tacrolimus and Glomerulosclerosis--Focal-Segmental

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

Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis. One of the patterns of bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS).. We describe a breast cancer patient who developed heavy proteinuria (protein/creatinine ratio 9.1) and nephrotic syndrome following treatment with oral ibandronate for 29 months. CFSGS was proven by biopsy. There was no improvement 1 month after ibandronate was discontinued. Prednisone and tacrolimus were started and she experienced a decreased in proteinuria.. In patient who develops ibandronate-associated CFSGS, proteinuria appears to be at least partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandronate is stopped.

Topics: Administration, Oral; Adult; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Diphosphonates; Female; Glomerulosclerosis, Focal Segmental; Humans; Ibandronic Acid; Prednisone; Proteinuria; Tacrolimus; Treatment Outcome

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

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

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

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 prognosis of untreated patients with focal segmental glomerulosclerosis is poor, as the disease progress to end-stage renal disease in approximately 50--70% of nephrotic patients. Although focal segmental glomerulosclerosis was initially considered to be a steroid-resistant disease, several studies have shown a better responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or -dependent focal segmental glomerulosclerosis, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Plasmapheresis or LDL-apheresis may represent a rescue treatment in patients who do not respond to other therapies. The role of other agents used in focal segmental glomerulosclerosis, including azathioprine, mycophenolate mofetil, tacrolimus, pefloxacin or vitamin E is still poorly defined.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Blood Component Removal; Cyclosporine; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosorbent Techniques; Pefloxacin; Purines; Tacrolimus; Vitamin E

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

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

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

The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS).. Patients with biopsy-proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5-0.75 g/m(2)·month, i.v.) received prednisone at 0.8 mg/kg·day, while patients treated with TAC (0.1 mg/kg·day) received prednisone at 0.5 mg/kg·day. The plasma concentration of TAC was monitored and maintained at 5-10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment.. A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 ± 0.21 versus 2.21 ± 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05).. These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function.

Topics: Adult; Albumins; Cyclophosphamide; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Function Tests; Male; Prospective Studies; Proteinuria; Remission Induction; Secondary Prevention; 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

The use of tacrolimus in steroid-resistant (SR) focal segmental glomerulosclerosis (FSGS) has been reported in single and small series case reports.. To determine the efficacy of tacrolimus in the management of SR FSGS in children.. This was a prospective study of 20 children with SR FSGS treated with tacrolimus (0.2-0.4 mg/kg/day in two divided doses over 12 h adjusted to a trough level between 7 and 15 ng/ml) for 12 months in combination with low-dose steroids. Other therapies included angiotensin-converting enzyme inhibitors, folic acid, multivitamins and lipid-lowering agents.. The mean age at study entry was 11.1 years (range 5.6-16.8). The mean duration of nephrotic syndrome before initiation of tacrolimus therapy was 4.7 years (range 2.1-7.6). At the end of the treatment period, 8 (40%) children were in complete remission, 9 (45%) were in partial remission, and 3 (15%) failed to respond. The average follow-up period following cessation of tacrolimus treatment was 27.5 months (range 13.7-43.7). At last hospital follow-up, 5 (25%) children were in complete remission, 10 (50%) in partial remission, and 2 (10%) in relapse. Three children died from dialysis-related complications following cessation of tacrolimus treatment. Adverse events included sepsis (2), nausea (2), diarrhea (2), anemia (4) and worsening of hypertension (4).. Tacrolimus is a safe and effective treatment for SR FSGS. However, like cyclosporine, some children tend to relapse following cessation of treatment.

Topics: Adolescent; Child; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Steroids; Tacrolimus; Treatment Outcome

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most prevalent histopathological lesions in idiopathic nephrotic syndrome (INS). The latter is associated with high morbidity and mortality due to symptomatic anasarca, bacterial infections, venous and arterial thromboembolism, and potential progression to end-stage renal disease in the case of FSGS. Traditionally, most patients are treated with corticosteroids, cyclophosphamide (CTX) or calcineurin-inhibitors (C-I). Unfortunately, many patients become steroid or C-I dependent, with the inherent risk of long-term side effects, or are resistant to both. The aim of this paper is to report on our experience with a new protocol of a combination of immunosuppressive agents added sequentially to improve the response of steroid and C-I refractory or resistant-INS and to minimize the long-term side-effects of single-agent treatment.. Twenty-one patients with corticosteroid-resistant and C-I refractory INS (6 with MCD and 15 with FSGS) were treated prospectively over 6 and a half years. Our protocol consisted of an initial regimen of C-I followed by the addition of mycophenolate mofetil (MMF) and then by monthly intravenous CTX for 3 consecutive months. Dose reduction of C-I or/and MMF was attempted afterwards at 4-months intervals. Patients who remained refractory to the previously mentioned protocol were treated with an additional course of pulse Solu-Medrol given for 3 days followed by oral corticosteroids tapered over 6 months in addition to a second course of intravenous CTX given for 3 consecutive months.. With the initial regimen, two patients with MCD, remained in complete remission (CR) without any therapy after the course of CTX. Fifteen patients had variable response to C-I and MMF, but they achieved CR after CTX and their initial dosage of C-I and MMF were reduced to nearly one half. The remaining four patients had refractory form of FSGS even after the initial regimen, yet responded with CR to the additional course of steroid/CTX. However, no success with dose-reduction, in C-I and MMF, was achieved in the latter four patients.. Our study represents the first clinical trial with prospective and adequate follow-up of combination therapy of immunosuppressive agents in INS. This method is effective and safe for treatment of patients who are refractory to the conventional single-agent therapy.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

The histopathological changes in 51 renal allograft biopsies from patients immunosuppressed with FK506 were compared with those seen in 30 needle biopsies obtained from patients on cyclosporine. The frequency and severity of rejection episodes were similar in both groups. Tubular vacuolation and myocyte vacuolation were found to be useful morphological markers to monitor short-term drug toxicity associated with both drugs. Long-term administration of FK506 led to striped interstitial fibrosis and arteriolar hyalinosis, similar to that previously documented for cyclosporine. One case each of hemolytic uremic syndrome and necrotizing arteriopathy was noted in patients receiving FK506. FK506 and cyclosporine are structurally unrelated compounds; hence the parallelism observed in their nephrotoxicity profile suggests that the interactions of these drugs with renal tissue involves the operation of two different initial signal-transducing mechanisms, ultimately activating the same final metabolic pathways.

Topics: Adult; Biopsy, Needle; Cyclosporine; Female; Fibrosis; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunosuppression Therapy; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Signal Transduction; Tacrolimus; Time Factors; Transplantation, Homologous

Kidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes.. Ninety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN).. At end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others.. Recipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.

Topics: Adult; Cyclosporine; Female; Glomerulonephritis; Glomerulonephritis, IGA; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

We aim to report our experience managing cases of recurrent focal segmental glomerulosclerosis (FSGS) in a group of pediatric renal transplant recipients.. This study was a retrospective chart review of pediatric patients who had their first kidney transplant at King Faisal Specialist Hospital & Research Center between 2014 and 2016.. We reviewed the files of 6 patients, 3 of whom were male. The median age of the children was 2.75 years (range, 2-4 years) at disease onset, with an average time of progression to end-stage renal disease of 19 months (range, 8-30 months). Five of the patients received a living related donor transplant, and 1 received a living nonrelated donor transplant. Patients had FSGS recurrence at varying intervals (1 to 3 days) post transplant. All cases had plasmapheresis prior to receiving abatacept or rituximab. The therapeutic strategy in 4 patients involved switching tacrolimus to cyclosporine. A complete response was observed in 5 of the 6 patients (83.3%), and treatment was well tolerated in 5 patients. Patient 1 had severe oliguria and required intermittent hemodialysis during the first 3 weeks post transplant. He showed minimal response to the therapeutic plasma exchange and rituximab and was subsequently treated with abatacept. However, he died 8 months post transplant of pneumonia and sepsis.. Rituximab and switching tacrolimus to cyclosporine, in conjunction with plasmapheresis, appeared to be effective and safe in children with recurrent FSGS. Conversely, abatacept did not appear to provide clinical benefit.

Topics: Abatacept; Adolescent; Child; Child, Preschool; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Plasmapheresis; Recurrence; Remission Induction; Retrospective Studies; Rituximab; Tacrolimus; Transplant Recipients

Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation.. Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated.. AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts.. These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

Topics: Allografts; Animals; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Interleukin-6; Janus Kinases; Kidney Transplantation; Piperidines; Pyrroles; Rats; Rats, Inbred Lew; Tacrolimus

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by rapid progression to end-stage renal disease (ESRD). We evaluated the clinicopathological spectrum of cFSGS and compared its clinical behavior to steroid and tacrolimus (TAC)-resistant noncollapsing focal segmental glomerulosclerosis (FSGS). All patients (>14 years) diagnosed with cFSGS were enrolled in the study. Staining for differentiated podocyte markers such as WT 1, PAX and KI67 were performed in all patients. The outcome and histological features of cFSGS was compared with a prospectively followed cohort of steroid and TAC-resistant noncollapsing FSGS. The study included 22 cFSGS patients and 19 cases of steroid and TAC-resistant FSGS. Complete remission, partial remission, steroid resistance, progression to ESRD and death were observed in 13.6%, 4.5%, 27.3%, 36.4% and 18.2% patients, respectively. Patients with cFSGS had higher serum creatinine and more advanced tubulointerstitial changes compared to resistant FSGS. Twenty-six percent of therapy resistant noncollapsing FSGS progressed to ESRD after two years of stopping TAC. However, there was no difference in progression to ESRD between cFSGS and therapy-resistant noncollapsing FSGS at the end of two years. Glomerular collapse in the setting of FSGS is poorly responsive to treatment and has a high rate of progression to ESRD. The long-term prognosis of cFSGS and steroid and TAC-resistant FSGS are similar.

Topics: Adolescent; Adult; Creatinine; Disease Progression; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Podocytes; Prognosis; Prospective Studies; Remission Induction; Steroids; Tacrolimus; Young Adult

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

Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent TRPC6 activation underlies glomerular diseases. Here, we developed a murine model in which a constitutively active Gq α subunit (Gq(Q209L), referred to herein as GqQ>L) is specifically expressed in podocytes and examined the effects of this mutation in response to puromycin aminonucleoside (PAN) nephrosis. We found that compared with control animals, animals expressing GqQ>L exhibited robust albuminuria, structural features of FSGS, and reduced numbers of glomerular podocytes. Gq activation stimulated calcineurin (CN) activity, resulting in CN-dependent upregulation of TRPC6 in murine kidneys. Deletion of TRPC6 in GqQ>L-expressing mice prevented FSGS development and inhibited both tubular damage and podocyte loss induced by PAN nephrosis. Similarly, administration of the CN inhibitor FK506 reduced proteinuria and tubular injury but had more modest effects on glomerular pathology and podocyte numbers in animals with constitutive Gq activation. Moreover, these Gq-dependent effects on podocyte injury were generalizable to diabetic kidney disease, as expression of GqQ>L promoted albuminuria, mesangial expansion, and increased glomerular basement membrane width in diabetic mice. Together, these results suggest that targeting Gq/TRPC6 signaling may have therapeutic benefits for the treatment of glomerular diseases.

Topics: Albuminuria; Animals; Calcineurin; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Deletion; Genes, Reporter; Glomerulosclerosis, Focal Segmental; GTP-Binding Protein alpha Subunits, Gq-G11; HEK293 Cells; Humans; Kidney Glomerulus; Kidney Tubules; Mice; Mice, Mutant Strains; Mice, Transgenic; NFATC Transcription Factors; Podocytes; Point Mutation; Puromycin Aminonucleoside; Recombinant Fusion Proteins; Signal Transduction; Tacrolimus; TRPC Cation Channels; TRPC6 Cation Channel

Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, are the targets of the microRNA-30 family (miR-30s). We found that these 5 genes are highly expressed as mRNA, but the level of the proteins is low in normal podocytes. Conversely, protein levels were markedly elevated in podocytes from rats treated with puromycin aminonucleoside (PAN) and from patients with focal segmental glomerulosclerosis (FSGS). In both FSGS patients and PAN-treated rats, miR-30s were downregulated in podocytes. In cultured podocytes, PAN or a miR-30 sponge increased TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3 expression; calcium influx; intracellular Ca2+ concentration; and calcineurin activity. Moreover, NFATC3 nuclear translocation, synaptopodin degradation, integrin β3 (ITGB3) activation, and actin fiber loss, which are downstream of calcium/calcineurin signaling, were induced by miR-30 reduction but blocked by the calcineurin inhibitor FK506. Podocyte-specific expression of the miR-30 sponge in mice increased calcium/calcineurin pathway component protein expression and calcineurin activity. The mice developed podocyte foot process effacement and proteinuria, which were prevented by FK506. miR-30s also regulated calcium/calcineurin signaling in cardiomyocytes. Together, our results identify miR-30s as essential regulators of calcium/calcineurin signaling.

Topics: Animals; Apoptosis; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Cells, Cultured; Doxorubicin; Gene Expression Regulation; Glomerulosclerosis, Focal Segmental; Humans; Mice; Mice, Transgenic; MicroRNAs; Myocytes, Cardiac; NFATC Transcription Factors; Podocytes; Proteinuria; Rats; RNA, Messenger; Tacrolimus; Transfection; TRPC Cation Channels

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular condition leading to end-stage renal disease (ESRD) and the third most common cause of ESRD in pediatric patients.. This is a retrospective study consisting of 22 pediatric patients with FSGS and heavy proteinuria. After demonstrating steroids resistance, the patients were treated with tacrolimus, targeting a trough level 5-8 ng/mL. The primary outcome is the induction of remission with tacrolimus.. Thirteen patients (59%) achieved remission (complete in 31.8% and partial in 27.2%) and 12 patients showed stable or improved renal function over an average follow-up of 2.9 years (range: 0.5-7 years). There was no significant difference in response rate between African American and Caucasian patients. None of the patients had significant side-effect to tacrolimus and none of the repeat biopsies showed an increase in interstitial fibrosis compared to baseline. The best renal outcome was for patients who achieved complete remission. Partially responsive patients had improved renal function compared with resistant patients.. Tacrolimus is a viable option in the treatment of children with idiopathic steroid resistant FSGS.

Topics: Adolescent; Child; Child, Preschool; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant; Male; Proteinuria; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

Topics: Antihypertensive Agents; Cyclophosphamide; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Fatigue; Glomerulosclerosis, Focal Segmental; Gynecomastia; Humans; Hypertension; Male; Mastodynia; Middle Aged; Muscle Weakness; Mycophenolic Acid; Prednisone; Proteinuria; Tacrolimus

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

Topics: Child, Preschool; Combined Modality Therapy; Cytokines; Drug Resistance; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Plasma Exchange; Pulse Therapy, Drug; Tacrolimus

Topics: Child; Child, Preschool; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

In general, anti-HLA antibody belongs to the IgG subclass, but there are very few reports of detection of anti-HLA IgM antibodies. In the present study, we report a renal transplant recipient with a positive NIH-complement dependent cytotoxicity (NIH-CDC) test. The patient was a 24-year-old male with focal segmental glomerulosclerosis (FSGS) as the underlying kidney disease. He had been on maintenance hemodialysis since December 2003 and finally received a living-donor allograft from his mother in October 2008. Pre-transplantation, the NIH-CDC test was positive for both B and T cells, but the flow-cytometric crossmatch test (FCXM) was negative for both cells. The result of the panel-reactive antibody assay (PRA)-single beads test using anti-IgM antibody as the second antibody demonstrated that the positive NIH-CDC test was due to the presence of anti-HLA IgM antibody against the donor-specific antigen A24. Biopsy specimens showed thrombus formation in a small number of glomeruli immediately after the transplantation, but this finding was no longer seen at three months postoperatively. We report successful renal transplantation in a case with anti-HLA IgM antibody.

Topics: Adult; Female; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Graft Rejection; Histocompatibility Testing; HLA-A Antigens; HLA-A24 Antigen; Humans; Immunoglobulin M; Immunosuppressive Agents; Kidney; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Tacrolimus

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

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

Topics: Biopsy; Cyclosporine; Cystic Fibrosis; Diabetic Nephropathies; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Kidney Tubules; Lung Transplantation; Retrospective Studies; Tacrolimus

Nephropathies associated with thymoma or myasthenia gravis (MG) have rarely been observed. Furthermore, among the renal pathology of patients presenting with thymic and renal disease, focal segmental glomerulonephritis (FSGS) is the uncommon type. Herein, we report a case of a 50-year-old woman who suffered from intractable MG and FSGS resistant to standard therapy. After the start of low-dose tacrolimus treatment, the patient showed simultaneous and significant improvement of myasthenic symptoms and proteinuria. Although a satisfactory explanation of the underlying mechanism has not been offered yet, T cell dysfunction involved in both diseases might explain their association and improvement. This case suggests that low-dose tacrolimus treatment appears to be effective not only for improving intractable myasthenia symptoms but also for obtaining complete remission of FSGS.

Topics: Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Middle Aged; Myasthenia Gravis; Tacrolimus

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

Topics: Child; Cyclosporine; Drug Resistance; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; 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

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

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

Focal segmental glomerulosclerosis (FSGS) commonly presents with nephrotic syndrome (NS), and spontaneous remission is rare. NS is a poor prognostic marker for renal survival, and has serious extra-renal complications. Rapid remission using drugs with minimal side effects is desirable. Tacrolimus (Tac) has a more potent immunosuppressive effect and may be less toxic at therapeutic doses than ciclosporin (CsA). Although CsA has a role in the treatment of FSGS, there are limited data regarding the use of Tac monotherapy in this setting, and this is limited to experience in children.. We prospectively report the outcome for six adult patients with FSGS treated with Tac from first presentation with NS, and for a further five adult patients in remission on CsA converted to Tac in an attempt to arrest a progressive decline in renal function on CsA.. All six patients treated with Tac from presentation with NS achieved remission after 6.5 +/- 5.9 months. The serum albumin for the group increased from 26.8 +/- 4.6 to 37.7 +/- 1.9 g/l (P = 0.003), and there was a significant reduction in the mean 24 h urinary protein excretion from 11.0 +/- 4.5 to 2.8 +/- 2.5 g (P = 0.003). All remissions were partial with a mean reduction in 24 h urinary protein of 75.2 +/- 16.8%. There was a non-significant reduction in MDRD GFR from 71.7 +/- 22.4 to 55.9 +/- 9.7 ml/min/1.73 m(2) (P = 0.07), which manifest within the first 3 months of Tac treatment but renal function was subsequently stable. The mean follow-up for the group was 12.8+/-5.5 months. Two of the five patients converted from CsA to Tac maintained complete remission, and the remaining three patients in partial remission had further reductions in proteinuria. There was an improvement in renal function concomitant with conversion to Tac in each case, with an overall improvement in MDRD GFR for the group of +1.9+/-1.1 ml/min/1.73 m(2)/month.. Tac rapidly and effectively induced remission of NS in FSGS. Conversion from CsA to Tac indicates that Tac might be a more potent agent with less nephrotoxicity in this setting.

Topics: Adult; Albuminuria; Cyclosporine; Diabetic Nephropathies; Female; Follow-Up Studies; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Proteinuria; Tacrolimus; Time Factors; Treatment Outcome

Cyclosporin has improved the outcome for steroid-resistant patients with focal glomerulosclerosis, but there is a proportion of patients that are either cyclosporin-resistant or suffer relapses, needing long-term therapy to sustain the remission. In these cases, preliminary reports suggest that tacrolimus could be an alternative therapy, but to date the evidence is limited to small series of patients with no long-term follow-up.. In this study we analysed the efficacy and safety of a combined therapy of tacrolimus and steroids in 25 patients (mean serum creatinine= 1.24+/-0.49 mg/dl; mean proteinuria=10.2+/-9.5 g/day; mean serum albumin=2.4+/-0.58 g/dl) with idiopathic primary focal glomerulosclerosis and proven resistance to or dependence on cyclosporin A.. After a 6 months trial of tacrolimus and steroids, proteinuria decreased in 17 patients (68%) (complete remission in 10 patients (40%), partial remission in two patients (8%) and a moderate reduction in proteinuria to levels <3 g/day was seen in five additional patients (20%)). The only predictor of response to tacrolimus was a previous response to cyclosporin and prednisone, either as a complete or partial remission (remission rate 75% vs 15.3; P=0.036). Mean time to remission was 112+/-24 days. After tacrolimus discontinuation, 13/17 patients (76%) relapsed and were treated with a second trial of tacrolimus for 1 year, achieving complete remission in five patients (38.4%), partial remission in four patients (30.7%) and reduction of proteinuria <3 g/day in four patients (30.7%). After 2 years of follow-up, 12 patients (48%) were on sustained remission. The main side effect was acute reversible nephrotoxicity (40%). Predictors of renal toxicity were age (P=0.037), baseline creatinine (P=0.046) and tacrolimus trough level (P=0.001).. We conclude that combined therapy of tacrolimus and steroids induce sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and cyclosporin A.

Topics: Adrenal Cortex Hormones; Adult; Aged; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Middle Aged; Prospective Studies; Tacrolimus

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

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Enalapril; Glomerulosclerosis, Focal Segmental; Immune System; Immunosuppressive Agents; Interleukin-2; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Tacrolimus; Tetrazoles; Triglycerides

Focal and segmental glomerulosclerosis (FSGS) is one of the most frequent and severe primary glomerulonephritis that recurs in transplanted kidneys. Although cyclosporine seems to have no effect on the frequency of FSGS recurrence, there is evidence that cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulonephritis after renal transplantation. The effect of tacrolimus on nephrotic syndrome after renal transplantation is controversial.. We describe the case of a 30-year-old man with steroid-resistant nephrotic syndrome due to FSGS who developed nephrotic syndrome 5 years after renal transplantation due to recurrent disease when he was switched from cyclosporine to tacrolimus.. He was given pulses of methylprednisolone and returned to cyclosporine. His proteinuria decreased, but he rapidly developed chronic renal failure.. This observation strongly suggests that tacrolimus should be given with considerable care in renal transplant recipients with FSGS.

Topics: Adolescent; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Recurrence; Tacrolimus; Transplantation, Homologous

Topics: Adult; Delivery, Obstetric; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Infant, Newborn; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Period; Pregnancy; Recurrence; Tacrolimus

Topics: Anti-Bacterial Agents; Bone Marrow Transplantation; Child; Glomerulosclerosis, Focal Segmental; Graft vs Host Disease; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestines; Islets of Langerhans Transplantation; Kidney Transplantation; Liver Transplantation; Tacrolimus

Topics: Adult; Anti-Bacterial Agents; Child, Preschool; Drug Resistance; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Prednisone; Tacrolimus