of antithymocyte globulin (ATG) induction and delayed initiation of cyclosporine (CsA) in heart transplant (HTx) patients with postoperative renal dysfunction (RD). The authors compared 15 adult HTx patients with postoperative RD (serum creatinine [SCr] > or =150 microM) to 17 controls without postoperative RD. ATG was given daily (1.5 mg/kg/day for 5 days) in controls and every 2 to 5 days in RD patients (total lymphocyte count <200/mm). All patients received corticosteroids and mycophenolate mofetil. The initiation of CsA was delayed in RD patients until SCr had decreased to less than 150 microM (day 12 +/- 8 vs. 2 +/- 1, P<0.0001). One-year patient survival and acute rejection rates were 87% and 27% in RD patients and 88% and 59% in controls, respectively (P=not significant). SCr improved in RD patients and did not differ from controls after the first month. The authors' results suggest that marked prolongation of the period of ATG induction permits a safe delay in the initiation of CsA in HTx patients with postoperative RD.

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Creatinine; Cyclosporine; Drug Administration Schedule; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Retrospective Studies; Survival Analysis; Time Factors

Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described.. In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus

Topics: Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Creatinine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid

The effect of mycophenolate mofetil (MMF) and azathioprine (AZA) in reducing renal interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) was studied. Fifty-nine rats with surgically induced UUO received oral MMF (n=19), AZA (n=19), or no treatment (n=21). The obstructed kidneys were analyzed by histology and morphometry on days 21 and 60 post UUO. Fibronectin- and collagen-stained areas were significantly lower in both treatment groups when compared with the control group 21 days post surgery. Transforming growth factor (TGF)-beta expression was significantly lower in the MMF-treated group than in the AZA-treated (P<0.01) and the control (P<0.001) groups. There was no significant difference in TGF-beta expression between the AZA-treated and the control groups 21 days post surgery (P>0.05). No significant difference was found in TGF-beta and fibronectin expression between treated and untreated groups on the 60th day post surgery. However, collagen expression was significantly lower in both treated groups than in the untreated group on the 60th day (P<0.005). We observed that MMF is more effective in preventing fibrosis than AZA in the UUO model in the short term; however, there is a less significant anti-fibrotic effect of these drugs in long-term than in short-term obstruction.

Topics: Animals; Azathioprine; Collagen; Fibronectins; Fibrosis; Immunohistochemistry; Kidney Diseases; Mycophenolic Acid; Rats; Rats, Wistar; Transforming Growth Factor beta; Ureteral Obstruction

Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies.. Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-beta1) were studied.. The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-beta1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT.. MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Body Weight; Chronic Disease; Cyclosporine; Drug Synergism; Fibrosis; Gene Expression; Immunosuppressive Agents; Kidney; Kidney Diseases; Losartan; Macrophages; Male; Mycophenolic Acid; Osteopontin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sialoglycoproteins; Transforming Growth Factor beta; Transforming Growth Factor beta1

The worsening shortage of cadaver donor kidneys has prompted use of expanded or marginal donor kidneys (MDK), i.e. older age or donor history of hypertension or diabetes. MDK may be especially susceptible to calcineurin-inhibitor (CI) mediated vasoconstriction and nephrotoxicity. Similarly, early use of CI in patients with delayed graft function may prolong ischaemic injury. We developed a CI-free protocol of antibody induction, sirolimus, mycophenolate mofetil, and prednisone in recipients with MDK or DGF.. Adult renal transplant recipients who received MDK or had DGF were treated with a CI-free protocol consisting of antibody induction (basiliximab or thymoglobulin), sirolimus, mycophenolate mofetil, and prednisone. Serial biopsies were performed for persistent DGF. Patients were followed prospectively with the primary endpoints being patient and graft survival, biopsy-proven acute rejection, and sirolimus-related toxicity.. Nineteen recipients were treated. Mean follow-up was 294 days. Actuarial 6- and 12-month patient survival was 100% and 100% and graft survival was 93% and 93%, respectively. The only graft loss was due to primary non-function (PNF). The incidence of AR was 16%. Mean serum creatinine at last follow-up was 1.6 mg/dL. Sirolimus-related toxicity included lymphocele (1), wound infection (2), thrombocytopenia (1). and interstitial pneumonitis (1).. A CI-free protocol with antibody induction and sirolimus results in low rates of AR and PNF and excellent early patient and graft survival in patients with MDK and DGF. CI-free protocols may allow expansion of the kidney donor pool by encouraging utilization of MDK at high risk for DGF or CI-mediated nephrotoxicity.

Topics: Adult; Aged; Calcineurin Inhibitors; Clinical Protocols; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Pilot Projects; Prednisone; Recovery of Function; Sirolimus; Tacrolimus

Registry databases offer the statistical power to analyze differences in graft survival rates that may not be detected in randomized clinical trials. This study analyses 2-year graft survival using tacrolimus (tac) or cyclosporine (CsA) with mycophenolate mofetil (MMF) and steroids.. Data reported to the United Network for Organ Sharing Renal Transplant Registry for living-donor kidney patients receiving a transplant during 1998 to 1999 were included. The primary end point was graft survival after adjustment for confounding variables. A Cox model multivariate analysis was used to adjust for potential confounding factors.. Patients receiving CsA-MMF (n=4,686) and tac-MMF (n=2,393) were included. Unadjusted all-cause 2-year graft survival rate was significantly higher with CsA-MMF than tac-MMF (94.3% vs. 92.2%, P=0.0006). After adjustment for potential confounding factors, risk of graft failure at 2 years was significantly higher in patients receiving tac-MMF versus CsA-MMF for both all-cause graft failure (hazards ratio [HR] 1.28, 95% confidence interval [CI] 1.09-1.49, P=0.002) and death-censored graft failure (HR 1.25, 95% CI 1.05-1.49, P=0.013). Other independent risk factors for graft failure were recipient or donor age greater than 55 years, female sex, pretransplant blood transfusions, one or two haplotype mismatches compared with zero haplotype mismatch, and panel reactive antibody (PRA) greater than 30%.. Our findings demonstrate that 2-year renal allograft survival is significantly higher in living-donor recipients receiving CsA compared with tac as initial immunosuppression in combination with MMF.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Child; Child, Preschool; Cyclosporine; Databases, Factual; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Racial Groups; Registries; Retrospective Studies; Tacrolimus; Time Factors

To overcome toxicity of calcineurin inhibitors, recent trials have proposed substituting cyclosporin (CysA) with mycophenolate mofetil (MMF). No data concerning the long-term side effects and long-term renal outcome of this strategy have been published.. We retrospectively compared 39 renal transplant patients with chronic graft dysfunction who were subjected to CysA to MMF substitution (group 1) with 39 matched renal transplant patients who were continued on conventional management (group 2). The mean serum creatinine and the slope of deterioration of renal function before the date of the therapeutic intervention (T(0)) were similar in both groups. Follow-up in both groups was 76 +/- 42 months before T(0) and 44 +/- 11 months after T(0).. In group 1, conversion was associated with a decrease of mean serum creatinine concentrations from 192 to 172 micro mol/l at 1 year (P = 0.004) and 159 micro mol/l at 3 years (P < 0.003) after T(0), whereas it remained unchanged in group 2. The systolic blood pressure decreased in group 1 from 155 mmHg before T(0) to 145 mmHg at 1 year (P < 0.01) and 133 mmHg at 3 years (P < 0.001) without any increase of the antihypertensive drug, whereas it did not change in group 2. Lipid profile tended to improve in group 1 after T(0) and was unchanged in group 2. None of the patients in group 1 developed acute rejection after T(0), whereas two acute rejections occurred in group 2. Graft survival, however, was similar in both groups. In group 1, several side effects occurred related to MMF treatment, and led to its discontinuation in two cases and the reduction of its dose for 18 patients (64%).. CysA/MMF substitution improves renal function and blood pressure in chronic allograft dysfunction when compared with conventional management. However, CysA/MMF substitution is associated with a high rate of MMF-related side effects, requiring modulation of its dose.

Topics: Adult; Cardiovascular Abnormalities; Cyclosporine; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Treatment Outcome

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Portugal; Postoperative Complications; Retrospective Studies; Time Factors

To investigate the effects of mycophenolate mofetil (MMF) on the process of renal interstitial fibrosis, unilateral ureteral obstruction (UUO) model was established in rats. Twenty Sprague-Dawley rats underwent UUO and received vehicle (n = 10) or MMF (20 mg.kg-1.d-1, by daily gastric gavage, n = 10) during a period of 5 days following surgery, and the additional 10 rats were served as sham-operated group. The rats were killed 5 days after surgery. Immunohistochemistry was performed on renal tissue for proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and type I and III collagen (col I, col III). Histological studies were also done by MASSON staining. Five days after surgery, proliferating cells in tubules, interstitium as well as interstitial myofibroblast (MyoF) infiltration and interstitial col I, col III deposition were all significantly reduced by MMF treatment. MMF also alleviated the histological changes of UUO rats. These results suggested that the reduction of interstitial MyoF infiltration may be an important event by which MMF prevents renal injury caused by UUO and MMF could be used to limit the progression of renal fibrosis.

Topics: Animals; Female; Fibrosis; Kidney; Kidney Diseases; Mycophenolic Acid; Random Allocation; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

Mycophenolate mofetil (MMF) has been used for the treatment of chronic allograft nephropathy (CAN) in adults with inconsistent results, but data in children are rare. To evaluate its impact on advanced CAN, we studied changes in glomerular filtration rate (GFR) and the correlation of GFR changes to histology.. Thirty-six children (13.1+/-3.6 years) with a progressive decline in GFR of 16.9+/-12.4 mL/min per 1.73 m2/year and biopsy confirmed CAN 4.3+/-2.9 years after transplantation were studied. MMF was added to conventional immunosuppression (IS) consisting of cyclosporine (CsA) and prednisolone (n=26) or tacrolimus (n=1) or replaced azathioprine in triple IS (n=9). Alterations of GFR were correlated to histologic guidelines according to the Banff chronic score (BCS).. One year after conversion, 22 (61%) children showed a rise in GFR (7.5+/-6 mL/min per 1.73 m2), 8 (22%) remained stable, and 6 (17%) showed a further decline of GFR (7.4+/-2 mL/min per 1.73 m2). Mean CsA trough levels were 114 ng/mL before and 98 ng/mL 1 year after conversion. MMF side effects required dose reduction in 14 children. Children responding to MMF with increasing GFR showed a trend toward less fibrosis, less incidence of vasculopathy, and transplant glomerulopathy in the initial biopsy but had a similar incidence of borderline tubulitis compared with the other groups.. Cotreatment with MMF reversed the progressive loss of GFR in approximately two thirds of children with CAN for at least 1 year. Less chronicity signs in histology seem to indicate a more favorable response to treatment.

Topics: Child; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid

Afferent arteriolopathy is the most characteristic lesion of chronic cyclosporine (CsA) nephrotoxicity. We investigated the effect of therapeutic doses of mycophenolate mofetil (MMF) in a model of chronic CsA nephrotoxicity where transforming growth factor-beta (TGF-beta) was shown to play a central role. Rats treated with vehicle, MMF 10 mg/kg/day, CsA 10 mg/kg/day or CsA + MMF were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to TGF-beta1 mRNA and protein expressions, and mRNA expression of plasminogen activator inhibitor-1 (PAI-1) and the extracellular matrix (ECM) proteins biglycan and types I and IV collagen. While MMF markedly ameliorated afferent arteriolopathy, it had no significant effect on interstitial fibrosis and tubular atrophy. In addition, MMF treatment reduced both TGF-beta1 mRNA and protein levels by 39% and 32%, respectively (p < 0.05 vs. CsA only). The expression of the ECM proteins followed that of TGF-beta1 and was significantly decreased with MMF; a similar effect was observed with PAI-1, suggesting an increase in ECM degradation. These results suggest that MMF exerts a beneficial effect on CsA arteriolopathy and that it decreases TGF-beta1. While this drug combination may be useful clinically, long-term studies are needed to determine if MMF has a lasting benefit.

Topics: Animals; Arteries; Cyclosporine; Extracellular Matrix Proteins; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Plasminogen Activator Inhibitor 1; Rats; Transforming Growth Factor beta

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.

Topics: Adult; Aged; Azathioprine; Chronic Disease; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Transplantation, Homologous

Chronic cyclosporine nephrotoxicity (CCN) after heart transplantation is a progressive condition that may lead to end-stage renal failure. The extent to which CCN is reversible with reduction or withdrawal of cyclosporine therapy is unknown. The aim of this study was to assess the reversibility of CCN and to assess the safety and efficacy of a strategy of cyclosporine dosage reduction, combined with conversion from azathioprine to mycophenolate mofetil (AZA/MMF switch) to maintain immunosuppression.. An AZA/MMF switch followed by cyclosporine dose reduction was undertaken in 30 heart transplant recipients (23 men, 7 women; mean age, 54 +/- 2 years) with established CCN at a mean of 90 +/- 9 months after transplantation (range, 17-182 months). The mean maintenance MMF dosage was 2.3 +/- 0.1 g/day (n = 28). Mean cyclosporine dosage was decreased from 2.3 +/- 0.2 mg/kg/day before AZA/MMF switch to 1.6 +/- 0.2 mg/kg/day.. Three patients (10%) were withdrawn from MMF, 2 because of diarrhea and the third because of severe pneumonia that developed within 2 weeks of AZA/MMF switch. All 3 were restabilized with AZA. One patient (4%) experienced acute rejection 7 months after AZA/MMF switch. This resolved after an oral pulse of prednisolone. Systemic infections occurred in 6 patients within 12 months of AZA/MMF switch. Actuarial survival 1 year after AZA/MMF switch was 86% +/- 6%. One patient died of infection and 3 of other causes. Serum creatinine concentration decreased from 248 +/- 15 micromol/liter before cyclosporine dosage reduction to 193 +/- 11 micromol/liter and 206 +/- 19 micromol/liter at 3 and 12 months after dosage reduction (both p < 0.01 versus baseline, n = 23). Of the 23 patients who remained on MMF at 12 months, a decrease in serum creatinine was documented in 19 (83%). Four patients showed no improvement or showed deterioration in renal function, and three of these progressed to end-stage renal failure.. Chronic cyclosporine nephrotoxicity has a significant reversible component in most patients. A strategy of AZA/MMF switch combined with cyclosporine dosage reduction is generally well tolerated and results in short-term improvement in renal function in most patients. Close vigilance is required during the first 12 months after AZA/MMF switch because both acute rejection and infection may occur.

Topics: Azathioprine; Chronic Disease; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Treatment Outcome

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antigens, CD; B7-2 Antigen; Blood Pressure; Dendritic Cells; Dexamethasone; Etanercept; Histocompatibility Antigens Class II; Humans; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Kidney; Kidney Diseases; Kinetics; Macrophage Migration-Inhibitory Factors; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mycophenolic Acid; NADPH Dehydrogenase; NADPH Oxidases; NF-kappa B; Phosphoproteins; Protective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Tumor Necrosis Factor; Renin; T-Lymphocytes

Topics: BK Virus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Tacrolimus

Topics: Adjuvants, Immunologic; Age Factors; Antimalarials; Antiphospholipid Syndrome; Cyclophosphamide; Dehydroepiandrosterone; Female; Heart Diseases; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Neoplasms

Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment.. One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18).. Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method.. This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.

Topics: Adrenal Cortex Hormones; Adult; Calcineurin; Chronic Disease; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Topics: Allopurinol; Azathioprine; Biopsy; Diagnosis, Differential; Drug Interactions; Humans; Kidney; Kidney Diseases; Mycophenolic Acid; Uric Acid

To study the efficacy of mycophenolate mofetil (MMF) as renal rescue in paediatric liver transplant recipients with calcineurin-inhibitor- (CI) related nephrotoxicity.. Pediatric liver transplant recipients with stable graft function and a glomerular filtration rate (GFR) <80 ml/min/1.73 m2 were enrolled. MMF was introduced at 20 mg/kg/day and increased to 40 mg/kg/day after 1 week. CI dose was then reduced 6 weeks to achieve blood levels 25% of baseline. GFR was reassessed after 6 and 12 months.. Fourteen children with a median (range) interval from transplant of 57 (4-111) months were studied. Their median (range) GFR in ml/min/1.73 m2 increased from a baseline of 52 (31-71), to 69 (38-111) and 73 (35-98) at 6 and 12 months, respectively (P=0.00014). Side effects of MMF include leucopaenia in two and backache in one, two of whom discontinued MMF. Acute allograft rejection occurred in three children. All 14 are well with a median (range) follow-up of 24 (14-38) months from MMF introduction.. MMF allows the recovery of renal function from CI related nephrotoxicity in more than 70% of paediatric liver transplant recipients with renal impairment.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Kidney; Kidney Diseases; Liver Transplantation; Mycophenolic Acid; Recovery of Function

Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Mycophenolic Acid

Topics: Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid; Postoperative Complications

Eight patients whose severe psoriasis was treated with long-term cyclosporin (range 2-11 years; mean 7.6 years) were changed to mycophenolate mofetil (MMF), because of nephrotoxicity in seven and hypertension and lack of efficacy in one. In five patients psoriasis control significantly deteriorated and in three patients disease control deteriorated slightly in periods ranging from 2 to 32 weeks. Renal function improved in all six patients with cyclosporin-induced nephrotoxicity treated with MMF for more than 2 weeks. From this data it would appear that MMF is not as effective as cyclosporin in controlling severe psoriasis. However, MMF did offer reasonable disease control in three of eight patients and allowed renal function to improve, and so may have a place in the treatment of some patients unable to take cyclosporin because of renal toxicity.

Topics: Aged; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Severity of Illness Index; Treatment Outcome

The immunosuppressant mycophenolate mofetil (MMF) inhibits the enzyme inosine-5' monophosphate dehydrogenase and thus interferes with cellular GTP synthesis. MMF suppresses the cellular and humoral immune response and has antiproliferative effects on vascular smooth muscle and mesangial cells in vitro and in vivo. In large multicenter trials with almost 1500 patients MMF has been proven highly efficacious for transplant rejection prophylaxis with the main side-effects of gastrointestinal disorders and a slightly increased incidence of viral infections. Recent investigations suggest MMF as an alternative immunosuppressant in cyclosporin A nephrotoxicity. Preliminary observations show promising results for MMF in the treatment of autoimmune-mediated renal disease. The rationale for its use in this patient group and evidence from experimental studies are discussed. As current therapy of this disease entity is still unsatisfactory, future clinical trials are necessary to investigate the efficacy and safety of MMF for this new indication.

Topics: Clinical Trials as Topic; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid

The successful use of tacrolimus (Tac)-based immunosuppressive therapy in organ transplantation and our own positive experience in heart transplantation led us to investigate regimens including this agent at our center for lung transplantation.. From 1991 to 1998, 86 patients underwent lung transplants at our center and 78 of them were included in this analysis. The first 34 patients were treated with cyclosporin (CsA), azathioprine (Aza), and rabbit antilymphocyte globulin; the subsequent 30 patients received Tac with Aza, and the most recent 12 patients Tac with mycophenolate mofetil (MMF). In addition, all patients received prednisone.. The number of acute rejection episodes per 100 patient days was 1.5, 0.6, and 0.3 for three treatment groups, respectively. Similarly, the incidence of refractory acute rejection per 100 patient days was lower in both Tac groups (0.20, 0.03, and 0, respectively). Freedom from acute rejection was highest in the Tac-MMF group (P=0.0037 vs. Tac/Aza, P=0.0007 vs. CsA/Aza). Freedom from recurrent acute rejection was significantly higher in both Tac groups (P=0.027 Tac/ Aza vs. CsA/Aza and P=0.025 Tac/MMF vs. CsA/Aza). The incidence of infections per 100 patient days was similar (0.8, 0.5, and 0.8) in all three treatment groups, with a similar distribution of fungal, bacterial, and viral infections. Freedom from infection also showed no difference. The survival rate was significantly higher for the Tac population, with actuarial 1- and 3-year survival rates of 93% and 71%, compared with the CsA group (71% and 51%, respectively, P=0.04). Prevalence of renal dysfunction (creatinine >2.0 mg/ dL) was 18%, 13%, and 0% in the 3 treatment groups, respectively. The development of glucose metabolism disorders was lower in the CsA group than in the Tac-Aza group (15% vs. 27%, P<0.05).. Tac-based immunosuppressive therapy results in a lower rate of acute rejection after pulmonary transplantation, with similar infection rates and a slightly higher incidence of new onset diabetes mellitus compared with CsA-based therapy.

Topics: Acute Disease; Adult; Animals; Antilymphocyte Serum; Azathioprine; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Rabbits; Retrospective Studies; Tacrolimus

Cyclosporine is the most common maintenance immunosuppressant in liver transplants patients, but it is often associated with nephrotoxicity.. We evaluated the safety and efficacy of monotherapy with mycophenolate mofetil (1 g twice daily) in five stable liver transplant patients with cyclosporine-induced renal impairment despite reduction of cyclosporine to subtherapeutic levels. Follow-up was 8.4+/-2.4 (range: 6-12) months.. No major side effects have been observed to date. Serum creatinine levels were significantly reduced from a median of 201 micromol/L before to 142 micromol/L at 3 months after mycophenolate (P=0.04) and remained low at 6 months. New onset cellular rejection occurred in only one patient after 3 months on mycophenolate monotherapy, and it responded completely to an intravenous course of methylprednisolone.. Monotherapy with mycophenolate mofetil in a dose of 1 g twice daily seems to significantly improve cyclosporine-induced renal impairment in stable liver transplant patients without major side effects or significant risk of rejection.

Topics: Creatinine; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Leukocyte Count; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Time Factors

Progressive deterioration of renal function in kidney transplant recipients is the leading cause of graft failure. Both nonimmunologic and immunologic mechanisms contribute to this deterioration.. Twenty-eight cyclosporine (CsA)-treated renal transplant recipients (21 cadaveric, 5 living, 2 simultaneous kidney-pancreas) with progressive deterioration of renal function were prospectively enrolled in a clinical trial and had their immunosuppressive regimen changed 24.3+/-7.7 months after transplant. All patients had their CsA dose reduced by 50%, azathioprine was discontinued, and mycophenolate mofetil was added to the medical regimen. The mean creatinine of the patients at the initiation of the change in immunosuppression was 3.5+/-1.2 mg/dl (range 1.9 to 6.2 mg/dl).. Before the change in immunosuppression, the mean loss in renal function as indicated by the least-squares slope of the reciprocal of creatinine versus time was -0.006+/-0.002 (mg/dl)-1 per month. The change in immunosuppression significantly decreased the rate of loss in renal function for most patients when compared with their pretreatment values with a mean slope of 0.007+/-0.003 (mg/dl)-1 per month (P=0.003). Renal function improved in 21 of 28 patients. Only one patient had continued deterioration of renal function. In a multivariate analysis adjusting for CsA dose, mean arterial blood pressure, and baseline creatinine, the change in immunosuppression was significantly associated with improved renal function (P=0.02). There were no acute rejections after the immunosuppression change.. We conclude that adding mycophenolate mofetil and reducing CsA in patients with chronic deterioration of graft function is well tolerated and results in a short-term improvement in renal function.

Topics: Adult; Cadaver; Chronic Disease; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies