tacrolimus and Nephrotic-Syndrome

This study aimed to compare the effectiveness of 13 types of immunosuppressive agents used to treat idiopathic membranous nephropathy (IMN) in adults with nephrotic syndrome.. Systematic review and network meta-analysis.. PubMed, EMbase, Cochrane Library, Web of Science, Clinical trials, SinoMed, Chinese Biomedicine, CNKI, WanFang and Chongqing VIP Information databases were comprehensively searched until February 2018.. Randomised clinical trials (RCTs) comparing the effects of different immunosuppressive treatments in adult patients with IMN and nephrotic syndrome were included, and all included RCTs had a study-duration of at least 6 months.. Two reviewers independently screened articles, extracted data and assessed study quality. Standard pairwise meta-analysis was performed using DerSimonian-Laird random-effects model.. This study ultimately included 48 RCTs with 2736 patients and 13 immunosuppressive agents. The network meta-analysis results showed that most regimens, except for leflunomide (LEF), mizoribine (MZB) and steroids (STE), showed significantly higher probabilities of total remission (TR) when compared with non-immunosuppressive therapies (the control group),with risk ratios (RRs) of 2.71 (95% CI) 1.81 to 4.06)for tacrolimus+tripterygium wilfordii (TAC+TW), 2.16 (1.27 to 3.69) foradrenocorticotropic hormone, 2.02 (1.64 to 2.49) for TAC, 2.03 (1.13 to3.64) for azathioprine (AZA), 1.91 (1.46 to 2.50) for cyclosporine (CsA), 1.86 (1.44 to2.42) for mycophenolate mofetil (MMF), 1.85 (1.52 to 2.25) for cyclophosphamide (CTX),1.81 (1.10 to 2.98) for rituximab (RIT), 1.80 (1.38 to 2.33) for TW, 1.72 (1.35 to 2.19) for chlorambucil. As for 24 hours UTP, the direct andindirect comparisons showed that AZA (standard mean difference (SMD), -1.02(95% CI -1.90 to -0.15)), CsA (SMD, -0.70 (95% CI -1.33 to -0.08)),CTX (SMD, -1.01 (95% CI -1.44 to -0.58)), MMF (SMD, -0.98 (95% CI -1.64 to -0.32)), MZB (SMD, -0.97 (95% CI -1.90 to-0.04]), TAC (SMD, -1.16 (95% CI -1.72 to -0.60)) and TAC+TW(SMD, -2.03 (95% CI -2.94 to -1.12)) could significantly superior thancontrol, except for chlorambucil, LEF, RIT and STE. Thechanges of serum creatinine (Scr) was not significantly different between eachtreatments of immunosuppressive agents and the control, except for STE whichhas the possibility of increasing Scr (SMD, 1.00 (95% CI 0.36 to 1.64)).Comparisons among all treatments of immunosuppressive agents showed nostatistical significance in the outcome of relapse. A drenocorticotropichormone (85.1%) showed the lowest probability of relapse under the cumulativeranking curve values among all immunosuppressants. Infection,gastrointestinal symptoms, and bone marrow suppression were the common adverseevents associated with most of the immunosuppressive therapies.. This study demonstrates that TAC+TW, TAC and CTX are superior to other immunosuppressive agents in terms of TR and 24 hours UTP. Moreover, they are all at risk of infection, gastrointestinal symptoms, and myelosuppression. Furthermore, TAC could increase the risk of glucose intolerance or new-onset diabetes mellitus. Conversely, STE alone, LEF and MZB seem to have little advantage in clinical treatment of IMN.. CRD42018094228.

Topics: Adult; Cyclophosphamide; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Network Meta-Analysis; Randomized Controlled Trials as Topic; Tacrolimus; Tripterygium

The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).. The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.. In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.. CsA is an effective and safe agent in the therapy of patients with SRNS.

Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

Amelioration of podocyte injury, which can lead to podocyte detachment, is the target of therapeutic intervention in glomerular diseases. Since podocytes are terminally differentiated cells with little or no proliferative ability, their loss results in permanent glomerular dysfunction. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression, which indirectly ameliorates podocyte injury by interrupting the input of immunological stress. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data now suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. Indeed, the therapeutic efficacy of immunomodulatory agents is, at least in part, derived by the direct action on podocytes. In this review, we discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance.

Topics: Abatacept; Adjuvants, Immunologic; Calcineurin Inhibitors; Everolimus; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Levamisole; Mycophenolic Acid; Nephrosis, Lipoid; Nephrotic Syndrome; Podocytes; Ribonucleosides; Rituximab; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It's important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.

Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Humans; Immunosuppressive Agents; Kidney Neoplasms; Nephrotic Syndrome; Tacrolimus

Cyclosporine began to be used as one of the immunosuppressive agents in transplantation in the beginning of the 1980s, and in the treatment of nephrotic syndrome in the pediatric nephrology. Therapeutic area of cyclosporine is narrow and its side effects limit its usage. Preference for cyclosporine and tacrolimus as a calcineurin inhibitor is left for the choice of the department. There are still countries with preferred-cyclosporine use because of economic reasons. Cyclosporine is currently being used in the treatment of nephrotic syndrome, but due to its high relapse rates in a short-term use, and nephrotoxicity in long-term use, search for new drugs with fewer side effects keeps continuing. As long as its use is indispensable, it will be necessary to keep track of kidney function and blood level of this medication closely to protect the patients from toxicity.

Topics: Calcineurin Inhibitors; Child; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Nephrotic Syndrome; Recurrence; Tacrolimus

Moyamoya syndrome (MMS) is a rare, chronic progressive cerebrovascular occlusive disease that is characterized by a stenosis or occlusion of the bilateral internal carotid arteries and the circle of Willis arteries leading to the development of collateral vessels as visualized by cerebral angiography. We report a case of a 24-year-old woman with nephrotic syndrome whose biopsy showed membranous nephropathy. Ten months after the diagnosis she suffered sudden right hemiplegia and seizure. She was diagnosed with MMS by angiogram seven months ago and received decompressive craniotomy. The patient was admitted to our hospital and a diagnosis of systemic lupus erythematosus (SLE) was made. Glucocorticoids and tacrolimus were used to control the symptoms of SLE. Following one month of immunosuppressant treatment, the patient died of brain hemorrhage. This case alongside another six reviewed cases shows that an underlying cerebrovascular lesion of moyamoya in the vessels of patients with SLE is susceptible to cerebrovascular accidents.

Topics: Craniotomy; Fatal Outcome; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Intracranial Hemorrhages; Lupus Erythematosus, Systemic; Moyamoya Disease; Nephrotic Syndrome; Tacrolimus; Young Adult

The development of lymphomas and solid malignancies in association with immunosuppression is a well-documented occurrence in the medical literature. We report the case of a young man who developed progressive diffuse lymphadenopathy with associated extremely high levels of serum Epstein-Barr virus in the setting of chronic immunosuppressive treatment of glomerulonephritis. Excisional biopsy of a right inguinal node revealed a sclerosing process with the morphologic appearance of angioimmunoblastic T-cell lymphoma with a CD3(+), CD4(+) immunophenotype. In situ hybridization of Epstein-Barr virus-encoded RNA was positive. Molecular probe studies demonstrated a clonal T-cell population. Upon reduction of immunosuppression, the patient's lymphadenopathy and Epstein-Barr virus titer have resolved without recurrence over 2 years time. This case demonstrates that a benign Epstein-Barr virus-associated process can mimic angioimmunoblastic T-cell lymphoma and should be considered particularly in the setting of immunosuppression, emphasizing the need for close communication with the treating physician in the interpretation of lymph node biopsies.

Topics: Adolescent; Diagnosis, Differential; Epstein-Barr Virus Infections; Glomerulonephritis; Herpesvirus 4, Human; Humans; Immunoblastic Lymphadenopathy; Immunocompromised Host; Immunosuppressive Agents; Lymph Nodes; Lymphadenitis; Lymphoma, T-Cell; Male; Nephrotic Syndrome; Tacrolimus; Treatment Outcome

The introduction of corticosteroids more than 50 years ago dramatically improved the prognosis of children with nephrotic syndrome. Corticosteroids remain the standard initial treatment for children with this disease, but a considerable proportion of patients do not respond and are therefore at risk of progressing to end-stage renal disease. Because of this risk, new therapeutic strategies are needed for steroid-resistant nephrotic syndrome. These strategies have historically focused on identifying effective alternative immunosuppressive agents, such as ciclosporin and tacrolimus, yet evidence now indicates that nephrotic syndrome results from podocyte dysfunction. Even conventional immunosuppressive agents, such as glucocorticoids and ciclosporin, directly affect podocyte structure and function, challenging the 'immune theory' of the pathogenesis of childhood nephrotic syndrome in which disease is caused by T cells. This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome.

Topics: Adalimumab; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Alkylating; Child; Cyclophosphamide; Cyclosporine; Enzyme Inhibitors; Galactose; Glucocorticoids; Homeostasis; Humans; Immunologic Factors; Immunosuppressive Agents; Interleukin-13; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Mycophenolic Acid; Nephrotic Syndrome; p38 Mitogen-Activated Protein Kinases; Plasmapheresis; Protein Serine-Threonine Kinases; Receptors, Notch; Ribonucleosides; Rituximab; Signal Transduction; Tacrolimus; Thiazolidinediones; Unfolded Protein Response

Idiopathic nephrotic syndrome (INS) is defined as massive proteinuria and hypoalbuminemia associated with dyslipidemia and generalized oedema in most cases. It is thought to be due to a plasma factor of immunologic origin. Most cases are steroid responsive. However, a considerable proportion of children run a steroid dependent course. Calcineurin inhibitors and alkylating agents have been classical treatment strategies for such cases, but specific toxicity limits the use of these drugs. Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase and thus de novo purine synthesis. Several uncontrolled clinical trials have demonstrated the efficacy of MMF in steroid dependent NS with or without prior use of CyP and in children with nephrotoxicity due to prolonged CyA treatment. Non-compliance to steroid therapy can be responsible for multiple relapses and may be misinterpreted as steroid dependency and may therefore lead to unjustified increase of immunosuppressive treatment. Triamcinolone acetonide, a long acting steroid for intramuscular injection, can replace the usual oral prednisone treatment if non-compliance is suspected. Whereas the treatment of the primary course of INS is well established, steroid dependent and steroid resistant forms are still a challenge for pediatric nephrologists. Both under-treatment with multiple relapses with disease or steroid associated morbidity on the one hand and over-treatment with specific side effects of immunosuppressive drugs may have severe consequences for the patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Child; Cyclosporine; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Levamisole; Mycophenolic Acid; Nephrotic Syndrome; Rituximab; Steroids; Tacrolimus; Triamcinolone Acetonide

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cyclophosphamide; Cyclosporine; Drug Administration Schedule; Glomerulonephritis; Humans; Immunosuppressive Agents; Mercaptopurine; Methylprednisolone; Nephrotic Syndrome; Prednisolone; Remission Induction; Rituximab; Tacrolimus

Topics: Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Cyclosporine; Cytochrome P-450 Enzyme System; Drug Monitoring; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Polymorphism, Genetic; Ribonucleosides; Rituximab; Tacrolimus

Corticosteroid, alkylating agents, like cyclophosphamide and chlorambucil, have been used to treat idiopathic nephrotic syndrome for more than fifty years, changing the outcome of these children. However, with long-term use of steroid, especially high dosages, they have unbearable side effects. Newer agents like cyclosporine A, levamisole, tacrolimus, mycophenolate mofetil, have been used to spare those unwanted side effects. In the choice of drugs, the benefits obtained will have to be evaluated against possible side effects, with drug cost also taken into consideration. Though most steroid sensitive nephrotic children may run a relapsing course, have a good prognosis with many becoming non-relapsers or infrequent relapsers in adulthood, the treatment approach should aim at using the minimal amount of drug required to keep patient in remission to tie them over childhood. As for steroid resistant nephrotic syndrome children, especially for focal segmental glomerulosclerosis (FSGS), because of possible grave prognosis of going into end-stage renal failure, more aggressive approach should be adopted, including the use of strong immunosuppressants, such as, cyclosporine, tacrolimus, or mycophenolate mofetil if necessary. The long-term goals of treatment, other than those of physical and medical conditions, should also consider the growth, education, and psychological impact of the disease and side effects of drugs on the child, especially during an adolescent period, so as to allow them having normal development into adulthood.

Topics: Child; Cyclosporine; Drug Therapy, Combination; Female; Humans; Levamisole; Male; Nephrotic Syndrome; Prednisolone; Tacrolimus

Idiopathic nephrotic syndrome in children is commonly associated with minimal change disease and response to steroid therapy. Steroid-unresponsive nephrotic syndrome is often characterized by persistent proteinuria and progression to chronic kidney disease. Focal segmental glomerulosclerosis is the leading cause of steroid-unresponsive nephrotic syndrome in childhood. There is no uniformed consensus as to the treatment of steroid-unresponsive nephrotic syndrome. Advances in the pathogenesis, genetics and biomarkers or surrogate markers may be useful for the diagnosis and identification of patients with steroid-unresponsive nephrotic syndrome, severity of disease, progression and response to therapy.. This review is intended to describe some of the recent changes in the epidemiology of steroid-unresponsive nephrotic syndrome, in particular focal segmental glomerulosclerosis, its pathogenesis and alternative therapies.. Recent studies in both children and adults have shown an increase in the incidence of focal segmental sclerosis as a cause of steroid-unresponsive nephrotic syndrome. Advances in the pathogenesis and noninvasive methods of diagnosis may allow for the identification of steroid-responsive patients.

Topics: Child; Cyclosporins; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus; Treatment Outcome

The immunosuppressant tacrolimus (FK-506) is a calcineurin inhibitor with a widespread use for the prevention of graft rejection in transplantation medicine. Tacrolimus inhibits the activation of an essential transcription factor for the transcription of cytokine genes in T cells leading to a decreased production of cytokines such as IL-2 and IFN-gamma. As T-cell activation plays a crucial role in the pathogenesis of inflammatory glomerular diseases, there is an increasing number of reports on the use of tacrolimus in nephrotic syndrome. In idiopathic nephrotic syndrome, corticosteroid treatment constitutes the first-line therapy to achieve remission. In the case of steroid resistance or steroid dependence, alternative immunosuppressive strategies are needed. Cyclophosphamide and ciclosporin are well-established drugs in this condition. The present article reviews the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome.

Topics: Adult; Biopsy, Needle; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational; Female; Follow-Up Studies; Graft Rejection; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Maximum Tolerated Dose; Nephrotic Syndrome; Risk Assessment; Severity of Illness Index; Tacrolimus; Transplantation Immunology; Treatment Outcome

Focal segmental glomerulosclerosis (FSGS) is not a disease, but a lesion affecting the podocyte. Secondary FSGS may be due to a host of various factors, and patients are rarely nephrotic, requiring symptomatic treatment only. The best prognostic feature of nephrotic FSGS is its response to corticosteroids. Some forms are most likely of immunological origin, relapse in a renal transplant and justify immunosuppressive treatment. In a growing number of cases, genetic profiling of molecules that contribute to the podocyte slit diaphragm permselectivity to albumin has identified defects that do not represent indications for immunosuppression. In the other forms, corticosteroids and cyclosporin A (CsA) remain the mainstay of treatment, with better efficacy when CsA is associated with steroids. The renal tolerability of CsA is reasonably good when the dosage is low. CsA dependency is not constant. Alkylating agents are reluctantly indicated in steroid-sensitive forms, which are rare. They are mostly ineffective in steroid-resistant forms. Tacrolimus seems a promising therapy with low toxicity, but it is usual for dependency on the drug to occur. Sirolimus seems to be ineffective. Azathioprine is not considered indicated, despite rare reports with favourable results, which would deserve further controlled trials. Recent publications indicate that mycophenolate mofetil might usefully find a place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the elusive substance that causes the nephrotic syndrome and its relapse on a transplant has not led to practical treatment options.

Topics: Alkylating Agents; Antimetabolites; Azathioprine; Contraindications; Cyclophosphamide; Cyclosporine; Drug Resistance; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunophilins; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Podocytes; Randomized Controlled Trials as Topic; Tacrolimus

A 5-year-old African-American male was diagnosed with nephrotic syndrome (NS). Because of concomitant leukopenia, bone marrow aspiration was performed, which did not demonstrate a hematological malignancy. The patient received standard daily steroid therapy for treatment of NS. Steroid resistance at 5 weeks of therapy led to a renal biopsy, which documented focal segmental glomerulosclerosis (FSGS). He was begun on cyclosporin A (CsA) and later switched to tacrolimus because of side-effects of CsA. Seven months after the initial diagnosis of NS, the patient was diagnosed with acute lymphoblastic leukemia (ALL). The patient is in complete remission of ALL and partial remission of NS with continued nephrotic-range proteinuria. Review of the literature shows four other cases of pediatric ALL after NS. No particular immunosuppressive agent seemed to be causative in the evolution of ALL. Although the exact mechanism for development of ALL after NS is unknown, the incidence of leukemia may be increased after immunosuppressive therapy when used in this context.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cyclosporine; Dexamethasone; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome; Vincristine

The nephrotic syndrome is commonly caused by various glomerulonephritides, i.e. minimal change nephrotic syndrome, focal segmental glomerulosclerosis and membranous nephropathy. A long term corticosteroid therapy is a first therapeutic approach for patients with nephrotic syndrome. In patients who have contraindication to steroids or in those who do not respond to steroids, immunosuppressive agents such as cyclosporine, mizoribine, azathioprine and cyclophosphamide are the next therapeutic approach for inducing the remission of the nephrotic syndrome. In this review, we described an appropriate use of systemic immunosuppressive agents for steroid resistant nephrotic syndrome, and the toxicity and side effects of each agent. And currently the clinical trials with new immunosuppressants like tacrolimus (FK 506) and mycophenolate mofetil are also described.

Topics: Azathioprine; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Ribonucleosides; Tacrolimus

Topics: Adolescent; Child; Child, Preschool; Drug Evaluation; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Tacrolimus

Multiple clinical trials have been undertaken during last years to assess indications, efficiency and safety of glomerulonephritis treatment with new immunosuppressive drugs as cyclosporine (CsA, Mycophenolate Mophetil (MMF) and Tacrolimus (FK 506). The main indication for cyclosporine is nephrotic syndrome resistance to steroids and cytotoxic agents, steroid-dependent and multi-relapsing cases with serious toxic side effects or with contraindications for steroids and cytotoxic drugs. CsA was administered at the dose of 4-5 mg/kg/day in adults and 5-6 mg/kg/day in children. The best results were achieved with minimal change disease. The durable remission occurred in 70-80% of cases of steroid-sensitive nephrotic syndrome and in 20-30% of steroid-resistant forms. There was a lower rate of remission and a high risk of cyclosporine nephrotoxicity in other types of glomerulonephritis. Therefore CsA, MMF and FK506 remain a late therapeutic option for patients with these types of glomerulonephritis and severe clinical course. As the long-term CsA therapy may be complicated by acceleration of renal fibrosis, a renal biopsy is mandatory before its administration.

Topics: Adult; Child; Clinical Trials as Topic; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glomerulonephritis; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Recurrence; Tacrolimus; Time Factors

Over the past 20 years the therapy of glomerulonephritis (GN) has evolved. Today apart from steroids and cyclophosphamide, newer agents like cyclopsorine A and tracrolimus (FK 506) have been reported to achieve remission (partial or complete) in patients with nephrotic syndrome due to various GN which have failed to respond to steroids and cyclophosphamide. For those patients who do not respond to any of the primary therapeutic agents, there are now other therapies available like angiotensin II converting enzyme inhibitors, angiotensin II receptor antagonists, dipyridamole, low dose warfarin including protein restriction and therapy aimed at hypercholesterolaemia in an attempt to retard progression to end stage renal failure. This paper presents a therapeutic approach for the various forms of primary GN.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Cyclophosphamide; Cyclosporine; Dipyridamole; Glomerulonephritis; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Remission Induction; Steroids; Tacrolimus; Vasodilator Agents; Warfarin

Topics: Adult; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cholangitis; Cyclosporine; Diabetes Mellitus, Type 1; Digestive System Diseases; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Kidney Diseases; Male; Mice; Multiple Sclerosis; Nephrotic Syndrome; Psoriasis; Rats; Swine; Tacrolimus

FK 506 is a superior immunosuppressive agent that should improve patient survival after the commonly performed transplant procedures, make feasible transplantations that have been previously impractical, allow immune intervention for serious autoimmune diseases, and create a better spin-off understanding of basic biologic processes including signal transduction.

Topics: Autoimmune Diseases; Bone Marrow Transplantation; Female; Graft Rejection; Graft vs Host Disease; Heart Transplantation; Humans; Kidney Transplantation; Liver Transplantation; Male; Nephrotic Syndrome; Psoriasis; Tacrolimus

Rituximab and tacrolimus are therapies reserved for patients with frequently relapsing or steroid-dependent nephrotic syndrome who have failed conventional steroid-sparing agents. Given their toxicities, demonstrating non-inferiority of rituximab to tacrolimus may enable choice between these medications.. This investigator-initiated, single-center, open-label, pilot randomized controlled trial examined the non-inferiority of two doses of intravenous (IV) rituximab given one-week apart to oral therapy with tacrolimus (1:1 allocation), in maintaining sustained remission over 12 months follow-up, in patients with difficult-to-treat steroid-sensitive nephrotic syndrome, defined as frequently relapsing or steroid-dependent disease that had failed ≥ 2 steroid-sparing strategies. Secondary outcomes included frequency of relapses, proportion with frequent relapses, time to relapse and frequent relapses, and adverse events (CTRI/2018/11/016342).. Baseline characteristics were comparable for 41 patients randomized to receive rituximab (n = 21) or tacrolimus (n = 20). While 55% of patients in each limb were in sustained remission at 1 year, non-inferiority of rituximab to tacrolimus was not demonstrated (mean difference 0%; 95% CI - 30.8%, 30.8%; non-inferiority limit - 20%; P = 0.50). Frequent relapses were more common in patients administered rituximab compared to tacrolimus (risk difference 30%, 95% CI 7.0, 53.0, P = 0.023). Both groups showed similar reductions in relapse rates and prednisolone use. Common adverse events were infusion-related with rituximab and gastrointestinal symptoms with tacrolimus.. Therapy with rituximab was not shown to be non-inferior to 12-months treatment with tacrolimus in maintaining remission in patients with difficult-to-treat steroid-sensitive nephrotic syndrome. Frequent relapses were more common with rituximab. While effective, both agents require close monitoring for adverse events. A higher resolution version of the Graphical abstract is available as Supplementary information.

Topics: Humans; Immunosuppressive Agents; Nephrotic Syndrome; Pilot Projects; Prednisolone; Recurrence; Rituximab; Steroids; Tacrolimus; Treatment Outcome

Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen.. Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC-MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene.. The data from 28 children were used for PPK analysis. A one-compartment model and first-order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg. The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Models, Biological; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Tandem Mass Spectrometry

Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy.. To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS.. A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility.. The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2).. Twelve-month relapse-free survival in the intention-to-treat population.. Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events).. In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy.. ClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.

Topics: Child; Disease-Free Survival; Female; Glucocorticoids; Humans; Male; Nephrotic Syndrome; Prednisolone; Rituximab; Tacrolimus; Treatment Outcome

Studies of nephrotic syndrome show that substitution of calcineurin inhibitors by mycophenolate mofetil (MMF) enables sustained remission and corticosteroid sparing and avoids therapy associated adverse effects. However, controlled studies in patients with steroid resistance are lacking. Here we examined the effect of switching from therapy with tacrolimus to MMF on disease course in an open-label, one-to-one randomized, controlled trial on children (one to 18 years old), recently diagnosed with steroid-resistant nephrotic syndrome, at a referral center in India. Following six months of therapy with tacrolimus, patients with complete or partial remission were randomly assigned such that 29 received MMF while 31 received tacrolimus along with tapering prednisolone on alternate days for 12 months. On intention-to-treat analyses, the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). The incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance. These findings have implications for guiding the duration of therapy with tacrolimus for steroid-resistant nephrotic syndrome.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Drug Substitution; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; India; Infant; Kaplan-Meier Estimate; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisolone; Prospective Studies; Recurrence; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

The purpose of the study is to evaluate the efficiency and safety of tacrolimus (TAC) monotherapy in the treatment of nephrotic idiopathic membranous nephropathy (IMN) compared with the protocol of cyclophosphamide (CTX) combined with corticosteroids.. Twelve months after the initial treatment, a total of 24 (80%) patients in the TAC group and 23 (82.1%) patients in the CTX group achieved remission (either partial or complete remission). The survival curve of the probability of remission and complete remission were similar between the two groups (p > .05). Proteinuria (based on 24 h urinary protein excretion) was significantly decreased, and serum albumin was significantly increased after immunosuppressive treatment in both the groups. Estimated glomerular filtration rate (eGFR) was comparable between before and after treatment. The main adverse effects in TAC treatment were glucose intolerance, diabetes and abnormal aminotransferase.. TAC monotherapy is an alternative therapeutic regimen for patients with nephrotic IMN. Its short-term efficiency and patient tolerance are both acceptable.

Topics: Adult; Cyclophosphamide; Diabetes Mellitus; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Glucocorticoids; Glucose Intolerance; Humans; Immunosuppressive Agents; Kidney; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Prospective Studies; Proteinuria; Remission Induction; Serum Albumin; Tacrolimus; Treatment Outcome

Cyclosporine A and tacrolimus (TAC) are often used as a second-line treatment for children with refractory nephrotic syndrome (NS). This study was undertaken to investigate the efficacy and safety of Tacrobell®, a locally produced generic form of TAC.. This study was a one-year prospective, open-label, single-arm, multicenter trial. Fourty-four children with steroid-dependent NS (SDNS) and 33 children with steroid-resistant NS (SRNS) were enrolled. The primary endpoints were defined as the remission rates, whereas the secondary endpoints were recognized as the duration of remission and adverse effects of TAC.. After one-year treatment, 34 (77.3%) of the 44 patients with SDNS were in complete remission, and 6 (13.6%) were in partial remission. Nineteen (43.2%) patients did not relapse during the study; for those who did relapse, the mean duration of remission was 4.6±2.9 months. The number of relapse episodes during the study period (0.90 per patient-year) was significantly lower than that in the preceding year (2.8 per patient-year). After treatment for 3 and 6 months, 12 (36.4%) of the 33 patients with SRNS were in remission, and after treatment for 12 months, the number of patients had increased to 13 (39.4%). The mean time to achieve remission was 4.0±3.2 months. After remission (duration, 3.7±2.7 months), 12 (54.5%) of 22 patients relapsed. The fasting blood glucose and blood pressure levels during the therapy were similar to those at the time of study entry.. Treatment with Tacrobell® was effective and safe for children with refractory NS. The efficacy of this generic form of TAC was better than that of the original TAC formula.

Topics: Adolescent; Child; Child, Preschool; Drugs, Generic; Female; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Time Factors

The treatment strategy for steroid-resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistance or intolerance. To date, few studies have been published using multiple combination therapy of immunosuppressive reagents for children with calcineurin inhibitor-resistant or -intolerant nephrotic syndrome.. Eighteen consecutive children with steroid- and tacrolimus (TAC)-resistant (n = 10) or TAC-sensitive but frequent relapsing nephrotic syndrome (n = 8) were randomly recruited in the present study. All of them received further triple-combination therapy by cyclophosphamide (CTX, n = 6), mycophenolate mofetil (MMF, n = 5) or leflunomide (LEF, n = 7). Their clinical data were collected and efficacy of triple-combination therapy was evaluated.. Compared with previous double-combination therapy of prednisone (Pre) and TAC, the short-term remission rate in all 18 patients was significantly improved after the triple-combination therapy, while the frequent relapse rate in the following 12 months was also significantly decreased. Among three different subgroups with CTX, MMF or LEF therapy, no significant difference was found in short-term remission rate and the relapse rate within 1 year follow up by Kaplan-Meier plot.. Triple-combination therapy with Pre + TAC + CTX/MMF/LEF is effective for short-term response and 1 year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term efficacy and safety of triple-combination therapy with Pre + TAC + CTX/MMF/LEF would be necessary for these patients.

Topics: Calcineurin Inhibitors; Child; Cyclophosphamide; Drug Resistance; Female; Glucocorticoids; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Prospective Studies; Recurrence; Tacrolimus

Drug resistant idiopathic nephrotic syndrome (DRNS) remains a therapeutic dilemma. In this pilot study, the efficacy of the new fully humanised, anti-CD20 monoclonal antibody ofatumumab was tested in 4 children with persistence of proteinuria for at least 12 months in spite of a full drug approach (including rituximab). We used a low-dose 2-infusion ofatumumab model (300+700 mg/1.73 m(2) 2 weeks apart) using specified premedication. Transient normalisation of proteinuria (persisting for 2 months) was achieved in 1 child while another presented stable remission after 12 months; both had normal renal function. The outcome was not modified in the remaining 2 children presenting an impaired renal function. These results demonstrate that low-dose ofatumumab may induce remittance of proteinuria in children with a long story of DRNS and normal renal function. Further studies are needed to test whether higher doses of ofatumumab can also modify proteinuria in patients with impaired renal function.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Mycophenolic Acid; Nephrotic Syndrome; Pilot Projects; Rituximab; Tacrolimus; Treatment Outcome

Topics: Adolescent; Adrenal Cortex Hormones; Albuminuria; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Child; Child, Preschool; Cyclophosphamide; Drug Resistance; Female; Glomerular Filtration Rate; Humans; Mycophenolic Acid; Nephrotic Syndrome; Recurrence; Remission Induction; Rituximab; Tacrolimus; Withholding Treatment

Management of adults with steroid-resistant (SR) nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is a challenging task. Is tacrolimus (TAC) effective in this situation without serious adverse effects? This prospective study was done to answer this question.. In patients with SR nephrotic syndrome due to FSGS, oral TAC (0.1 mg/kg/day) was started targeting a trough level of 5-10 ng/mL along with oral prednisolone (0.15 mg/kg/day) for 48 weeks. In patients with complete remission (CR), TAC dose was reduced to a target of 3-6 ng/mL whereas in partial responders, TAC trough levels were kept at 5-10 ng/mL. TAC was discontinued in those with no remission at 24 weeks and was deemed TAC resistant. Outcome, namely CR and partial remission (PR), was assessed at the end of 24 and 48 weeks. All patients were prospectively followed for 60 weeks. Relapses after CR or PR were recorded; adverse effects, namely nephrotoxicity (>25% rise in creatinine), cosmetic effects, infections and hyperglycemia, were recorded every month.. A total of 44 SR-FSGS [not otherwise specified 33 (75%), tip lesion 03 (6.8%) and cellular variant 8 (18.1%)] were analyzed. Mean age was 25.16 ± 8.26 (18-51) years. Of 44 patients, CR and PR were achieved in 17 (38.6%) and 06 (13.6%) patients, respectively. TAC resistance was seen in 21 (47.7%) patients. Time taken to achieve remission was 15.2 ± 6 weeks. Five (21.7%) patients with CR had relapse on tapering the dose and seven (30.4%) after stopping TAC. Reversible nephrotoxicity was seen in seven (15.9%) and irreversible in four patients (9%). TAC-related diarrhea was the problem in 10 (22.7%), and infections were seen in 19 patients (43.1%). Impaired fasting glucose and diabetes mellitus were seen in 10 patients (22.7%).. TAC is an effective agent in the management of SR-FSGS. However, strict renal function and blood sugar monitoring is required due to its potential nephrotoxicity and diabetogenic potential.

Topics: Adolescent; Adult; Creatinine; Drug Resistance; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisolone; Prospective Studies; Recurrence; Remission Induction; Steroids; Tacrolimus; Young Adult

Tacrolimus has been used for idiopathic membranous nephropathy (IMN) therapy, but most patients who achieved remission showed a high relapse rate when tacrolimus was withdrawn after 6-12 months of therapy. We proposed that a prolonged therapeutic course should help reduce the relapse rate.. A total of 42 patients with nephrotic syndrome caused by IMN were randomly divided into short-term (n = 20) and long-term (n = 22) groups. All patients received initial treatment with tacrolimus and prednisone for 6 months, and afterward only the long-term patient group was tapered with low-dose tacrolimus until 24 months.. Over 85% of the patients achieved proteinuria reduction, serum albumin improvement and serum lipid recovery; the probability of remission in both groups was over 80% at 6 months. The remission rate was steady at over 80% after 12 and 24 months in the long-term group, but only 50 and 45%, respectively, in the short-term group. Nine patients (45%) relapsed in the short-term group after tacrolimus withdrawal, while not a single patient suffered recurrence in the long-term group. The concentration of tacrolimus remained similar between the two groups at 5-8 ng/ml during the initial 6 months, and was significantly decreased at 12 months compared to 6 months (p < 0.05), along with reduction of oral administration in the long-term group.. Combined therapy of tacrolimus with prednisone can relieve IMN significantly; prolonged tacrolimus treatment at a low blood concentration can alleviate the illness persistently, with a low recurrence rate and gratifying safety.

Topics: Adult; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Proteinuria; Serum Albumin; Tacrolimus; Treatment Outcome

The treatment of adult refractory idiopathic membranous nephropathy with steroid and other immunosuppressant-resistant nephrotic syndrome can be a significant challenge. The authors investigated the efficacy and safety of tacrolimus (TAC) as a promising regimen.. A prospective, multicenter trial was conducted in 9 nephrology centers from 2006 to 2008. Fourteen patients were enrolled. In conjunction with prednisone, TAC was started at 0.05 mg/kg/d, titrated to achieve a trough blood level of 5 to 10 ng/mL for the first 6 months, then reduced to 4 to 6 ng/mL for the subsequent 6 months. The primary endpoints included complete or partial remission. Secondary endpoints included relapse, change of clinical parameters and adverse events.. After 12 months, complete remission was achieved in 35.7% of patients and partial remission in 42.9%, yielding a response rate of 78.6%. Proteinuria, serum albumin, cholesterol, triglyceride and low-density lipoprotein were improved significantly (P < 0.001, P < 0.001, P = 0.002, P = 0.01, P = 0.004, respectively). Proteinuria and serum albumin were significantly improved (42.0% ± 13.2%, P = 0.02; 15.2% ± 4.5%, P = 0.01, respectively) even after the first month of treatment. One patient relapsed during the subsequent 6 months of follow-up. Adverse events included 2 cases of infection and 1 case each of hyperglycemia, hand tremor, sudden death (nondrug related) and diarrhea.. TAC plus prednisone may be an alternative therapeutic option for steroid and general immunosuppressant-resistant membranous nephrotic syndrome patients, with a favorable safety profile. However, given the limitation of a small number of patients in this trial, further study with a larger number and longer follow-up is needed.

Topics: Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Prospective Studies; Tacrolimus; Treatment Outcome

The optimal therapy for adult steroid-resistant nephrotic syndrome (SRNS) remains a therapeutic challenge. We investigated the efficacy and safety of tacrolimus as a promising regimen in Chinese adult patients.. A prospective, multicenter trial was conducted in 9 nephrology centers from 2006 to 2008, in patients with SRNS (defined as failure to respond to 1 mg/kg/day of prednisone for 8, and 16 weeks, in focal segmental glomerulosclerosis). Patients were treated with tacrolimus (TAC) plus prednisone for 12 months. TAC dose was titrated to achieve a target trough blood concentration of 5-10 ng/ml for the first 6 months and 4-6 ng/ml for the subsequent 6 months. The primary outcomes included complete or partial remission [complete remission (CR): proteinuria <0.3 g/24 h, with serum albumin ≥ 3.5 g/dl and stable renal function; partial remission (PR): proteinuria between 0.3 and 3.5 g/24 h and a decrease of at least 50 % from the baseline level, with serum albumin ≥ 3.0 g/dl and stable renal function]. Secondary end-points included relapse rate, changes of clinical parameters (proteinuria, serum albumin, and lipid profile) and adverse events.. Twenty-four patients with SRNS were enrolled. After 6 months of therapy, CR was achieved in 58.3 % of patients and PR in 16.7 %, yielding a final response rate of 75.0 %. The decrease in proteinuria was 43.1 ± 17.5 % after the first month of treatment (P < 0.001). Complete or PR was achieved in 6 of 8 patients with minimal change disease, 4 of 6 patients with mesangioproliferative glomerulonephritis (MsPGN), 6 of 7 patients with focal segmental glomerulosclerosis (FSGS), and all 2 patients with IgA nephropathy. Two patients (1 with MsPGN and 1 with FSGS) experienced relapses during the subsequent 6 months of follow-up. Adverse events included infection, hand tremor, diarrhea, acute reversible or persistent nephrotoxicity.. In conjunction with prednisone, TAC may be an alternative therapeutic regimen for adult SRNS patients. However, adverse events in these patients should be carefully monitored, especially at the beginning of treatment. Randomized controlled trials with longer follow-up are warranted.

Topics: Adult; Drug Resistance; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prednisone; Prospective Studies; Tacrolimus

This pilot study compared mycophenolate mofetil (MMF) and tacrolimus (Tac) in the treatment of severe membranous lupus nephritis (MLN).. This was a 24 month prospective, randomized, open-label multi-centre exploratory study on Chinese patients with biopsy-proven pure Class V MLN with nephrotic syndrome. Patients were randomized to treatment with either MMF or Tac, both in combination with prednisolone and the efficacy and tolerability outcomes were examined.. Sixteen patients were included, seven in the MMF and nine in the Tac treatment arm. At 24 months the complete response, partial response and overall response rates were 57.1% vs. 11.1% (P = 0.049), 14.3% vs. 44.4% (P = 0.197) and 71.4% vs. 55.6% (P = 0.515) in the MMF and Tac groups, respectively. The two groups had similar reduction of proteinuria and longitudinal profiles of serum albumin and creatinine levels. Serum creatinine remained stable in both groups, except in two patients who had a transient increase associated with high Tac blood levels. Adverse events in the MMF group included herpes zoster in one patient and reversible leucopenia in another, while in the Tac group four patients had severe infections and one developed new onset diabetes. No relapse occurred during the study period.. Both MMF and Tac when combined with corticosteroids are effective treatment options for severe MLN.

Topics: Adult; Biomarkers; Biopsy; Chi-Square Distribution; China; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Nephrotic Syndrome; Pilot Projects; Prednisolone; Prospective Studies; Serum Albumin; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

Topics: Adolescent; Chi-Square Distribution; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; India; Infusions, Intravenous; Kaplan-Meier Estimate; Logistic Models; Male; Nephrotic Syndrome; Odds Ratio; Prednisolone; Proportional Hazards Models; Prospective Studies; Proteinuria; Recurrence; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

An effective treatment for children with refractory nephrotic syndrome (NS), especially in those with cyclosporine (CsA)-resistant or CsA-intolerant NS, has yet to be established. Recently, the efficacy of multidrug therapy consisting of tacrolimus (Tac), mycophenolate mofetil (MMF) in combination with prednisolone (PDN) in adult patients with refractory NS has been reported. We successfully treated 14 consecutive children with refractory CsA-resistant or CsA-intolerant NS using combination therapy consisting of relatively low-dose Tac, mizoribine (MZR), which has a mechanism of action very similar to that of MMF, and PDN. There were no serious clinical toxicities. Of the 14 children, 9 with a mean age of 13.0 years had steroid-dependent NS (SDNS) and 5 with a mean age of 9.6 years had steroid-resistant NS (SRNS). All SDNS patients had minimal change disease (MCD), 4 with SRNS had focal segmental glomerulosclerosis (FSGS), and the remaining child had MCD on renal biopsy. All patients were in a prospective cohort, but were evaluated retrospectively. The mean follow-up from the initiation of multidrug therapy was 18.4 months in SDNS and 18.6 months in SRNS patients. At the last observation point, the calculated relapse rate and minimum dose of PDN required for maintenance of clinical remission after the start of multidrug therapy were significantly decreased compared with those prior to this therapy, while on CsA, in SDNS patients (0.4 ± 0.5 times/year vs 2.9 ± 1.5 times/year, P = 0.0077, and 0.3 ± 0.2 mg/kg on alternate days vs 0.5 ± 0.2 mg/kg on alternate days, P = 0.0184 respectively). All SDNS and two SRNS patients (40%) achieved complete remission, allowing further decreases in the minimal doses of PDN required for maintenance of clinical remission in most our patients. However, one patient with FSGS remained refractory to multidrug therapy and subsequently developed end-stage renal disease. These clinical observations, although preliminary and involving a small number of patients, suggest that multidrug therapy consisting of relatively low-dose Tac, MZR, and PDN might be effective and safe for treating children with refractory CsA-resistant or CsA-intolerant NS. However, further studies involving larger numbers of patients are needed.

Topics: Adolescent; Child; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Pilot Projects; Prednisone; Ribonucleosides; Tacrolimus; Young Adult

Idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults, is usually treated with corticosteroids in combination with cyclophosphamide or cyclosporine. A recent placebo-controlled study suggested that tacrolimus monotherapy was effective in IMN. However, the effectiveness of tacrolimus versus classic regimen and its potential nephrotoxicity remain inconclusive. This study evaluated the efficacy and safety of tacrolimus plus prednisone in patients with nephrotic IMN.. Seventy-three patients with nephrotic IMN were recruited in this multicenter randomized controlled trial, 39 receiving tacrolimus and prednisone, while 34 receiving cyclophosphamide and prednisone. Tacrolimus was given at 0.1 mg/kg/d initially and adjusted to a blood trough level at 5 to 10 ng/mL for 6 months and then reduced to 2 to 5 ng/mL in the subsequent 3 months.. Intention-to-treat analysis suggested that the remission rate at the end of the sixth month was significantly higher in tacrolimus group than that in cyclophosphamide group (85% versus 65%, P < 0.05). The decrease of proteinuria was significantly greater in tacrolimus group. At the end of the 12th month, the remission rates were comparable between these 2 groups. Patients treated with tacrolimus were more likely to develop glucose intolerance (or diabetes mellitus), infection, and hypertension. No obvious nephrotoxicity of calcineurin inhibitor was found in repeat renal biopsy.. Tacrolimus plus corticosteroids is an alternative therapeutic regimen for nephrotic IMN. The short-term efficacy might be better than cyclophosphamide plus prednisone.

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Treatment Outcome

To examine whether tacrolimus is more effective and safe than cyclosporine (CsA) in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS).. Randomized controlled trial, nonblind, parallel group.. Tertiary-care hospital; 41 consecutive patients with idiopathic SRNS, estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2), and histological characteristics showing minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis were randomly assigned to treatment with tacrolimus (n = 21) or CsA (n = 20).. Tacrolimus (0.1 to 0.2 mg/kg/d) or CsA (5 to 6 mg/kg/d) for 1 year; cotreatment with alternate-day prednisolone and enalapril.. Patients achieving complete remission (urinary protein-creatinine ratio < 0.2 g/g and serum albumin > or = 2.5 g/dL) or partial remission (urinary protein-creatinine ratio, 0.2 to 2 g/g, and serum albumin > or =2.5 g/dL) at 6 and 12 months; time to remission; proportion with relapses; side effects.. No patient was lost to follow-up. After 6 months of therapy, remission occurred in 18 (85.7%) and 16 patients (80%) treated with tacrolimus and CsA, respectively (relative risk [RR], 1.07; 95% confidence interval [CI], 0.81 to 1.41). Rates of remission at 12 months were also similar (RR, 1.14; 95% CI, 0.84 to 1.55). The proportion of patients who experienced relapse was significantly greater in those receiving CsA compared with tacrolimus (RR, 4.5; 95% CI, 1.1 to 18.2; P = 0.01). The decrease in blood cholesterol levels was greater with tacrolimus compared with CsA (difference in mean values, 45.1 mg/dL; 95% CI, 19.1 to 71.2). Persistent nephrotoxicity necessitating stoppage of medicine was seen in 4.7% and 10% patients, respectively. Cosmetic side effects (hypertrichosis and gum hypertrophy) were significantly more frequent in CsA-treated patients (P < 0.001).. Single-center study, small sample size, and short duration of follow-up.. Tacrolimus or CsA in combination with low-dose steroids show similar efficacy in inducing remission in patients with SRNS. Therapy with tacrolimus is a promising alternative to CsA in view of the lower risk of relapses and lack of cosmetic side effects.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Male; Microscopy, Fluorescence; Nephrotic Syndrome; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

This study was conducted to evaluate the safety and efficacy of tacrolimus (TAC) in children with SRNS. The study group comprised of 22 consecutive children with steroid-resistant nephrotic syndrome (SRNS) who were studied prospectively. TAC was initiated with a dose of 0.10 mg/kg/day, and the dose was increased to attain a trough level of 5.0-10.0 g/l. These patients were treated with concomitant prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). The mean age of onset was 7.33 +/- 5.9 years, and there were 20 boys and 2 girls. Of the 22 children, 9 had minimal change disease, 11 had focal segmental glomerulosclerosis and the other 2 had diffuse mesangial hypercellularity on histopathology. TAC had to be withdrawn in 3 children because of its side effects. Of the remaining 19 children who received adequate therapy and were able to achieve target levels, CR was seen in 16 (84%) children, 2 (10.5%) attained PR and 1 was nonresponsive. The mean time to achieve remission was 63.2 +/- 44 days and the mean dose of TAC was 0.18 +/- 0.07 mg/kg. The mean urine spot protein/creatinine ratios were significantly lower (0.33 +/- 0.58 vs. 13.5 +/- 21.9 mg/mg, p = 0.002) and the mean serum albumin levels were significantly higher (3.92 +/- 0.35 g/dl vs. 2.39 +/- 0.56 g/dl, p = 0.00005), as compared to those prior to starting TAC. The mean glomerular filtration rate values at the end of the study were similar to those prior to starting TAC (97.9 +/- 21.2 ml/min/1.73 m(2) vs. 96.4 +/- 18.4 ml/min/1.73 m(2), p = 0.30). The mean duration of follow-up was 290 +/- 126 days. This is the largest study so far on the safety and efficacy of TAC therapy in SRNS. Our results suggest that TAC is an effective therapeutic modality for SRNS, including the subgroup of children who are nonresponsive to the current therapeutic modalities like cyclophosphamide and cyclosporine.

Topics: Biopsy; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Dose-Response Relationship, Drug; Drug Resistance; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Prospective Studies; Steroids; Tacrolimus; Treatment Outcome

Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.

Topics: Adult; Blood Pressure; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Tacrolimus; Treatment Outcome

Steroid resistance and steroid dependence constitute a major problem in the treatment of minimal-change disease and focal segmental glomerulosclerosis (FSGS). Cyclophosphamide and cyclosporine are well-established alternative immunomodulating agents, whereas data on FK 506 (tacrolimus) are rare.. The present work provides data from 10 patients of an open, monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid-dependence, prednisolone was tapered off in presence oftacrolimus within one month.. Within 6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients (40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroid-refractory minimal-change), another patient became secondarily resistant to tacrolimus after an initial remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/- 1.4 - 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 - 64.6 +/- 1.9 g/l (p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 - 5.1 +/- 0.2 mmol/l), systolic blood pressure (131.4 +/- 7.1 - 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 103.2 +/- 15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4 of them (80%). Relapse occurred at tacrolimus levels between 2.6 and 6.9 ng/ml.. Our data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.

Topics: Adult; Blood Glucose; Blood Pressure; Blood Proteins; Creatinine; Drug Resistance; Drug Therapy, Combination; Female; Glomerulosclerosis, Focal Segmental; Humans; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Proteinuria; Steroids; Tacrolimus

Tacrolimus is a calcineurin inhibitor that has been increasingly used in transplant medicine. However, the efficacy and safety of combined therapy of low-dose tacrolimus and prednisone in the treatment of nephrotic syndrome (NS) with slight mesangial proliferation has not been reported.. Sixty patients with NS with slight mesangial proliferation were randomly divided into a prednisone therapy group (control), a combined low-dose tacrolimus (2 mg/day) and a prednisone therapy group (tacrolimus group). The efficacy and safety of tacrolimus was analysed. The initial dose of prednisone was 1 mg/kg per day and 30 mg/day in the control group and tacrolimus group, respectively. The duration of treatment was 6 months.. After a 6-month trial of combined low-dose tacrolimus and prednisone, complete remission was achieved in 29 patients (96.66%) and partial remission in one patient (3.33%). In the control group, complete remission was achieved in 27 patients (90%) and partial remission in three patients (10%). A significant improvement in proteinuria levels was observed in the tacrolimus group compared with the control group, starting at the second week and remaining throughout the study period. Furthermore, a significant improvement in serum albumin levels was observed in the tacrolimus group compared with the control group, starting at the first month and remaining until the third month. The main side-effect was obesity (100%) and acne (46.66%) in the control group. However, these adverse events were not observed in the tacrolimus group.. The results demonstrated that combined therapy of low-dose tacrolimus and prednisone is an effective and safe therapeutic method for NS with slight mesangial proliferation.

Topics: Adult; Cell Division; Cholesterol; Drug Therapy, Combination; Female; Glomerular Mesangium; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Proteinuria; Serum Albumin; Tacrolimus; Treatment Outcome; Triglycerides

The pharmacokinetics and pharmacodynamics of tacrolimus (TAC) vary greatly among individuals, hindering its precise utilization. Moreover, effective models for the early prediction of TAC efficacy in patients with nephrotic syndrome (NS) are lacking. We aimed to identify key factors affecting TAC efficacy and develop efficacy prediction models for childhood NS using machine learning algorithms.. This was an observational cohort study of patients with pediatric refractory NS.. Guangzhou Women and Children's Medical Center between June 2013 and December 2018.. 203 patients with pediatric refractory NS were used for model generation and 35 patients were used for model validation.. All patients regularly received double immunosuppressive therapy comprising TAC and low-dose prednisone or methylprednisolone. In this observational cohort study of 203 pediatric patients with refractory NS, clinical and genetic variables, including single-nucleotide polymorphism (SNPs), were identified. TAC efficacy was evaluated 3 months after administration according to two different evaluation criteria: response or non-response (Group 1) and complete remission, partial remission, or non-remission (Group 2).. Logistic regression, extremely random trees, gradient boosting decision trees, random forest, and extreme gradient boosting algorithms were used to develop and validate the models. Prediction models were validated among a cohort of 35 patients with NS.. The random forest models performed best in both groups, and the area under the receiver operating characteristics curve of these two models was 80.7% (Group 1) and 80.3% (Group 2). These prediction models included urine erythrocyte count before administration, steroid types, and eight SNPs (ITGB4 rs2290460, TRPC6 rs3824934, CTGF rs9399005, IL13 rs20541, NFKBIA rs8904, NFKBIA rs8016947, MAP3K11 rs7946115, and SMARCAL1 rs11886806).. Two pre-administration models with good predictive performance for TAC response of patients with NS were developed and validated using machine learning algorithms. These accurate models could assist clinicians in predicting TAC efficacy in pediatric patients with NS before utilization to avoid treatment failure or adverse effects.

Topics: Child; Cohort Studies; DNA Helicases; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Prednisone; Tacrolimus

Topics: Biomarkers; Humans; Immunosuppressive Agents; Machine Learning; Nephrotic Syndrome; Tacrolimus

Topics: Biomarkers; Humans; Immunosuppressive Agents; Machine Learning; Nephrotic Syndrome; Tacrolimus

Topics: Humans; Immunosuppressive Agents; Nephrotic Syndrome; Recurrence; Rituximab; Tacrolimus

The association between membranous nephropathy (MN) and Kimura's disease (KD) has been reported in recent years. The treatment, effect, and prognosis of KD are still unclear.. A 47-year-old KD patient developed a left axillary mass for 3 years and received surgical resection because of the lager mass in August 2016. Then he developed nephrotic syndrome 3 months later. Laboratory index revealed increased eosinophil count, decreased albumin and heavy proteinuria. Lymph node biopsy suggested KD, and renal biopsy suggested MN. He relapsed after a treatment with methylprednisolone (52 mg/d) alone and then tacrolimus (1.5 mg/12h) was added. The patient had no symptoms of relapse in the next 2 years.. The combination therapy of surgery, methylprednisolone, and immunosuppressive agents may be effective in KD with MN.

Topics: Angiolymphoid Hyperplasia with Eosinophilia; Glomerulonephritis, Membranous; Humans; Kimura Disease; Male; Middle Aged; Nephrotic Syndrome; Tacrolimus

Membranous nephropathy (MN) is the most common cause of glomerulopathy after hematopoietic cell transplantation (HCT), most often occurring in the setting of graft versus host disease (GVHD). Twenty percent of patients will fail to respond to standard therapy and may progress to end stage renal disease. Here we present the case of a pediatric patient who developed chronic oral GVHD more than one-year post-HCT, who subsequently developed nephrotic syndrome (anasarca, nephrotic range proteinuria, hypoalbuminemia) and had a renal biopsy consistent with MN. Treated with ibrutinib for her GVHD, and steroids, tacrolimus, and rituximab for her MN, she failed to achieve even partial remission of her kidney disease after 8 months. Due to steroid toxicity and 0% CD19 cells on lymphocyte subpopulation flow cytometry, the decision was made to trial plasma cell depletion therapy with daratumumab.. She received three doses of daratumumab at weeks 1, 4, and 17.. Her nephrotic syndrome resolved and her serum albumin was greater than 3.0 gm/dl by week 10. She was weaned off of both steroids and tacrolimus by week 16, at which time she had near-complete remission of her renal disease.. Daratumumab may be an important, novel therapeutic option for post-HCT MN patients who are not responsive to standard therapies.

Topics: Antibodies, Monoclonal; Child; Female; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Male; Nephrotic Syndrome; Steroids; Tacrolimus

The generalizability of numerous tacrolimus population pharmacokinetic (popPK) models constructed to promote optimal tacrolimus dosing in patients with primary nephrotic syndrome (PNS) is unclear. This study aimed to evaluate the predictive performance of published tacrolimus popPK models for PNS patients with an external data set.. We prospectively collected 223 concentrations from 50 Chinese adult patients with PNS who were undergoing tacrolimus treatment. Data on published tacrolimus popPK models for adults and children with PNS were extracted from the literature. Model predictability was evaluated with prediction-based and simulation-based diagnostics and Bayesian forecasting.. In prediction-based evaluation, none of the 11 identified published popPK models of tacrolimus had met a predefined criteria of a mean prediction error ≤  ± 20%, and the prediction error within ± 30% of the identified models didn't exceed 50%. Simulation-based diagnostics also indicated unsatisfactory predictability. Bayesian forecasting demonstrated amelioration in the model predictability with the inclusion of 2-3 prior observations. Moreover, the predictive performance of nonlinear models was not better than that of one-compartment models.. The prediction of tacrolimus concentrations for patients with PNS remains challenging; published models are not applicable for extrapolation to other hospitals. Bayesian forecasting significantly improved model predictability and thereby helped to individualize tacrolimus dosing.

Topics: Adult; Bayes Theorem; Child; China; Humans; Immunosuppressive Agents; Models, Biological; Nephrotic Syndrome; Tacrolimus

The study aimed to establish a population pharmacokinetic (PPK) model of tacrolimus for Chinese patients with nephrotic syndrome using the patient's genotype and Wuzhi capsule dosage as the main test factors.. Ninety-six adult patients with nephrotic syndrome, who were receiving tacrolimus treatment, were enrolled. A nonlinear mixed-effects model was used to determine the influencing factors of interindividual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10,000 Monte Carlo simulations were performed.. The 1-chamber model of first-order absorption and elimination was the most suitable model for the data in this study. The typical population tacrolimus clearance (CL/F) value was 16.9 L/h. The percent relative standard error (RSE%) of CL/F was 12%. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F. In CYP3A5 homozygous mutation carriers, the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were coadministered glucocorticoids was 1.23-fold higher than that of the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme.. An improved tacrolimus PPK model for patients with nephrotic syndrome was established, and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus, facilitating the selection of a more economical and safe administration regimen.

Topics: Adult; China; Glucocorticoids; Humans; Immunosuppressive Agents; Models, Biological; Monte Carlo Method; Nephrotic Syndrome; Tacrolimus

The present study aimed to investigate the efficacy and safety of tacrolimus for treating incipient minimal change disease in adults. The clinical data of 52 adult patients with minimal change disease of nephrotic syndrome diagnosed by renal biopsy in the First affiliated hospital of Zhengzhou University between August 2013 and August 2015 were retrospectively analyzed. According to the treatment plan, the patients were divided into a tacrolimus group and a glucocorticoid group. The efficacy and safety of tacrolimus in the treatment of minimal change disease in adult patients was analyzed and compared with that of glucocorticoids. The results revealed that the baseline characteristics of the two groups were similar (P>0.05). At 24 weeks, there was a significant difference in serum albumin between the two groups (P<0.01). The serum albumin levels of tacrolimus group was higher compared with the glucocorticoid group. In addition, the complete remission rates in the tacrolimus and glucocorticoid groups were 93.75 and 77.8%, respectively (P=0.095), and the mean complete remission time was 6.33±4.21 and 5.14±2.45 weeks, respectively (P=0.175). The relapse rate was 12.5 and 22.2% in the tacrolimus and glucocorticoid groups, respectively (P=0.368). During the follow-up, in tacrolimus group, the incidence of new onset diabetes or impaired glucose tolerance, osteoporosis, infection, abnormal liver function, Cushing's syndrome, acne and gastrointestinal symptoms were significantly less than those of glucocorticoids (P<0.05). In conclusion, tacrolimus treatment after short-time intravenous methylprednisolone is an effective treatment option with fewer adverse effects in adult onset minimal change disease.

Topics: Adult; Glucocorticoids; Humans; Immunosuppressive Agents; Methylprednisolone; Nephrosis, Lipoid; Nephrotic Syndrome; Retrospective Studies; Serum Albumin; Tacrolimus; Treatment Outcome

BACKGROUND Nephrotic syndrome caused by minimal mesangial lupus nephritis is considered rare. Nephrotic syndrome can be caused by minimal mesangial lupus nephritis with diffuse epithelial foot-process effacement and lupus podocytopathy. CASE REPORT A 23-year-old Japanese woman diagnosed with mixed connective tissue disease was admitted because of weight gain and generalized edema for 2 weeks prior to admission. She had butterfly-shaped erythema on her cheeks, proteinuria, leukocytopenia with lymphocytopenia, and hypoalbuminemia. She was positive for antinuclear antibodies, and specific autoantibodies were only positive for the ribonucleoprotein (RNP) antigen. She was diagnosed with systemic lupus erythematosus. Renal biopsy showed minor glomerular abnormalities, and immunofluorescence revealed peripheral deposits of IgM and complement C3c. Electron microscopy revealed diffuse podocyte foot-process effacement of >80% of the capillary loop surfaces, with only a few subendothelial deposits. Consequently, we diagnosed minimal mesangial lupus nephritis with lupus podocytopathy. On hospital day 4, we administered 1000 mg/day of methylprednisolone for 3 days, followed by prednisolone 50 mg/day, but proteinuria persisted. On day 12, we administered tacrolimus (3 mg/day). Proteinuria improved and then disappeared on day 17. Prednisolone was gradually tapered and stopped after 3 years, although tacrolimus 3 mg/day was continued. No flare-up was observed 4 years after admission. CONCLUSIONS Tacrolimus showed good efficacy in this case of minimal mesangial lupus nephritis with lupus podocytopathy. Prospective and randomized controlled trials should be conducted to demonstrate the efficacy of tacrolimus for this indication.

Topics: Adult; Female; Humans; Induction Chemotherapy; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Prospective Studies; Proteinuria; Tacrolimus; Young Adult

Given its narrow treatment window, high toxicity, adverse effects, and individual differences in its use, we collected and sorted data on tacrolimus use by real patients with kidney diseases. We then used machine learning technology to predict tacrolimus blood concentration in order to provide a basis for tacrolimus dose adjustment and ensure patient safety.. This study involved 913 hospitalized patients with nephrotic syndrome and membranous nephropathy treated with tacrolimus. We evaluated data related to patient demographics, laboratory tests, and combined medication. After data cleaning and feature engineering, six machine learning models were constructed, and the predictive performance of each model was evaluated via external verification.. The XGBoost model outperformed other investigated models, with a prediction accuracy of 73.33%, F-beta of 91.24%, and AUC of 0.5531.. Through this exploratory study, we could determine the ability of machine learning to predict TAC blood concentration. Although the results prove the predictive potential of machine learning to some extent, in-depth research is still needed to resolve the XGBoost model's bias towards positive class and thereby facilitate its use in real-world settings.

Topics: Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus; Technology; Treatment Outcome

FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F-actin). FKBP12 interacted with the actin-associated proteins 14-3-3 and synaptopodin. RNA silencing for FKBP12 reduced 14-3-3 expression, F-actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F-actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.

Topics: Actin Cytoskeleton; Animals; Female; HEK293 Cells; Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Rats; Rats, Wistar; Tacrolimus; TOR Serine-Threonine Kinases

The blood concentration of tacrolimus can be affected by co-administrated drugs. The objective is to draw more attention to herb-drug interactions in China, where herbal medicines are commonly used.. The blood concentration of tacrolimus in a girl with refractory nephrotic syndrome decreased nearly a half despite no change in dose. Nebulizer therapy, cyclophosphamide and a compound Chinese herbal medicine were the only additional treatments than usual.. The most possible cause of the decrease in tacrolimus concentration was the administration of Radix Astragali among compound Chinese herbal medicine granules.

Topics: Astragalus propinquus; Child; Drugs, Chinese Herbal; Female; Herb-Drug Interactions; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

The present study aimed to optimize the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on population pharmacokinetics and pharmacogenomics.Demographic characteristics, concomitant medication, laboratory data, pharmacogenomics were collected to build the model and Monte Carlo was used to simulate the optimization of initial dosing scheme.Weight, the polymorphisms of

Topics: Child; Cytochrome P-450 CYP3A; Drug Combinations; Drugs, Chinese Herbal; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Pharmacogenomic Variants; Tacrolimus

Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS.. Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated.. High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

Topics: Case-Control Studies; Child; Child, Preschool; Diarrhea; Drugs, Chinese Herbal; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Nephrotic Syndrome; Retrospective Studies; Risk Factors; Tacrolimus

Tacrolimus dosing is routinely tailored based on its trough level (C0) drawn by therapeutic drug monitoring in pediatric patients with primary nephrotic syndrome. However, this concentration is often inaccurate owing to inappropriate practice, such as deviation of sampling time (DST). The quantitative relationship between DST and C0 remains unclear.. Tacrolimus concentration at nominal sampling times (12 hours after last dose) and 32 deviation scenarios (12 ± 4 hours every 15 minutes) was predicted using a previously validated population pharmacokinetic model based on 162 scenarios of 100 primary nephrotic syndrome patients involved in the population pharmacokinetic model and derived virtual patients. Concentration error (CE) and relative CE (RCE) were evaluated, and the correlation between DST and RCE was evaluated by subgroup analysis using linear regression. Ultimately, the inappropriate dosing possibly misled by incorrect C0 was simulated in a real-patient cohort according to the target range (5-10 ng/mL).. Approximately 7% of RCE was caused at every 1-hour of DST. DST was the most major contributor of RCE (r = 0.773-0.804). Patients with early sampling, older age, high body weight, high dose, low aspartate transaminase level, high corticosteroid dose, and without combination of azole antifungal agents were revealed to have high RCE. Approximately 7%-36% and 9%-25% of inappropriate dose tailoring may be caused by early and delayed sampling, respectively. In addition, patients with early sampling or high-dose tacrolimus had a higher risk of inappropriate dosing than patients with delayed sampling [hazard ratio = 1.53, 95% confidence interval (CI): 1.03-2.27, P = 0.048], and low-dose tacrolimus (P < 0.0001).. A moderate bias of concentration and dose tailoring was revealed within 4 hours of DST. In addition, a high risk of bias was found in patients with early sampling and high-dose tacrolimus.

Topics: Adolescent; Adrenal Cortex Hormones; Age Factors; Antifungal Agents; Area Under Curve; Aspartate Aminotransferases; Body Weight; Child; Child, Preschool; Computer Simulation; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Tacrolimus

Topics: Area Under Curve; Child; Cytochrome P-450 CYP3A; Drug Monitoring; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

Topics: Acute Kidney Injury; Anti-Inflammatory Agents; Diuretics; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Nephrotic Syndrome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Rituximab; Tacrolimus; Transplantation, Homologous

Skin and soft tissue infection (SSTI) is the most common of infectious diseases with high morbidity and mortality. However, the clinical characteristics of SSTI in patients with nephrotic syndrome (NS), especially in those patients who received immunosuppressive therapy, are still lacking. The present study was conducted to investigate the clinical characteristics and outcomes of SSTI in patients with NS.. A retrospective study was carried out among the patients diagnosed with NS and SSTI, who have priorly received or currently have been receiving immunosuppressive therapy between April 2011 and January 2019; the clinical profile included patient's baseline characteristics, clinical presentation, microbiological findings, treatment, and prognosis.. A total of 70 patients were analyzed. Results showed that more than half of the patients were under 35 years old, and moderate infection was the most common type of SSTI. Leg and cellulitis were the most common site of lesion and the typical clinical manifestation of SSTI, respectively. Patients in the severe infection group have a higher level of procalcitonin (PCT) and C-reactive protein (CRP), while a lower level of albumin, CD4. Patients with NS and SSTI usually showed a satisfying outcome with proper anti-infection treatment, but severe SSTI can be life-threatening.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; C-Reactive Protein; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cellulitis; Child; Cyclophosphamide; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Leg; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Procalcitonin; Retrospective Studies; Serum Albumin; Severity of Illness Index; Soft Tissue Infections; Tacrolimus; Young Adult

Primary nephrotic syndrome (PNS) is one of the most common primary glomerular diseases in children. Patients complicated nephrotic syndrome with pancreatic lesions are rarely reported, and the clinical manifestations in children are atypical. This study has observed the incidence, clinical types, and prognosis of acute pancreatitis (AP) in children with primary nephrotic syndrome, and analyzed its related factors, early diagnosis, and treatment.Seven children with PNS and AP in Shanghai Children's Hospital from January 2015 to December 2017 were reviewed. The clinical data including age, height, weight, body mass index (BMI), diet, biliary tract disease, PNS durations, drugs, proteinuria, creatinine, glucose, glycated hemoglobin, amylase and lipase, albumin, cholesterol, triglyceride, ultrasound, computerized tomography (CT), renal pathology and estimated glomerular filtration rate (eGFR) were retrospectively analyzed. All patients were followed for >2 years.Ten in 589 patients with PNS were detected pancreatic lesions by abdominal ultrasound. Seven were diagnosed as AP, which the incidence was 1.2%. Only 1 of 7 patients had elevated serum amylase. Lesions of pancreas were found by ultrasound and/or enhanced CT. Four of 7 patients had been treated with tacrolimus. All patients with AP were improved after octreotide acetate injection and supportive treatment. Only 1 patient suffered recurrent AP during the relapse of PNS 10 months later.AP in children with PNS is not common, and the clinical manifestations are not typical. Abdominal ultrasound and enhanced CT are of high value in diagnosis. The adverse effects of tacrolimus should be concerned. Early diagnosis and timely treatment can be helpful for a prognosis.

Topics: Adolescent; Child; Child, Preschool; China; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Incidence; Kidney; Male; Nephrotic Syndrome; Octreotide; Pancreatitis; Prognosis; Recurrence; Retrospective Studies; Tacrolimus

Tacrolimus (FK506), an immunosuppressant, is a popular option for combination drug treatment of nephrotic syndrome. It is well-tolerated by most patients and rarely induces anaemia. We report a case of anaemia in a girl with immunoglobulin A (IgA) nephropathy that occurred after FK506 treatment.. A 12-year-old girl received a combination treatment of FK506 and hormones. During the therapy, the red blood cells (RBCs), haemoglobin (HGB) and red blood cell-specific volume (HCT) continued to decrease following an increase in the whole blood concentration of FK506. Moderate anaemia was found in the patient. The levels of RBC, HGB and HCT gradually improved after discontinuation of the FK506 and symptomatic treatment.. The mechanism by which FK506 induces anaemia remains unclear. The genetic polymorphisms of CYP3A5 or the chemical structure may have an effect in the onset of the disease. Thus, when a patient presents with a newly developed anaemic condition during FK506 treatment, after elimination of haematuria and any underlying disease, the possibility of the effect of the medication should be considered.

Topics: Anemia; Child; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

Chronic nephrotoxicity with potentially irreversible lesions is a major concern regarding calcineurin inhibitor (CNI) treatment in children with severe forms of idiopathic nephrotic syndrome (INS).. We retrospectively included all children on CNI for steroid-dependent INS with a duration of CNI treatment of more than 1 year. Only patients in whom CNI could not be replaced by mycophenolate mofetil were included. All included patients underwent a kidney biopsy. All results were expressed as median and range. Twenty-one children (6 girls) were included. Age at disease onset was 49 (29-66) months and treatment duration on CNI was 30 (20-45) months. Age at kidney biopsy was 108 (78-170) months. Number of relapses was 7 (3-9) since disease onset. Serum creatinine level was transiently and moderately increased in two patients. Kidney biopsy revealed minimal change disease in 20/21 patients and focal segmental glomerulosclerosis in 1/21. Evidence for chronic CNI nephrotoxicity was found in one patient revealed by arteriolar hyalinosis and fibrosis in 50% of glomeruli.. CNI-induced chronic nephrotoxicity was infrequent. In patients who require long-term and/or high-dose CNI treatment, kidney biopsies might be useful to exclude chronic CNI-induced lesions.

Topics: Child, Preschool; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Renal Insufficiency, Chronic; Retrospective Studies; Tacrolimus

Nephrotic syndrome (NS) is one of the commonest pediatric renal disorders. Most of these patients are steroid responsive. About 10%-20% of children with new onset NS are resistant to steroid treatment. Patients who are resistant to steroids have limited treatment options such as calcineurin inhibitors (CNIs), mycophenolate mofetil (MMF) and rituximab. Despite several studies had documented that tacrolimus is superior to cyclosporine A (CsA) and MMF in treating SRNS but there are no studies on the efficacy of tacrolimus in treating CsA and MMF resistant NS in pediatric populations. Study objective was to evaluate the role of tacrolimus in treating refractory idiopathic nephrotic syndrome .One hundred-twenty patients with idiopathic nephrotic syndrome were included in the study. Patients with steroid resistant NS were given cyclosporine (CsA) (first step protocol). In patients with cyclosporine resistant NS a combination of CsA+ MMF was given as a second step protocol. Unresponsive patients received tacrolimus as a third step treatment protocol. Tacrolimus was given at a starting dose of 0.1mg/kg/day then the dose was modified according to serum trough levels and patients were followed up for 12 months to evaluate the outcome. Out of 120 patients, 15 were both cyclosporine and MMF resistant and received tacrolimus. Tacrolimus had induced remission in 11 (73.3%) patients during the 1st 6 months of therapy. Eight patients achieved complete remission and three patients had partial remission.Conclusions: Tacrolimus is effective in treating refractory multi-drug resistant NS with favorable outcomes in childhood onset NS.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Protocols; Cyclosporine; Drug Resistance; Female; Humans; Male; Mycophenolic Acid; Nephrotic Syndrome; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Child; Child, Preschool; Cytochrome P-450 CYP3A; Diltiazem; Drug Interactions; Drug Resistance; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Retrospective Studies; Tacrolimus; Treatment Outcome

The aims of this study were to investigate the population pharmacokinetic (PPK) characteristics of tacrolimus in Chinese children with nephrotic syndrome and to apply it in clinical practice.. A total of 137 concentrations from 61 patients were collected from routine therapeutic drug monitoring data between 2011 and 2018. Population modeling was performed with the nonlinear mixed-effects model (NONMEM) program, using a one-compartment model with first-order absorption and elimination. The mean population estimate values of clearance (CL/F) and volume of distribution (V/F) were determined. Common demographic and clinical variables were tested for their influence on these parameters. External validation was conducted, and Monte Carlo simulation, based on the final model, was carried out to determine optimal dosage regimen.. Age and body weight were the covariates that displayed a significant influence on CL/F and V/F according to the final regression model. Goodness-of-fit plots, bootstrap outcomes, and external validation confirmed the relatively good stability and prediction capability of the model. The interindividual variability of CL/F was 31.10%, and the residual variability was 0.91 ng/mL. Mean prediction error (MPE, %) and Mean absolute prediction error (MAPE, %) were 10.3% and 16.6%, respectively. Monte Carlo simulation based on the final model was carried out to determine optimal dosage regimen.. A PPK model of tacrolimus in children with nephrotic syndrome was developed. Age and bodyweight could partly explain the interindividual variability in the CL/F and V/F of tacrolimus. The final model could be used to accurately predict tacrolimus individual pharmacokinetic parameters and assist in dosage optimization.
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Topics: Child; China; Humans; Immunosuppressive Agents; Monte Carlo Method; Nephrotic Syndrome; Nonlinear Dynamics; Tacrolimus

Topics: B-Lymphocytes; Child; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Recurrence; Rituximab; Tacrolimus

The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients.. Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus.. The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers.. A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Nephrotic Syndrome; Polymorphism, Single Nucleotide; Tacrolimus; Young Adult

Topics: Animals; Animals, Genetically Modified; Cyclosporine; Disease Models, Animal; Disease Progression; Drug Resistance; Gene Knockout Techniques; Glucocorticoids; Humans; Immunosuppressive Agents; Membrane Proteins; Monomeric GTP-Binding Proteins; Nephrotic Syndrome; Podocytes; Proteinuria; Signal Transduction; Tacrolimus; Treatment Outcome; Zebrafish; Zebrafish Proteins

Membranous nephropathy (MN) caused by disease-modifying antirheumatic drugs is relatively common in patients with rheumatoid arthritis (RA). However, MN rarely occurs due to RA itself. We describe a 61-year-old woman with RA who showed nephrotic syndrome. She was admitted because of systemic edema and severe arthritis. She had a long history of RA successfully treated with methotrexate (MTX), but discontinued all treatments 4 years before hospitalization. She had never been treated with bucillamine or gold. Laboratory test results were positive for anti-cyclic citrullinated peptide antibody and negative for anti-nuclear antibody. Renal pathologic findings were compatible with MN. Immunofluorescence microscopy showed IgG, IgA, κ, λ, and C3 along the glomerular capillary wall, whereas deposition of IgM or C1q was not detected. In terms of the IgG subclasses, only IgG2 findings were positive. Results for glomerular antigen and serum antibody for M-type phospholipase A2 receptor and thrombospondin type 1 domain-containing 7A were negative. HLA type did not include the HLA-DQA1 gene that is a concern in primary MN (PMN). She responded to intensive immunosuppressive therapy consisting of prednisolone, tacrolimus, and MTX with a parallel reduction of proteinuria. Based on assessments for differentiating PMN from secondary MN (SMN), the diagnosis of the present case was incompatible with PMN. Taken together, we consider that SMN in the present case was due to RA itself rather than drug-induced MN.

Topics: Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Female; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Methotrexate; Middle Aged; Nephrotic Syndrome; Prednisolone; Proteinuria; Tacrolimus; Treatment Outcome

The present study aimed to explore the equivalence of CHL and tacrolimus (TAC), despite reports regarding the efficacy and safety of TAC in treating SRNS patients.. A retrospective cohort study of CHL or TAC treatment was performed by collecting the medical records of SRNS patients with a pathological classification of focal segmental glomurular sclerosis (FSGS) or membranous nephropathy (MN) from December 2008 to December 2014 in a 3A grade hospital in southern China. The treatment regimen includes 6 months of induction therapy and a subsequent 6 to 30 months of maintenance therapy, which were evaluated by the scheduled follow-up and the detection of proteinuria and serum creatinine levels. The treatment outcomes were classified as complete remission, partial remission or no remission.. In a total of 146 SRNS patients, CHL treatment showed a higher proportion of complete remission (27.8% vs 14.9%) or partial remission (52.8% vs 37.8%) compared to TAC treatment (P < 0.10) at the stage of induction therapy. The CHL treatment of SRNS patients with FSGS showed better efficacy than treatment of the TAC group, but the difference of efficacy in the pathological type of MN between CHL and TAC group was not significant (P > 0.10). During maintenance therapy, the difference between the CHL and TAC groups was not significant in the SRNS patients with FSGS or MN (P > 0.10). In addition, the difference of adverse effects between CHL and TAC group was not significant (P > 0.10), although there was a slightly higher proportion of nausea and vomiting in the CHL group.. The non-inferior efficacy of CHL treatment on the SRNS patients with FSGS or MN compared to TAC treatment, which highlighted CHL can be considered to be alternative treatment for SRNS patients in the clinical setting.

Topics: Adult; Drug Resistance; Female; Humans; Male; Mechlorethamine; Nephrotic Syndrome; Remission Induction; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome; Young Adult

The efficacy of tacrolimus (TAC) is variable in the treatment of nephrotic syndrome (NS), which might be related to genetic variation among patients. Therefore, we aim to investigate the effects of CYP3 A4, CYP3 A5 and ABCB1 gene polymorphisms on the clinical efficacy of TAC in the treatment of NS patients. Methods 100 NS patients were treated with TAC and prednisone and followed up for 3 months. Genotype differences (CYP3 A4*1G, CYP3 A5*3, ABCB1 1236C > T and ABCB1 2677G > T/A) were detected by Sanger sequencing. The clinical efficacy was evaluated by the 24 h urinary protein quantitation, albumin, renal function and the degree of edema. Multivariable logistic regression was used to analyze the effect of gene polymorphisms on the clinical efficacy of TAC.. There were 35 patients (35%) with complete remission, 43 patients (43%) with partial remission, 22 patients (22%) without remission, and no patients with recurrence. For CYP3A4, there were 56, 42, and 2 patients with *1/*1, *1/*1G and *1G/*1G genotype, respectively. For CYP3A5, there were 8, 36 and 56 cases with*1/*1, *1/*3 and *3/*3 genotype, respectively. For ABCB1 C1236T, there were 10, 44, and 46 cases with 1236CC, 1236CT and 1236TT genotype, respectively. For ABCB1 G2677 T/A, there were 13, 57, and 30 patients with 2677GG genotype, 2677GT/GA genotype and 2677TT/AA/TA genotype, respectively. The mutant allele frequencies of CYP3A4*1G, CYP3A5*3, ABCB1 C1236T and ABCB1 G2677 T/A were 23%, 74%, 68% and 58.5%, respectively. Results reveal that the gene polymorphisms of CYP3A4 and CYP3A5 and CCB do not affect the clinical efficacy of TAC. For ABCB1 C1236T,TT genotype can increase the effectiveness 12.085 times compared with CC and CT genotype (P = 0.018, OR = 12.085, 95%CI 1.535-95.148). For ABCB1 G2677 T/A, the clinical efficacy of patients with mutant genotype is 8.683 times than that of wild-type and heterozygous patients (P = 0.042, OR = 8.683, 95%CI 1.080-69.819). Overweight patients can improve the clinical efficacy by 15.838 times (P = 0.020, OR = 15.838, 95%CI1.550-161.788).. ABCB1 C1236T, ABCB1 G2677 T/A genotype and BMI are probably the factors influencing the clinical efficacy of TAC in treating patients with NS.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily B; Child; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Polymorphism, Single Nucleotide; Tacrolimus; Treatment Outcome; Young Adult

Topics: Aged; Antiviral Agents; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Remission Induction; Ribavirin; Sofosbuvir; Tacrolimus

Topics: Adrenal Cortex Hormones; Child; Humans; Nephrotic Syndrome; Precision Medicine; Rituximab; Tacrolimus

Patients with difficult-to-treat idiopathic nephrotic syndrome (INS), steroid-dependent nephrotic syndrome (SDNS), or frequently relapsing nephrotic syndrome (FRNS) require long-term immunosuppressive therapy. Rituximab offers an alternative treatment for patients with disease that has not responded to multiple therapies.. Our objective was to determine the efficacy and safety of rituximab in adult patients with difficult-to-treat (SDNS or FRNS) INS.. We performed a retrospective multicenter study that included 50 adults with difficult-to-treat INS in six Spanish centers. All patients were treated with steroids in combination with another immunosuppressant: 28 patients received rituximab as the additional treatment (rituximab group), and the other 22 patients not treated with rituximab served as the control group.. Of the patients treated with rituximab, 23 (82%) experienced complete remission, 20 (71%) had no relapses after receiving rituximab, and 13 (46%) did not receive any immunosuppressant. Of those in the control group, 14 (63%) experienced complete remission, including eight without immunosuppressants (29%). The rituximab group experienced highly significant reductions in total number of relapses per year (p < 0.001), proteinuria (p = 0.03), steroid doses (p = 0.002), and tacrolimus doses (p = 0.001). Mean follow-up after rituximab was 31 ± 26 months (range 8-86). The need for steroids and other immunosuppressants to achieve sustained remission was lower in the rituximab group than in the control group.. Rituximab treatment was safe and well tolerated. It effectively reduced the incidence of relapses and need for maintenance immunosuppressive therapy in adults with difficult-to-treat INS.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Immunological; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Male; Middle Aged; Nephrotic Syndrome; Recurrence; Retrospective Studies; Rituximab; Spain; Steroids; Tacrolimus; Young Adult

Calcineurin inhibitors (CNI), mycophenolate mofetil (MMF), and levamisole are common treatment choices for patients with frequently relapsing (FRNS) and steroid-dependent nephrotic syndrome (SDNS).. Tacrolimus was associated with a higher rate of 30-month relapse-free survival when compared to MMF (61.7 vs. 38.5 %, p < 0.001), or levamisole (61.7 vs. 24 %, p < 0.001). However, relapse rate increased almost threefold once tacrolimus was stopped, resulting in a higher relapse rate per patient-year when compared to the MMF group (2.0 vs. 1.5, p = 0.013). The cumulative prednisolone dose per patient during the last year of the study period was also increased among tacrolimus group in comparison with MMF group (96.4 vs. 74.4 mg/kg/year, p = 0.004). Independent of the impact of drug choice, the relapse risk was higher in patients with steroid dependency at baseline (HR 2.14, 95 %CI 1.79-2.96, p < 0.0001). In comparison with few minor adverse events in other two cohorts, several serious adverse events were documented in the tacrolimus group.. Although there are serious safety concerns regarding tacrolimus, it is more effective than MMF or levamisole in maintaining relapse-free survival. However, unlike MMF, the relative efficacy of tacrolimus in preventing further relapses is seen only when the patient is on the drug. Taking together the long-term efficacy and safety data observed, MMF appears as a safe and effective alternative to tacrolimus in managing pediatric FRNS/SDNS.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Disease-Free Survival; Drug Administration Schedule; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Levamisole; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisolone; Recurrence; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Approximately 30-40% of children with steroid sensitive nephrotic syndrome have frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Mycophenolate mofetil (MMF) and tacrolimus (TAC) are often alternative treatment choices for these patients.. A single-center prospective study was conducted to compare the efficacy of MMF or TAC in reducing relapses and maintaining remission in children with FRNS or SDNS. Of the 72 recruited patients, either MMF (20∼30 mg/kg/d, n = 34) or TAC (0.05∼0.15 mg/kg/d, n = 38) was administered for 12 months.. The mean 6-month relapse rates decreased from 2.56 episodes before therapy to 0.76 episodes in the first 6 months after therapy (c(2) = 44.362, p < 0.001) and 0.67 in the next 6 months (c(2) = 37.817, p < 0.001) in the MMF group. In the TAC group, the mean 6-month relapse rates decreased from 2.39 episodes before therapy to 0.41 episodes in the first 6 months after therapy (c(2) = 62.242, p < 0.001) and 0.42 in next 6 months (c(2) = 67.482, p < 0.001). No significant difference in the relapse rate was found between the groups (before therapy, c(2) = 0.902, p = 0.637; first 6 months, c(2) = 5.358, p = 0.147; second 6 months, c(2) = 4.089, p = 0.252). And there was also no significant difference in cumulative sustained remission and the incidence of adverse events between two groups.. In combination with low-dose steroids, MMF or TAC presented similar efficacy in maintaining remission in children with FRNS/SDNS in the present study. Therapy with MMF or TAC is a promising strategy with a moderate risk of side effects in children who are steroid sensitive but have FRNS/SDNS.

Topics: Age Factors; Biopsy; Child; Child, Preschool; China; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Mycophenolic Acid; Nephrotic Syndrome; Prospective Studies; Recurrence; Remission Induction; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles ofCNremained in each type of the cells are not well understood yet. ACNinhibitor (CNI) has been used for steroid-resistant nephrotic syndrome. ACNIis assumed to ameliorate proteinuria by preventing the overproduction of T-cell cytokines. However, recent reports suggest thatCNIhas a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell-cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized thatCNIhas an effect on theSD In this study, we analyzed the expression ofCNin physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of theSD We observed thatCNis expressed at theSDin normal rat and human kidney sections and has an interaction with nephrin. The staining ofCNat theSDwas reduced in the nephrotic model, whileCNactivity in glomeruli was increased. We also observed that the treatment with tacrolimus, aCNI, in this nephrotic model suppressed the redistribution ofCN, nephrin, and otherSDcomponents and ameliorated proteinuria. These observations suggested that the redistribution and the activation ofCNmay participate in the development of theSDinjury.

Topics: Animals; Antibodies, Monoclonal; Calcineurin; Calcineurin Inhibitors; Cell Line; Child; Disease Models, Animal; Female; Humans; Intercellular Junctions; Male; Membrane Proteins; Mice; Nephrotic Syndrome; Podocytes; Protein Transport; Proteinuria; Rats, Wistar; Tacrolimus; Time Factors

Although tacrolimus therapy is not the first-line therapy for childhood nephrotic syndrome, it is often used instead of cyclosporine to ameliorate the side effects. The pharmacokinetics (PK) of tacrolimus (Tac) can be influenced by many conditions, and it has a high plasma protein binding. The Tac PK during relapse and remission of childhood nephrotic syndrome has not been well described.. We performed 14 PK profiles (with measurements before intake and 0.5, 1, 2, 4, and 12 hours postintake) in 7 children with steroid-resistant nephrotic syndrome at week 1 (all nephrotic) and week 16 after Tac therapy (all in remission). These data were compared with historical PK data of 161 PK profiles in 87 pediatric renal transplant recipients with measurements before intake and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postintake. Tac levels were measured using the Abbott Tacro II assay. We used descriptive statistics to generate percentiles and compared these with those of patients with steroid-resistant nephrotic syndrome.. The median age of patients with nephrotic syndrome was 3.2 years (range 2.5, 17.2), male gender 71.4%, significantly younger than the control group. Median Tac dose was similar during both PK profiles (0.11 mg·kg·d at week 1 versus 0.13 mg·kg·d at week 16, P = 0.81). There were no statistically significant differences in median dose-normalized area-under-the-time-concentration profiles, peak concentration, time to reach peak concentration, and Tac trough levels. Individual dose-normalized Tac levels for each time point during the PK profile were also not different (P = 0.81).. We conclude that Tac PK profiles are unaltered during relapse of nephrotic syndrome.

Topics: Adolescent; Area Under Curve; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Recurrence; Tacrolimus; Time Factors

Topics: Adolescent; Adult; Calcineurin Inhibitors; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Female; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Phospholipases A2; Prednisolone; Proteinuria; Receptors, Phospholipase A2; Recurrence; Respiratory Tract Infections; Tacrolimus; Treatment Outcome; Young Adult

To compare the efficacy of tacrolimus versus cyclosporine (Calcineurin Inhibitors) in the management of childhood steroid-resistant nephritic syndrome (SRNS).. Quasi-experimental study.. Department of Paediatric Nephrology at The Children's Hospital and Institute of Child Health, Lahore, from August 2014 to September 2015.. Patients of either gender aged 1 - 12 years, with the diagnosis of mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal-change disease (MCD) were included. Patients were assigned into two groups, one given tacrolimus in dose of 0.1 - 0.2 mg/kg/day in two divided doses, and other given cyclosporine in dose of 150 - 200 mg/m2/day in two divided doses along with oral steroids 30 mg/m2/day in divided doses, followed by alternate day with tapering dosage. Trough drug levels were done with dose adjustment accordingly. Patients were monitored and followed for the response to treatment and adverse effects of these two calcineurin inhibitors.. Atotal of 84 patients, 58% males and 42% females, were included in the study. The age ranged from 1.25 to 12 years. The most common histopathological diagnosis was MesangioPGN (69.04%), FSGS (21.4%), and MCD (9.52%). Complete response was seen in 80.95% and 97.6% patients treated with cyclosporine and tacrolimus, respectively. Partial response was in 19.05% patients treated with cyclosporine and 2.4% in patients with tacrolimus. The most common adverse effect with cyclosporine and tacrolimus was hypertrichosis in 80.95% and 2.38%, hypertension 16.66% and 11.9% respectively while gum hypertrophy with cyclosporine was seen in 26.19% patients.. Tacrolimus was more efficacious than cyclosporine in achieving remission in childhood SRNS with insignificant adverse effects.

Topics: Child; Child, Preschool; Creatinine; Cyclosporine; Drug Resistance; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Receptors, Urokinase Plasminogen Activator; Recurrence; Rituximab; Tacrolimus

To investigate the clinical characteristics and histopathological features of kidney disease in elderly patients.. We retrospectively analyzed the results of 4,185 consecutive renal biopsies, and 288 patients aged >60 years at the Second Hospital of Jilin University from January 1998 to December 2013 were finally included. All patients had been clinically and histologically diagnosed with kidney disease.. Nephrotic syndrome was the main clinical indication for biopsy. Twenty-four patients (8.33 %) experienced a minor complication related to their biopsy procedure. Among patients diagnosed as primary glomerulonephritis (GN), membranous nephropathy (MN) was the most frequent subclassification (24.7 %), followed by mesangioproliferative glomerulonephritis (MsPGN, 11.1 %) and IgA nephropathy (IgAN, 8.0 %). Amyloidosis (8.7 %) was the most common secondary GN, followed by antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune GN (5.2 %) and diabetic nephropathy (DN, 3.8 %). Based on renal biopsies results, 143/288 patients received immunosuppressive therapy and showed an overall remission rate (complete plus partial remissions) of 74.1 %. Among 71 MN patients, 29 patients received steroids plus cyclophosphamide and showed a remission rate of 79.3 %, while 42 patients received steroids and tacrolimus and showed a remission rate of 90.5 %. Among 25 patients with amyloidosis, 22 cases received melphalan plus dexamethasone and showed a remission rate of 40.9 %, while three patients received vincristine, adriamycin, and dexamethasone and showed a remission rate of 66.7 %.. Making an accurate pathologic diagnosis by renal biopsy is crucial for selecting the proper treatment for elderly patients with kidney disease.

Topics: Aged; Aged, 80 and over; Amyloidosis; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Antineoplastic Agents, Alkylating; Autoimmune Diseases; Biopsy; Cyclophosphamide; Dexamethasone; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Retrospective Studies; Tacrolimus; Treatment Outcome

Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0-6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7-12.0 weeks) in combination therapy (p = 0.076). Twenty-seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6-125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen.

Topics: Adolescent; Adult; Azathioprine; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Isoxazoles; Kidney; Leflunomide; Lupus Nephritis; Male; Mycophenolic Acid; Nephrotic Syndrome; Podocytes; Prednisone; Proteinuria; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Cyclophosphamide; Humans; Immunosuppressive Agents; Nephrosis, Lipoid; Nephrotic Syndrome; Tacrolimus

Tacrolimus has gained acceptance in the management of steroid-resistant nephrotic syndrome (SRNS) in children. Due to limited data, therapeutic range is extrapolated from pediatric renal transplant recipients. This study was designed to assess therapeutic efficacy of tacrolimus in children with SRNS and its correlation with inter-dose area under concentration curve (AUC0-12 h) and trough concentration (C0).. Pre dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4, 8, and 12 h after drug administration blood samples were collected in 25 children who were on tacrolimus for a minimum of 3 months and AUC0-12 h was calculated.. There was an 80% (20/25) response rate with 64% (16/25) children achieving complete remission. Median C0 in remission was higher than in relapse group (2.95 ng/ml, versus 1.20 ng/ml, p = 0.005). Median AUC0-12 h in remission was higher compared to those in relapse group (79.75 versus 35.15 μg × h/l; p = 0.025). Maximum concentration after drug administration (Cmax) among the groups was not significantly different. There was a significant correlation between C0 and AUC0-12 h (r = 0.79); and Cmax and AUC0-12 h (r = 0.84). Five patients had a rise in serum creatinine, of which four were still proteinuric and had lower C0 and AUC0-12 h. No other adverse effect was noted.. Tacrolimus had beneficial clinical response in SRNS. Target C0 and AUC0-12 h level for treatment remission was higher than those in relapse in children with SRNS but was lower than required in transplant recipient.

Topics: Adolescent; Area Under Curve; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Tacrolimus

Topics: Child, Preschool; Cyclosporine; Drug Substitution; Humans; Hypertrophy; Immunosuppressive Agents; Lip; Lip Diseases; Male; Nephrotic Syndrome; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Child; Child, Preschool; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi-target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN.

Topics: Adolescent; Antihypertensive Agents; Biphenyl Compounds; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Infusions, Intravenous; Irbesartan; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Pulse Therapy, Drug; Recurrence; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tetrazoles

To evaluate the efficacy of tacrolimus (Tac) in steroid resistant and steroid dependent nephrotic syndrome (NS) in children.. Retrospective chart reviews of 18 children from outpatient clinic at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital were diagnosed with steroid resistant (SR) and steroid dependent (SD) NS during 2002-2008 were enrolled in the present study. The boy to girl ratio was 2:1. The mean age at diagnosis was 6.0 years (1-14.4 years). There were nine SR and nine SDNS. Nine patients had focal segmental glomerulosclerosis (FSGS), 4 IgMnephropathy and two had minimal change diseases (MCD). Three children did not receive renal biopsy. All patients received prednisolone at the start of Tac. The average time from the diagnosis to initiation of Tac was 3.5 years (0.2-14years). The mean duration of Tac treatment was 1.3 year (0.3-6.2 years). The average Tac trough blood level was 4.09 mcg/L (1.3-9.9 mcg/L). The average dosage of Tac was 0.09 mg/kg/day (0.03-0.2 mg/kg/day). Thirteen (72.2%) children achieved complete response (CR). Five (27.80%) children did not respond to Tac. Nine (69.2%) children could stop prednisolone whereas four (30.8%) could lower prednisolone doses. The mean time to achieve CR was 24.6 days (0.1-3 months). The mean follow up period was 3.1 years (0.2-6.4 years). There was no change in an estimation of glomerular filtration rate (eGFR). In SRNS, there were CR in four (44.4%) and five (55.6%) children that FSGS did not respond to Tac. In SDNS, all responded to Tac and four (44.4%) children relapsed while on Tac and had upper respiratory tract infection (URI).. Tac is well-tolerated and effective treatment for SR and SDNS.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Drug Resistance; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Infant; Male; Nephrotic Syndrome; Prednisolone; Retrospective Studies; Statistics, Nonparametric; Tacrolimus; Treatment Outcome

AIHA is a rare and serious complication of solid organ transplantation. Herein, we report four cases of warm or mixed AIHA in pediatric patients following combined liver, small bowel and pancreas transplant. The hemolysis was refractory to multiple treatment modalities including steroids, rituximab, IVIG, plasmapheresis, cytoxan, discontinuation of prophylactic penicillin, and a change in immunosuppression from tacrolimus to cyclosporine. All patients had resolution or marked improvement of hemolysis after discontinuation of maintenance of CNI and initiation of sirolimus immunosuppression. One patient developed nephrotic syndrome but responded to a change in immunosuppression to everolimus. Three of the four patients continue on immunosuppression with sirolimus or everolimus without further hemolysis, evidence of rejection or medication side effects. Based on our experience and review of similar cases in the literature, we have proposed a treatment algorithm for AIHA in the pediatric intestinal transplant patient population that recommends an early change in immunosuppressive regimen from CNIs to sirolimus therapy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Murine-Derived; Calcineurin; Cyclophosphamide; Cyclosporine; Everolimus; Female; Hemolysis; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestines; Liver Transplantation; Male; Medical Records; Nephrotic Syndrome; Pancreas Transplantation; Penicillins; Plasmapheresis; Retrospective Studies; Rituximab; Sirolimus; Steroids; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation; Treatment Outcome

Topics: Adolescent; Antidiarrheals; Berberine; Creatinine; Herb-Drug Interactions; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

Some adult patients with minimal change nephrotic syndrome (MCNS) who are refractory to steroid treatment or combination with immunosuppressive drug developed reversible acute renal failure (ARF) due to persistent severe hypoalbuminemia and proteinuria. It is a challenge to find rescue therapies that are effective and safe in treating such difficult patients.. In this prospective observational study, 13 patients with adult-onset MCNS, all unresponsive to treatment with a steroid or a steroid with other immunosuppressive drugs, were studied from January 2005 to February 2009. All patients developed ARF before enrollment. Oral tacrolimus (TAC) was started at 1 mg/day (target trough levels of 3-6 ng/mL) before serum creatinine (SCr) decreased to ≤133 μmol/L, and then increased doses were given (target trough level of 5-10 ng/mL) when SCr decreased to ≤133 μmol/L. Primary outcome variables were remission, and recovery from ARF. Secondary outcome variables were time to recovery from ARF, time to remission, relapse rate, changes in SCr and estimated glomerular filtration rate (eGFR).. One patient discontinued TAC due to deterioration of ARF, and 12 patients recovered from ARF. The mean time to recovery from ARF was 15.8 ± 4.4 days. Nine patients (69.2%) experienced complete remission (CR) and two patients (15.4%) experienced partial remission (PR). The mean time to PR and CR was 4.8 ± 2.7 and 9.4 ± 2.3 weeks, respectively. After a mean follow-up of 69.6 months, 36.4% (4/11) of patients who had remission experienced relapses. One patient who was resistant to TAC therapy had a doubling of serum creatinine concentration during follow-up.. TAC may be a suitable therapeutic option for treatment of adult-onset refractory MCNS with reversible ARF.

Topics: Acute Kidney Injury; Adult; Age of Onset; Aged; Drug Resistance; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Prognosis; Prospective Studies; Risk Factors; Steroids; Tacrolimus; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Dacarbazine; Doxorubicin; Glomerulonephritis, Membranous; Hodgkin Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Nephrotic Syndrome; Prednisone; Remission Induction; Tacrolimus; Time Factors; Vinblastine

Tacrolimus, a reversible calcineurin inhibitor, is known for its diabetogenic potential. The incidence of diabetes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients. Diabetic ketoacidosis (DKA) is even rarer. DKA as the first presentation of new onset tacrolimus induced transient type 1 diabetes despite a lower dose range and low trough level of the drug is being reported in a 12-y-old girl with steroid resistant nephrotic syndrome.

Topics: Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

Children with steroidresistant (SR) and steroid-dependent (SD) nephrotic syndrome (NS) pose a treatment challenge. Literature on the use of tacrolimus (TAC), a calcineurin inhibitor, for maintenance treatment of NS is sparse. We aimed to evaluate the efficacy and safety of low-dose, long-term TAC for inducing and sustaining remission in children with SD/SR NS.. Data from patients treated at our center from 1999 to 2009 were analyzed.. 40 patients with NS were treated with TAC for 3 - 80-month periods (median 25.2 months). Diagnoses included focal segmental glomerulosclerosis (FSGS) (60%), IgM nephropathy (15%), minimal change disease (20%) and membrano-proliferative glomerulonephritis (MPGN) (5%). 58% of patients had been previously treated with alternate agents. After 1, 2, and 3 years on TAC, complete remission was achieved in 26%, 48%, and 29% of patients; complete or partial remission was achieved in 85%, 100%, and 86%, respectively (p < 0.05). Median time to remission was 41 days (range: 10 - 270 days). FSGS and SR diseases were associated with lower likelihood of remission (p < 0.05). Remission was equally likely in both treatment naïve patients and those who had received prior second-line agents.. Our results demonstrate that TAC treatment for children with SR/SD NS is associated with high rates of sustained remission, even when prior second-line agents failed.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Although therapy with intravenous (IV) rituximab and tacrolimus reduces the relapse rate in steroid-dependent nephrotic syndrome (SDNS), studies on comparative efficacy are lacking. We retrospectively reviewed the records of patients with difficult-to-treat SDNS who had previously received levamisole, cyclophosphamide and/or mycophenolate mofetil, then treated with either rituximab or tacrolimus and followed for 12 months. Between January 2009 and April 2010, ten patients received two to three doses of IV rituximab (375 mg/m(2)/week) and 13 received tacrolimus (0.1-0.2 mg/kg/day) for 12 months; none had previously received either agent. Patients received tapering doses of alternate-day prednisolone; other immunosuppressive agents were discontinued. The mean age of the patients at treatment initiation with rituximab and tacrolimus was 12.2 ± 2.3 and 12.3 ± 3.0 years, respectively. The respective pre-treatment relapse rates (3.1 ± 1.1 and 3.5 ± 1.6 relapses per year) and cumulative prednisolone dose (137.2 ± 69.4 and 140.5 ± 59.0 mg/kg/year) were similar. Therapy resulted in a decline in relapse rate in both groups (P < 0.001). The number of relapses in the rituximab and tacrolimus groups was similar at 6 months (0.3 ± 0.5 vs. 0.3 ± 0.6 episodes, respectively), 12 months (0.8 ± 1.0 vs. 0.9 ± 1.1 episodes) and last follow-up (1.2 ± 1.0 vs. 1.5 ± 1.3 episodes). There were no differences in relapse-free survival at 6, 12 and 18 months. Therapy resulted in a significant decline in the cumulative prednisolone dose (67.2% in the rituximab group and 43.6% in the tacrolimus group) and a reduced body mass index. These findings suggest that in our patients with difficult-to-treat SDNS, treatment with two to three doses of rituximab was as effective as 12 months of therapy with tacrolimus in terms of steroid sparing and reduction in the relapse rate.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal, Murine-Derived; Child; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Recurrence; Retrospective Studies; Rituximab; Tacrolimus; Treatment Outcome

Nephrotic syndrome (NS) associated with hematopoietic stem cell transplantation (HSCT) is usually related to chronic graft-versus-host disease (GVHD) and invariably occurs later than 100 days after transplantation. Here, we report the case of a 6-year-old boy who presented with NS only 61 days after cord blood stem cell transplantation (CBSCT). At 4 years old he was diagnosed with acute lymphoblastic leukemia and underwent bone marrow transplantation. Six months later, a recurrence was noted in the thymus, which required CBSCT at the age of 6. Acute GVHD and hemophagocytic syndrome occurred on day +13 and day +15, respectively, and were successfully treated with tacrolimus and a steroid. After tacrolimus was switched from intravenous infusion to oral administration, NS occurred on day +61. Complete remission was achieved in 3 weeks by resuming steroid treatment. Dry erythema with pigmentation and elevation of Th2 cytokine level suggest that NS in this case was also related to chronic GVHD. To our knowledge, this is the earliest occurrence of NS after HSCT. Hematologists and nephrologists should be aware that this condition may occur even in early periods after HSCT.

Topics: Bone Marrow Transplantation; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Humans; Male; Nephrotic Syndrome; Pleural Effusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Remission Induction; Tacrolimus

This study reports initial results of the development of the SIAM, a non-adherence risk assessment system for tacrolimus and sirolimus for the pediatric kidney transplant population. Forty-eight youths between 10 and 25 yr of age diagnosed with chronic kidney disease or a kidney transplant used an electronic pill bottle (EM; time stamps each bottle opening) to dispense their medication for at least 30 days or until their next clinic appointment. Youth also completed a self-report adherence measure, and standard deviations were calculated for the last four medication serum trough levels obtained for each patient. Estimation models were developed for each medication (i.e., SIAM(TACRO) and SIAM(SIRO) ) to assign weights to these clinically available adherence measures (self-report and trough levels) for the calculation of a non-adherence risk composite score. SIAM(TACRO) models included both self-report and tacrolimus trough levels and significantly predicted EM. For sirolimus, the model predictive of adherence as measured by EM consisted of the standard deviation of sirolimus trough levels only (SIAM(SIRO) ). Non-adherence risk can be effectively assessed using clinically available assessment tools. However, the best methods for using self-report and trough levels to predict non-adherence likely differ based on the medication for which adherence is being assessed.

Topics: Adolescent; Adult; Child; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Linear Models; Logistic Models; Male; Medication Adherence; Nephrotic Syndrome; Risk Assessment; Self Report; Sirolimus; Tacrolimus; Young Adult

Topics: Algorithms; Cyclophosphamide; Drug Resistance; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Prednisolone; Proteinuria; Secondary Prevention; Tacrolimus; Treatment Outcome

There is very little information in the literature on the treatment and prognosis of primary focal segmental glomerulosclerosis (FSGS) among children in Pakistan. This is a review of 94 children (≤16 years) with a diagnosis of primary FSGS who presented to the Sindh Institute of Urology and Transplantation between 1995 and 2008. The clinical records and original renal biopsy reports were reviewed to determine demographic, clinical, laboratory and pathologic features. Renal biopsies were studied by light microscopy, immunofluoroscence and electron microscopy. Thera-peutic regimens and response to therapy were analyzed. Majority of the children (60, 63.8%) had steroid-dependant nephrotic syndrome (SDNS) and 33 (35%) had steroid-resistant nephrotic syndrome (SRNS). Cyclosphosphamide was used in SDNS, and this produced complete remission (CR) in 25/36 (69.4%), partial response (PR) in 4/36 (11%) and no response in 7/36 (19.4%) cases. Cyclosporine was used in SRNS and some SDNS children, and showed a CR in 30 (52.6%), PR in 20 (35%) and no response in seven (12.2%) cases. Tacrolimus was used in seven (7.44%) children. CR was obtained in two (28.5%) and PR in five (71.4%) cases. Renal insufficiency developed in 12 (12.7%) children. Results from this study show that majority of the children with primary FSGS at our center could achieve high rates of sustained remission with second- and third-line immunosuppressive therapies with fairly good prognosis.

Topics: Adolescent; Age Factors; Biopsy; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Disease Progression; Female; Fluorescent Antibody Technique; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant; Kidney Glomerulus; Male; Microscopy, Electron; Nephrotic Syndrome; Pakistan; Remission Induction; Renal Insufficiency; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

Cyclosporine A (CsA) and tacrolimus (TAC) are often alternative treatment choices for patients with nephrotic syndrome.. In this prospective study, the efficacy and safety of CsA and TAC in inducing and maintaining remission in 74 children with idiopathic nephrotic syndrome (INS) were evaluated.. In terms of short-term efficacy, TAC was more effective than CsA in children with steroid-resistant nephrotic syndrome (χ(2) = 13.75, P = 0.001), although no significant difference in number of episodes of relapse were found in patients with complete remission between the two treatment groups (first year: χ(2) = 0.261, P = 0.88; second year: χ(2) = 2.685, P = 0.26). In patients with frequently relapsing or steroid-dependent nephrotic syndrome, no significant difference in short-term remission (χ(2) = 1.908, P = 0.39) or in relapse frequency during follow-up (within first year: χ(2) = 1.046, P = 0.59; within second year: χ(2) = 0.587, P = 0.75) were found between the two groups. There was a difference in the rate of adverse effects between the two treatment groups [nephrotoxicity: 4/24 (CsA) vs .0/50 (TAC), P = 0.002; hirsutism: 8/24 (CsA) vs. 0/50 (TAC), P < 0.001].. In our pediatric patient cohort, the treatment of steroid-resistant nephrotic syndrome with tacrolimus was associated with higher efficacy and lower renal toxicity in comparison to CsA, although no favorable outcome in relapse rate during long-term follow-up was seen. On the other hand, tacrolimus was not always the better choice to replace CsA in the treatment of severe frequently relapsing or steroid-dependent nephrotic syndrome.

Topics: Adolescent; Chi-Square Distribution; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prospective Studies; Recurrence; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Tacrolimus is commonly used as an immunosuppressant in organ transplantation. Although it is well tolerated, visual loss has been known as a rare but serious complication of this drug. We report a woman developing visual complaints while on tacrolimus therapy for nephrotic syndrome. Omission of the drug led to partial visual field recovery. Visual complications in patients receiving tacrolimus should alert the treating physicians for timely discontinuation of the drug.

Topics: Adult; Anti-Inflammatory Agents; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Optic Neuropathy, Ischemic; Prednisolone; Tacrolimus; Vision, Low; Withholding Treatment

Calcineurin inhibitors (CNIs) are frequent first-line agents in children with steroid-resistant nephrotic syndrome (SRNS). However, limited randomized controlled trial (RCT) data are available comparing CNIs with alternative therapies. Gulati and colleagues report their experience with tacrolimus versus cyclophosphamide in childhood SRNS. Their results establish clear superiority of tacrolimus over cyclophosphamide and give further proof that RCTs in childhood SRNS are both feasible and vital for improving the standard of care.

Topics: Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prednisolone; Tacrolimus

Nephrotic syndrome (NS) presented within three weeks in siblings aged six and ten years. Both children experienced proteinuria, hypoalbuminaemia and oedema, with the most pronounced symptoms in the older. Standard treatment with prednisolone led to remission of the nephrotic syndrome in the younger, whereas the older required additional therapy with tacrolismus before remission. In view of the low incidence of NS in children, a near simultaneously onset in two siblings must lead to genetic elucidation. Genetic disorders and other causes of childhood NS are discussed.

Topics: Biopsy; Child; Female; Genetic Predisposition to Disease; Glucocorticoids; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Mutation; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Tacrolimus; Treatment Outcome; Ultrasonography

To study the clinical and pathological features of Denys-Drash syndrome (DDS).. Three DDS cases who were treated in our department from December 2009 to June 2011 were subjected to this study by reviewing of literature.. Both case 1 and case 2 were female, with karyotype 46, XX. Case 3 was male with bilateral cryptorchidism. The ages of nephropathy onset of the three cases were 1 year and 9 months, 2 years and 8 moths, and 3 months respectively. Proteinuria in case 2 and case 3 were evidenced to be resistant to steroid. Case 1 was partially responsive to tacrolimus, plasma albumin and cholesterol were improved, although proteinuria was persistent after Tacrolimus was administered. Remission was achieved in case 2 after administration of cyclosporine A and later tacrolimus, and her renal function remains normal till present (4 years and 9 months). Residue renal histology revealed diffused mesangial sclerosis (DMS) in all three patients. All of the three patients had developed right unilateral Wilms tumor. A novel WT1 missense mutation exon 9 c.1213C > G was detected in case 1. WT1 exon 9 c.1168C > T nonsense mutation and exon 8 c.1130A > T missense mutation were detected in case 2 and case 3, respectively.. The clinical manifestation of nephropathy in DDS is variable. The majority present with early onset nephropathy and reach renal failure before the age of 4 years. But in a few patients, nephropathy can also be present much later and progress slowly. Proteinuria in DDS is resistant to steroid but is responsive to calcineurin inhibitors, including Cyclosporine A. The effectiveness of tacrolimus was also observed in this study. DDS is evidently caused by WT1 mutation. DMS is the characteristic renal pathological change in DDS.

Topics: Cyclosporine; Denys-Drash Syndrome; Fatal Outcome; Female; Genes, Wilms Tumor; Heterozygote; Humans; Infant; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sclerosis; Tacrolimus; Treatment Outcome; Wilms Tumor; WT1 Proteins

Steroid-dependent, steroid-resistant or frequently relapsing nephrotic syndrome carries a poor prognosis, including progression to renal failure. There are a number of studies confirming the efficacy of FK506 in steroid-resistant or steroid-dependent nephrotic syndrome. Although the use of this medication is becoming more common, we know very little about the potential nephrotoxicity when used in nephrotic syndrome.. We retrospectively reviewed the characteristics and biopsy findings of 11 children with steroid-dependent or frequently relapsing nephrotic syndrome treated with FK506. Two sequential biopsies were evaluated for the change in interstitial fibrosis, measured by a quantitative stereological method, and the change in arteriolar hyaline thickening, tubular atrophy and interstitial fibrosis, graded according to Banff criteria.. There was an increase in interstitial fibrosis (P = 0.005), with a median absolute change in the per cent volume density between initial and follow-up biopsies of 1.8% [interquartile range (IQR) 3.9%]. Median percentage change in volume density of interstitial fibrosis, relative to volume density of interstitial fibrosis prior to initiating FK506, was 93% (IQR 138%). Banff scores for interstitial fibrosis and tubular atrophy also increased following tacrolimus therapy (P = 0.04 for both). Average FK506 trough level over the treatment period was significantly associated with change in fibrosis (Spearman's rho = 0.67 and P = 0.02).. This is some of the first histological data concerning tacrolimus nephrotoxicity in childhood nephrotic syndrome. Although the role of the natural progression of the underlying disease in the observed change is not definitively clear, the changes seen are in keeping with the known nephrotoxic effects of FK506 demonstrated in renal transplant. This increase is small when presented as a median change. However, there were a number of children who had a larger change in fibrosis. The factors predictive of interstitial fibrosis while on FK506 are not well defined; the findings from this study suggest that FK506 level may be a factor. Given the observations and limitations of the few published studies, there is an obvious need for further study in a large multicenter prospective trial.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Fibrosis; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Nephrotic Syndrome; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome

To analyze and evaluate the efficacy and safety of tacrolimus and low-dose steroids in the treatment of steroid-resistant nephrotic syndrome in children.. Twenty-one children with steroid-resistant nephrotic syndrome enrolled from October 2008 to July 2010 into this retrospective longitudinal study received oral tacrolimus treatment, 0.1 to 0.15 mg/kg per day and once every 12 hours, and prednisone 0.2 to 0.75 mg/kg per day simultaneously. During the treatment, the plasma concentration of tacrolimus, urine volume, urine, serum creatinine and liver function were regularly monitored.. After 1 to 3 months treatment, 14 cases showed complete remission and 7 cases had partial remission. Sixteen patients received renal biopsy, of whom 6 revealed minimal change nephropathy with complete remission in 3 cases, 3 cases had partial remission;4 cases revealed focal segmental glomerulosclerosis with 2 complete remission and 2 partial remission; other 5 children with IgM nephropathy and 1 mesangial proliferative glomerulonephritis achieved complete remission. Within treatment period, 6 patients presented transient adverse reactions, without altering the principle treatment strategy, but only taking the symptomatic treatment. During follow-up, 1 case was lost to follow-up and the remaining 20 cases were followed up from 2 months to 21 months. In 4 patients the disease relapsed within 1st-year follow-up, while at 2nd-year follow-up, 4 cases had (6 times) recurrence.. Tacrolimus showed a reliable effect in children with steroid-resistant nephrotic syndrome. Less adverse reactions were seen, and most of them could be tolerated. Nevertheless, the patients had a higher relapse rate after 1 to 2 years treatment. Therefore, the long-term effects of tacrolimus for steroid-resistant nephrotic syndrome remains to be further evaluated.

Topics: Adolescent; Child; Child, Preschool; Drug Resistance; Female; Humans; Infant; Longitudinal Studies; Male; Nephrotic Syndrome; Prednisone; Retrospective Studies; Tacrolimus; Treatment Outcome

We report the outcome of our single-center, long-term follow-up study of tacrolimus therapy in children with steroid-resistant nephrotic syndrome (SRNS). All cases of nephrotic syndrome (NS) with kidney biopsies treated at our center between January 2000 and July 2008 were reviewed. Children with systemic lupus erythematosus and steroid-dependent NS were excluded. Nineteen children with SRNS received tacrolimus. Histopathological analysis of the biopsy revealed the underlying conditions of these 19 patients to be focal segmental glomerulosclerosis (ten patients), C1q nephropathy (four), membranous nephropathy (two), minimal change disease (one), membranoproliferative glomerulonephritis (one), and immunoglobulin A nephropathy (one). The mean follow-up was 55 months, and the median age of the patient cohort was 10 years. We observed complete remission in 11 (58%) patients, partial remission in six (32%), and failure to respond in two (9%). The median time to response was 8 weeks. Side effects were mild and transient (one case of acute kidney injury and three cases of hyperglycemia). The initial rate for combined partial and complete remission of the NS in children with SRNS was 81%, which was sustained in 58% of the patients on follow-up. Among children with FSGS, the sustained remission rate was 50%, while 40% progressed to end-stage renal disease (ESRD) (mean time 52 months). Based on the results of this study, we conclude that tacrolimus is an effective and well-tolerated therapeutic option for the treatment of SRNS in children. However, the occurrence of relapses of the NS with progression to ESRD during the long-term follow-up indicates the need for careful monitoring of such patients.

Topics: Adolescent; Child; Child, Preschool; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

Acute antibody mediated rejection (AMR) is rarely reported as a long-term com-plication of renal transplantation, and it can present on top of another chronic pathology affecting the graft. A 45-year-old gentleman with chronic kidney disease due to unknown etiology received renal transplantation from his sister with 4 HLA mismatches. He received antithymocte globulin induction therapy and was maintained on steroids, azathioprine (AZA) and cyclosporine A (CsA). Up to eight years post-transplantation he was clinically and biochemically stable. He lost follow-up for about one year, and then presented with nephritic nephrotic syndrome and rise of serum creatinine (SCr.) to 210 μmol/L. Graft biopsy revealed picture suggestive of acute AMR on top of de novo membranoprolipherative glomerulonephritis (MPGN) with focal crescent formation, diffuse immune complex deposition and peritubular capillaries C4d positivity. Anti-HLA donor specific antibodies were highly positive for B and T cells class I and class II. The patient was treated with intravenous immunoglobulin, plasma exchange and anti-CD20 (rituximab). AZA was changed to mycophenolate mofetil and CsA to tacrolimus. He had partial response, but SCr. continued at 220 μmol/L.

Topics: Acute Disease; Antibodies; Antibodies, Monoclonal, Murine-Derived; Drug Therapy, Combination; Glomerulonephritis, Membranoproliferative; Graft Rejection; Histocompatibility Testing; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Nephrotic Syndrome; Plasmapheresis; Rituximab; Tacrolimus; Time Factors; Treatment Outcome

In a proportion of adults with steroid-resistant nephrotic syndrome (SRNS), intravenous cyclophosphamide therapy fails. Tacrolimus may be a promising alternative to cyclophosphamide for such patients.. Prospective observational study.. 19 adults with SRNS (6 with minimal change nephropathy, 8 with focal segmental glomerulosclerosis [FSGS], and 5 with mesangioproliferative glomerulonephritis) that did not respond to intravenous cyclophosphamide therapy were studied from January 2003 to September 2006. Oral tacrolimus was administered (target trough levels, 5 to 10 ng/mL) for 24 weeks, then reduced doses were given (target trough level, 3 to 6 ng/mL) for another 24 weeks.. Histopathologic types: minimal change nephropathy (n = 6), FSGS (n = 8), and mesangioproliferative glomerulonephritis (n = 5).. outcome variables included complete remission (decrease in daily proteinuria to protein < or = 0.3 g/d), partial remission (decrease in daily proteinuria to protein < 3.5 g/d but > 0.3 g/d), relapse (increase in daily proteinuria to protein > or = 3.5 g/d in patients who had partial or complete remission), change in kidney function, and tacrolimus dosing and serum levels.. 17 patients completed at least 24 weeks of tacrolimus therapy. Complete remission was achieved in 11 patients (64.7%), and partial remission was achieved in 3 (17.6%). Complete or partial remission was achieved in 5 of 5 patients with minimal change nephropathy, 4 of 7 patients with FSGS, and 5 of 5 patients with mesangioproliferative glomerulonephritis. Primary resistance to tacrolimus was seen in 3 patients (17.6%), all with FSGS. Mean times to achieve partial and complete remission were 5.6 +/- 1.4 and 8.0 +/- 5.1 weeks, respectively. In patients who achieved complete or partial remission, 35.7% experienced relapse during follow-up (mean, 37.6 +/- 13.4 months). Two patients had doubling of serum creatinine levels, both with FSGS.. Observational study.. Tacrolimus rapidly and effectively induced remission of SRNS in Chinese adults with disease refractory to treatment with intravenous cyclophosphamide. Treatment may be less effective in patients with FSGS.

Topics: Administration, Oral; Adolescent; Adult; China; Creatinine; Cyclophosphamide; Drug Resistance; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Injections, Intravenous; Male; Nephrosis, Lipoid; Nephrotic Syndrome; Prospective Studies; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome; Young Adult

Children with steroid-resistant nephrotic syndrome (SRNS) are at risk of developing renal failure. We report here the results of a single-center retrospective observational study of the remission rate in pediatric patients with SNRS receiving tacrolimus. Serial renal biopsies from children on tacrolimus therapy were evaluated for tubulointerstitial fibrosis and transforming growth factor-beta immunostaining. Of the 16 children with SRNS, 15 went into complete remission after a median of 120 days of therapy. Nine children were able to stop steroids, while the others were on tapering doses. Forty-seven percent had relapses, most of which were steroid-responsive. Serial renal biopsies were obtained from seven children after a median treatment duration of 24 months; two of these children had increased tubulointerstitial fibrosis and four showed increased transforming growth factor-beta tissue staining. Children with worsening histological findings were younger. There was no significant association between tacrolimus exposure and biopsy changes, although the average trough level was higher in those children with worsening histological findings. In conclusion, tacrolimus may be a safe and effective alternative agent for inducing remission in children with SRNS. However, caution needs to be taken when prescribing this agent due to its narrow therapeutic index. Serial renal biopsies are necessary to check for subclinical nephrotoxicity, especially in younger children and those with higher trough levels.

Topics: Adolescent; Child; Child, Preschool; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Retrospective Studies; Steroids; Tacrolimus

Topics: Acute Disease; Child, Preschool; Drug Overdose; Ecchymosis; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Recurrence; Tacrolimus

A 13-year-old girl with obesity and hyperinsulinism developed steroid-resistant nephrotic syndrome due to collapsing glomerulopathy with dominant C1q-containing mesangial immune deposits (CG/C1qN). She became overtly diabetic while receiving alternate-day prednisone and tacrolimus, requiring insulin injections. Despite the addition of mycophenolate mofetil to the treatment regimen, renal function subsequently declined. Rituximab (four weekly doses of 375 mg/m2) was tried 6 months after initial presentation and 3 months after weaning all glucocorticoids. Glomerular filtration rate (GFR) and proteinuria improved. Unexpectedly, blood sugar control normalized 6 weeks after antibody infusion. Rituximab was readministered 20 months after the first course because of deteriorating renal function, but the effect on GFR and proteinuria was modest. A retrospective analysis revealed that tubulointerstitial infiltrates present in the biopsies prior to treatment with rituximab contained numerous CD20+ and CD3+ (CD4 > CD8) lymphocyte aggregates. Rebiopsy 10 weeks after repeat rituximab therapy demonstrated the elimination of B-cell infiltrates and the apparent decrease of interstitial T-cell infiltrates, yet persistent, advanced global glomerulosclerosis, interstitial fibrosis and tubular atrophy. In conclusion, CG/C1qN was associated with B- and T-cell-rich tubulointerstitial infiltrates. B-cell-directed therapy delayed clinical progression during early disease but failed to prevent or ameliorate chronic changes, despite effective tissue B-cell clearance. The incidental resolution of diabetes was noted after rituximab treatment.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Biopsy; CD4-CD8 Ratio; Complement C1q; Drug Therapy, Combination; Female; Glomerulonephritis; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Glomerulus; Nephrotic Syndrome; Prednisone; Rituximab; Tacrolimus

Topics: Adrenocorticotropic Hormone; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Prognosis; Risk Assessment; Rituximab; Tacrolimus; Treatment Outcome

Acute renal failure (ARF) is an uncommon complication in children with nephrotic syndrome. We report here the case of a 10-year-old male child with primary steroid-resistant nephrotic syndrome who was non-responsive to steroids and cyclophosphamide. A kidney biopsy revealed that he had focal segmental glomerulosclerosis. His treatment was initiated with tacrolimus (dose of 0.15 mg/kg/day) in two divided doses along with prednisolone 60 mg/m(2)/daily. After 1 month of treatment, he was diagnosed as having acute renal failure secondary to HUS. This was postulated to be due to the tacrolimus therapy, which was withdrawn. Two weeks after stopping the adminsitration of tacrolimus, his urine output improved, and the hemoglobin and serum creatinine normalized. Thus, tacrolimus-induced HUS is a rare cause of ARF in nephrotic syndrome. With the increasing use of tacrolimus in steroid-resistant nephrotic syndrome, the treating physicians need to be aware of this rare, but potentially life-threatening side effect.

Topics: Acute Kidney Injury; Biopsy; Child; Drug Resistance; Glomerulosclerosis, Focal Segmental; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Steroids; Tacrolimus

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cyclosporine; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Rituximab; Tacrolimus

The treatment of idiopathic membranous nephropathy is heavily debated because of wide variation in outcome. A rational treatment strategy is needed to appropriately administer conservative treatment to the low-risk group but immunosuppressive therapy to those with medium or high risk of renal deterioration. Currently, combinations of steroids with alkylating agents are best studied. Newer forms of immunosuppressive treatment are currently under study.

Topics: Adrenal Cortex Hormones; Angiotensin-Converting Enzyme Inhibitors; Cyclosporine; Drug Therapy, Combination; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney Function Tests; Nephrotic Syndrome; Tacrolimus

Membranoproliferative glomerulonephritis, albeit uncommon, is associated with considerable morbidity and mortality in children. Corticosteroids are the mainstay of therapy for severe disease, although data supporting their use are limited. We report our experience in treating two children with nephrotic-nephritic syndrome from idiopathic membranoproliferative glomerulonephritis. Both children experienced a suboptimal response to prolonged courses of steroids and were started on tacrolimus as a steroid-sparing agent. Rapid and complete remission was achieved in both children after initiation of tacrolimus. The purpose of our report is to increase awareness of health care professionals to the potential benefits of this agent in inducing remission in children with severe membranoproliferative glomerulonephritis.

Topics: Child; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranoproliferative; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Tacrolimus; Treatment Outcome

Severe steroid-dependent nephrotic syndrome (SDNS) is a common type of nephrotic syndrome (NS) observed in childhood. Steroid-sparing agents such as calcineurin inhibitors (CNIs) are used to avoid steroid toxicity in SDNS. Tacrolimus (TAC) has been prescribed for maintaining remission of NS in patients who have developed treatment resistance or adverse effects with cyclosporin A (CYA) at our institution since 1995. The aim of this study was to compare the efficacy and complications of TAC with CYA in the management of severe SDNS.. We report a retrospective longitudinal clinical series of patients with SDNS, all of whom have been treated with TAC.. Ten SDNS children (eight males) were reviewed quarterly from time of initial referral to the present day during 93 completed treatment patient years. Nine patients had minimal change disease and one had focal segmental glomerulosclerosis on their first biopsy. The median age at diagnosis was 2.9 years (range 1.6-12.9). The median age at initial referral was 3.9 years (range 2.2-12.9). All patients initially responded to prednisolone at 60 mg/m2/day, and subsequent frequent relapses were treated sequentially with oral cyclophosphamide 168 mg/kg over 8-12 weeks (n = 10), CYA (n = 10), intravenous mustine or a second course of cyclophosphamide (n = 7) and then TAC (n = 10). The initial daily treatment of CYA and TAC in two divided doses was 5 and 0.1 mg/kg/day, respectively; targeted 12 h blood drug levels were of 50-100 microg/l for CYA and 5-10 microg/l for TAC. Patients underwent renal biopsy and the formal glomerular filtration rate (GFR) was measured using plasma clearance of the Inutest method every 2-3 years while receiving CNIs. Six patients continued with TAC; in four patients, TAC was discontinued because of poor response (n = 2), hypertension (n = 1) and glucose intolerance (n = 1). For CYA and TAC treatment periods, the median NS relapse rate was two and one relapses per year, respectively, and cumulative steroid dosage was 73.9 and 105.2 mg/kg/day, respectively (P = 0.54). The reduction in GFR was 5.8 and 11.7 ml/min/1.73 m2 during these periods. Three of the 10 patients showed histological evidence of mild CNI nephrotoxicity over the whole of the CNI treatment period despite achieving target therapeutic drug levels; no significant change in measured or calculated GFR over this prolonged CNI therapy was observed. Antihypertensive medication was prescribed for 11 of 31 CYA and 22 of 40 TAC treatment years. Growth was maintained during the entire CNI therapy period with median change in height SD scores (SDS) of +0.37 and -0.03 over CYA and TAC, respectively (P = 0.13).. In conclusion, we observed that the replacement of CYA by TAC does not lead to a better management of severe SDNS.

Topics: Calcineurin Inhibitors; Child; Child, Preschool; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infant; Longitudinal Studies; Male; Nephrotic Syndrome; Retrospective Studies; Steroids; Tacrolimus; Time Factors

Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

Topics: Anemia, Hemolytic, Autoimmune; Child, Preschool; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Topics: Child; Cyclosporine; Glucocorticoids; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Steroids; Tacrolimus

Topics: Antibodies, Monoclonal; Child, Preschool; Cyclosporine; Diagnostic Errors; Dwarfism; Granuloma; Hematuria; Humans; Immunosuppressive Agents; Infliximab; Male; Nephritis, Interstitial; Nephrosis, Lipoid; Nephrotic Syndrome; Obesity; Prednisolone; Proteinuria; Puberty, Delayed; Recurrence; Remission Induction; Tacrolimus; Tumor Necrosis Factor-alpha

Despite the availability of immunosuppressive drugs such as prednisone, cyclophosphamide, cyclosporine A (CyA) and mycophenolate mofetil for the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS), medication-free remission is not achieved in a number of patients. To avoid excessive steroid toxicity, the use of tacrolimus (Tac) has been discussed. We report on five children diagnosed with SDNS on the histological basis of minimal change glomerulopathy or focal segmental glomerulosclerosis. Following the failure of other medications to achieve sustained remission, Tac was administered to these patients who varied in age from 10.5 to 13.5 years. Only one patient showed a substantial reduction in the number of relapses with the Tac treatment. Two boys, after 9 and 44 months on therapy, respectively, developed insulin-dependent diabetes mellitus (IDDM), necessitating the withdrawal of Tac and the daily use of insulin for 3 and 6 months. In both patients hyperglycemia had occurred during prednisone-based relapse therapy of SDNS. The patients had low serum protein concentrations, presumably increasing the free active Tac fraction, while trough levels of the drug remained unchanged. Both of the affected patients had additional risk factors for impaired glucose tolerance, such as morbid obesity (patient 1; BMI: 41.6 kg/m(2)) and African American origin (patient 2). Our case reports demonstrate that the use of Tac in patients with SDNS may be associated with an increased risk for IDDM, especially during relapse of NS, and particularly if additional risk factors are present. Moreover, Tac does not appear to substantially increase the success of treatment.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prognosis; Recurrence; Risk Factors; Tacrolimus

To evaluate the efficacy of FK506 in the treatment of children with nephrotic syndrome of different underlying pathology.. 12 patients were treated with FK506 with a dosage of 0.1 - 0.15 mg/kg/d while corticosteroid dose was tapered stepwise. This therapeutic course lasted 3 - 6 months during which the plasma concentration ofFK506 was monitored.. 12 children with different pathological types nephrotic syndrome were treated with FK506, including 4 cases of MCN, 6 cases of MsPGN, and 1 case of MPGN and 1 case of FSGS. After 2-month duration, 8 patients got complete remission including 4 cases of MCN and 4 cases of MsPGN and 3 children including 1 case of MsPGN, 1 case of MPGN, and 1 case of FSGS got partial remission. Only 1 child with MsPGN was considered to be a treatment failure. The overall response rate was 91.67% with the plasma concentration of FK506 maintained at 5 approximately 12 ng/ml, and the response time was 10 - 38 days. After 1-month duration, all patients except one experienced a reduction in proteinuria to normal levels or a partial response (50% reduction in protein excretion), significant increase in serum albumin, decrease in serum cholesterol and triglyceride and disappearance of edema. 2 months later, in 11 patients, blood biochemical values had returned to normal levels. The drug was generally well-tolerated. 3 patients had anorexia, nausea, vomiting. 2 patients experienced transient elevated serum creatinine which was reversible after the adjustment of dosage. 3 patients had minor changes in urine NAG. Only 2 of all patients relapsed.. FK506 is one of the effective immunosuppressants. In this study, FK506 in combination with a small doses of steroid while decreasing FK506 dosage plays a role in consolidating the curative effect and preventing relapse. In conclusion, FK506 may be effective in the treatment of nephrotic syndrome.

Topics: Adolescent; Adrenal Cortex Hormones; Child; Child, Preschool; Female; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Tacrolimus

Topics: Adolescent; Adult; Child; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Tacrolimus; Treatment Outcome

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.

Topics: Adult; Anemia, Megaloblastic; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Blood Proteins; Combined Modality Therapy; Cyclophosphamide; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosorbent Techniques; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Plasmapheresis; Proteinuria; Sepharose; Staphylococcal Protein A; Tacrolimus

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning

This is a retrospective analysis of 16 children started on tacrolimus with various types of treatment-resistant nephrotic syndrome. There are 13 patients with focal glomerulosclerosis, 1 minimal change disease, and 2 IgA nephropathy with nephrosis. The mean age of the children was 11.4 years (range 3.5-18.1 years) with a mean age at diagnosis of 5.6 years (range 1.6-13.3 years). All patients initially received prednisone 2 mg/kg per day. Other therapies for 15 of 16 included cyclosporine (n=15), chlorambucil (n=5), mycophenolate mofetil (n=5), levamisole (n=3), i.v. methylprednisolone (n=3), and cyclophosphamide (n=2). The major indication for the initiation of tacrolimus included treatment resistance/dependence (n=15) and intolerable side effects from other therapies (n=1). The average time from the diagnosis to initiation of tacrolimus was 5.3 years (range 0.3-13.3 years, median 6 years). The initial dosage of tacrolimus utilized was 0.1 mg/kg per day divided into two doses. The mean follow-up period was 6.5 months (range 2.5-18 months). Thirteen patients (81%) went into a complete remission within an average of 2 months (range 0.5-5.5 months), with 3 patients relapsing while on treatment. Three patients did not respond. Of these, 2 had partial remissions (13%) and 1 failed to respond. Adverse events included anemia (n=1), seizure (n=1), worsening or new-onset hypertension (n=5), and sepsis (n=1). All patients remain on tacrolimus. Tacrolimus is an effective, well-tolerated medication for treatment-resistant forms of nephrotic syndrome in children, with a complete remission rate of 81% and a partial remission rate of 13% (totaling 94%).

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Child; Child, Preschool; Drug Resistance; Female; Glucocorticoids; Humans; Hypertension, Renal; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Retrospective Studies; Tacrolimus; Treatment Outcome

We report here the case of a 9-year-old Japanese boy with nephrotic syndrome caused by focal segmental glomerulosclerosis, which was refractory to treatment. Although aggressive immunosuppressive therapy consisting of methylprednisolone pulse therapy combined with cyclosporine A (CsA) and intermittent low density lipoprotein apheresis was effective in overcoming his steroid-resistant state, the child became persistently steroid-dependent, that is, more than 0.75 mg/kg per day of prednisolone combined with CsA was required to maintain a negative test for proteinuria. Since adverse effects of prednisolone, such as short stature, obesity, osteoporosis and cataract, were noted, CsA in his treatment regimen was replaced with tacrolimus at the dose of 0.1 mg/kg per day, with the trough blood level of the drug maintained at around 10 ng/ml. Within 4 months of the inclusion of tacrolimus in the treatment regimen, complete remission was achieved, with no recurrence of the proteinuria, while the prednisolone dose could be tapered to 0.3 mg/kg per day. No adverse effects of tacrolimus were observed. These clinical results suggest that tacrolimus may be the drug of choice in selected patients with refractory nephrotic syndrome, even if pediatric-onset cases, at least those in whom the steroid-sparing effects of CsA is unsatisfactory.

Topics: Child; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prednisone; Tacrolimus; Treatment Outcome

Topics: Adolescent; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Severity of Illness Index; Tacrolimus

Topics: Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Nephrotic Syndrome; Postoperative Complications; Tacrolimus

Topics: Adult; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Proteinuria; Tacrolimus

Seven patients with steroid-resistant nephrotic syndrome were treated with FK 506 monotherapy. Four patients were children with focal sclerosing glomerulonephritis (FSGS). Three of these had evidence for chronic progressive renal disease consisting of interstitial fibrosis and tubular atrophy on pretreatment renal biopsies. Two patients had also failed cyclosporin A (CsA), two cyclophosphamide, and one chlorambucil prior to treatment with FK 506. Three patients were adults with mesangial proliferative, membranoproliferative, and membranous glomerulonephritis. Three patterns of response were noted: (1) a reduction in proteinuria to normal levels; (2) partial response (50% reduction) or; (3) no improvement. All patients except one experienced at least a 50% reduction in protein excretion at some time during FK 506 therapy. Two of the children and one adult reduced protein excretion to essentially normal values. One patient had no sustained reduction in protein excretion and is considered to be a treatment failure, although her protein excretion was approximately 50% of pretreatment values intermittently. The drug was generally well tolerated. The most common side-effect was nephrotoxicity, which was reversible. These encouraging results suggest that FK 506 monotherapy may be effective in controlling the proteinuria of some patients with steroid-resistant nephrotic syndrome. The use of this drug may extend our understanding of the role of T lymphocytes and cytokines in the pathogenesis of glomerulonephritis. Further study of this agent in a larger population of patients is warranted.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Drug Resistance; Female; Humans; Male; Nephrotic Syndrome; Pilot Projects; Proteinuria; Tacrolimus

Topics: Azathioprine; Biopsy; Creatinine; Cyclosporine; Graft Rejection; Humans; Kidney Transplantation; Nephrotic Syndrome; Pilot Projects; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Transplantation, Homologous

Topics: Adolescent; Adult; Child, Preschool; Creatinine; Drug Resistance; Humans; Kidney Function Tests; Kidney Transplantation; Middle Aged; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus