tacrolimus and Glomerulonephritis

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

There has been considerable excitement in the kidney community surrounding the research findings on the genetic contributions to kidney diseases. However, positive outcomes of personalized therapeutic interventions can be circumvented by unpredictable pharmacokinetics of prescribed drugs. Furthermore, unpredictable drug disposition can result in toxicities such as kidney injury. Patient covariates, disease covariates, and pharmacogenetics all contribute to variability in drug disposition. Further treatment personalization and avoidance of drug- and biologic- induced kidney injury will require extensive knowledge and expertise in renal clinical pharmacology. The current review will focus on the pharmacogenetics of drugs and biologics used in the treatment of glomerular kidney diseases and drugs implicated in inducing kidney injury phenotypes.

Topics: Acute Kidney Injury; Azathioprine; Calcineurin Inhibitors; Cisplatin; Cyclophosphamide; Cytochrome P-450 Enzyme System; Enzymes; Glomerulonephritis; Humans; Hydroxychloroquine; Membrane Transport Proteins; Mycophenolic Acid; Pharmacogenetics; Polymorphism, Genetic; Rituximab; Tacrolimus; Tenofovir

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

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

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

Cyclosporine and tacrolimus are potent immunosuppressant agents that have been used extensively in humans, primarily for prevention of transplant rejection but also for the treatment of autoimmune disorders. Both agents have similar mechanisms of action and pharmacokinetic profiles. However, the expected toxicity of the agents is dissimilar. Although cyclosporine usage in veterinary medicine is limited, it has been used enough for therapeutic guidelines to be established. Tacrolimus, however, has undergone limited use in veterinary medicine. The drug is too toxic in dogs for its use to be recommended in most clinical situations. This article reviews the mechanism of action, pharmacokinetics, expected drug interactions and toxicities, and clinical usage of cyclosporine and tacrolimus in veterinary medicine.

Topics: Animals; Autoimmune Diseases; Cat Diseases; Cats; Cyclosporine; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Eye Diseases; Glomerulonephritis; Graft Rejection; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Transplantation

The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN.. Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events.. There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29).. In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy.. ClinicalTrials.gov Identifier NCT03062813.

Topics: Adult; Antiviral Agents; DNA, Viral; Glomerulonephritis; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Prospective Studies; Proteinuria; Serum Albumin; Single-Blind Method; Tacrolimus; Treatment Outcome

Thy1.1 glomerulonephritis (Thy1.1 GN) in rats is widely used as an experimental model of mesangial proliferative glomerulonephritis (GN). We previously reported that T-helper (Th) cells were accumulated in glomeruli from the early phase of this model and that not Th2 cells but Th1 cells play an important role in the development of glomerular alterations. Although Th17 is reported to be involved in the pathogenesis of several autoimmune diseases, the role of Th17 cells in the pathogenesis of mesangial alterations in Thy1.1 GN remains unclear.. The kinetics of the infiltration of subsets of Th cells and the expression of IL-17 in Thy1.1 GN were analyzed. Next, the localization and the cell types of IL-17 receptor (IL-17R)-positive cells and IL-6-positive cells were analyzed. Then, the effect of tacrolimus on the expressions of Th17-related cytokines in Thy1.1 GN was analyzed.. Not only Th1 cells but also Th17 cells were recruited into glomeruli from the early phase of the disease. mRNA expression of IL-17 in glomeruli was elevated. The increased positive expression of IL-17R was detected in the mesangial area, and some of IL-17R-positive cells were co-stained with IL-6. Tacrolimus treatment ameliorated mesangial alterations by suppressing the expressions of Th17-related cytokines such as IL-17 and IL-6.. Th17 cells participate in the development of Thy1.1 GN, a mimic of mesangial proliferative GN, and Th17 cells and their related cytokines are pertinent therapeutic targets.

Topics: Animals; Cytokines; Glomerulonephritis; Humans; Interleukin-17; Interleukin-6; Rats; Tacrolimus; Th1 Cells; Th17 Cells; Thy-1 Antigens

Topics: Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Glomerulonephritis; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

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

Topics: Antibodies, Antineutrophil Cytoplasmic; Biopsy; Cyclophosphamide; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Middle Aged; Ribonucleosides; Tacrolimus; Treatment Outcome

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

Topics: Azathioprine; Cyclophosphamide; Female; Glomerulonephritis; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Mycophenolic Acid; Prednisone; Tacrolimus

We report the successful allotransplantation of cryopreserved parathyroid tissue to reverse hypocalcemia in a kidney transplant recipient. A 36-year-old male received a second deceased donor kidney transplant, and 6 weeks later developed severe bilateral leg numbness and weakness, inability to walk, acute pain in the left knee and wrist tetany. His total calcium was 2.6 mg/dL and parathormone level 5 pg/mL (normal 10-60 pg/mL). He underwent allotransplantation of parathyroid tissue cryopreserved for 8 months into his left brachioradialis muscle. Immunosuppression included tacrolimus (target C(0) 10-12 ng/mL), mycophenolate mofetil and steroids. Within 2 weeks, the left knee pain, leg weakness and numbness resolved, and by 1 month he could walk normally. After a peak at month 2, his parathyroid hormone (PTH) level fell to <10 pg/mL; therefore at month 3 he received a second parathyroid transplant from the same donor. Eight months later (11 months after initial graft) he has a total calcium of 9.3 mg/dL, PTH level 15 pg/mL and is clinically asymptomatic. The amount of parathyroid tissue needed to render a patient normocalcemic is not known. In our case, the need for second transplant suggests that the amount of tissue transferred for an allograft may need to be substantially greater than for an autograft.

Topics: Adult; Cryopreservation; Drug Therapy, Combination; Glomerulonephritis; Glucocorticoids; Humans; Hypocalcemia; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Muscle, Skeletal; Mycophenolic Acid; Parathyroid Glands; Prednisone; Reoperation; Severity of Illness Index; Tacrolimus; Transplantation, Heterotopic; Transplantation, Homologous

Recurrent glomerulonephritis is a major problem in kidney transplantation but the role of immunosuppression in preventing this complication is not known. We used data from the United States Renal Data System to examine the effect of immunosuppressive medication on allograft failure due to recurrent glomerulonephritis for 41,272 patients undergoing kidney transplantation from 1990 to 2003. Ten-year incidence of graft loss due to recurrent glomerulonephritis was 2.6% (95% confidence interval [CI]: 2.3-2.8%). After adjusting for important covariates, the use of cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus or prednisone was not associated with graft failure due to recurrent glomerulonephritis. There was no difference between cyclosporine and tacrolimus or between azathioprine and mycophenolate mofetil in the risk of graft failure due to recurrent glomerulonephritis. However, any change in immunosuppression during follow-up was independently associated with graft loss due to recurrence (adjusted hazard ratio 1.30, 95% CI: 1.06-1.58, p = 0.01). In patients with a pretransplant diagnosis of glomerulonephritis, the risk of graft loss due to recurrence was not associated with any specific immunosuppressive medication. The selection of immunosuppression for kidney transplant recipients should not be made with the goal of reducing graft failure due to recurrent glomerulonephritis.

Topics: Adult; Azathioprine; Cyclosporine; Female; Glomerulonephritis; Hepatitis B Surface Antigens; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Markov Chains; Middle Aged; Monte Carlo Method; Mycophenolic Acid; Recurrence; Risk Factors; Tacrolimus; Transplantation, Homologous; Treatment Failure

Immunotactoid glomerulopathy is a glomerular disorder typified by hollow cylindrical and sometimes spherical microtubular deposits, with a diameter of 30-40 nm, but up to 90 nm, often in a parallel arrangement or in intersecting bundles. These patients frequently end up receiving kidney transplants due to progressive renal insufficiency. Known to recur in renal transplant recipients with variable outcomes, its treatment options are limited. Classically steroids, cyclophosphamide, mycophenolate mofetil, and plasma exchanges have been used to treat these recurrences. More recently, rituximab has been suggested as a treatment and has demonstrated improved outcomes in other glomerular diseases. Herein we describe a case of a middle-aged female renal transplant recipient for end-stage renal disease secondary to immunotactoid glomerulopathy, who experienced a recurrence of this condition in the transplanted kidney. Following a failure of conventional therapy we administered a course of rituximab, resulting in a reduction and stabilization of her serum creatinine level while her proteinuria persisted.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Prednisone; Proteinuria; Recurrence; Rituximab; Tacrolimus; Transplantation, Homologous

To investigate the risk factors of insulin resistance (IR) and the role of IR and metabolic syndrome in the pathogenesis of chronic allograft nephropathy (CAN).. One hundred and twenty-seven kidney transplant recipients with normal renal function and no proteinuria at the 6th month after transplantation, and without the experience of acute rejection, calcinurine intoxication and severe infection, were involved in the study. Their primary disease of ESRF was chronic glomerulonephritis but not diabetes mellitus and hypertension. Half year and one year after transplantation, blood and urine biochemical determinations and physical examination were performed in the recipients, and HOMA calculated. 200 ordinary community residents were randomized selected as controls.. The incidence of MS in the recipients was significantly higher than controls. The incidences of obesity and overweight between recipients and controls were no significant difference. While the insulin resistance level and urine albumin level, and the incidence of MS and microalbuminuria (MAU) were significantly higher in recipients with obesity or overweight than that in recipients without obesity or overweight. The insulin resistance level in tacrolimus-treated recipients was markedly higher than CsA-treated recipients, and there was a positive correlation between the blood concentration of tacrolimus and insulin resistance level. MAU positive recipients had higher insulin resistance levels than the recipients without MAU. The recipients with metabolic syndrome had higher insulin resistance levels compared to recipients without metabolic syndrome, and higher insulin resistance levels existed in recipients with hypertriglyceridemia or hypercholesterolemia, hypertension.. It is shown in the study that obesity or overweight, tacrolimus (especially when its blood concentration was high) were risk factors resulting in insulin resistance in kidney transplant recipients. It is suggested in the study that insulin resistance often accompanied with hypertriglyceridemia, hypercholesterolemia and hypertension in kidney transplant recipients might be involved in the pathogenesis of the pathogenesis of CAN.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Glomerulonephritis; Humans; Incidence; Insulin Resistance; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Overweight; Risk Factors; Tacrolimus

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Glomerulonephritis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; 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

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerulonephritis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

We have previously shown the long-term influence of renal ischemia/reperfusion (I/R) injury and immunosuppression on fibrotic genes and apoptosis in a rat model. For the first time, we have now investigated the effects of I/R and immunosuppression on inflammation and caspase activation.. I/R injury was induced in the right kidney and the left was removed. Cyclosporin (CsA) (10 mg/kg), tacrolimus (0.2 mg/kg), rapamycin (1 mg/kg), or mycophenolate mofetil (MMF) (10 mg/kg) was then administered for 16 weeks. The effects of I/R and immunosuppressants on interstitial inflammation, interleukin (IL)-1beta expression, caspase-1 and caspase-3 activation, tubulointerstitial damage, and fibrosis were evaluated.. ED-1+ (a specific rat monocyte/macrophage marker) cells were mainly localized in the tubulointerstitium and periglomerular areas and increased in I/R group compared to controls (P < 0.01). This was further increased by CsA, but decreased by tacrolimus, rapamycin, or MMF (P < 0.05). The 17 kD active IL-1beta remained unchanged, but 35 kD IL-1beta precursor was decreased by rapamycin in comparison with I/R group (P < 0.05). The 45 kD or 20 kD caspase-1 was increased by I/R or CsA, respectively, and decreased by rapamycin (P < 0.05). The 24 kD caspase-3, which proved to be an active caspase-3 subunit, was increased in I/R and CsA groups and deceased by tacrolimus, rapamycin, or MMF (P < 0.05), but not 32 kD precursor or 17 kD active caspase-3. The activity data of caspase-1 and caspase-3 exhibited the same trend as Western blotting data. The staining of active caspase-3 was scattered in kidneys, mainly in tubular and interstitial areas, which was consistent with that of ED-1+ cells. There was a strong positive correlation between interstitial inflammation and 24 kD caspase-3 expression or caspase-3 activity (r = 0.814 or 0.484), all of which were also closely related with urinary protein (r = 0.537, 0.529, or 0.517), serum creatinine (r = 0.463, 0.573, or 0.539), tubulointerstitial damage (r = 0.794, 0.618, or 0.712) and fibrosis (r = 0.651, 0.567, or 0.469), all P < 0.01.. This study shows that the mechanisms of long-term I/R injury and immunosuppressants treatment include interstitial inflammation and caspase activation, most clearly demonstrated by the 24 kD active caspase-3.

Topics: Animals; Apoptosis; Caspase 1; Caspase 3; Caspases; Chronic Disease; Cyclosporine; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix; Fibrosis; Glomerulonephritis; Immunosuppressive Agents; Interleukin-1; Male; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion Injury; Sirolimus; Tacrolimus

We have previously reported that CD4 T lymphocytes and their cytokines contribute to development of Thy 1.1 glomerulonephritis (GN). FK506 is reported to suppress the production of Th1 cytokines. The aims of this study were to elucidate the role of Th1 cytokines on mesangial alteration and to examine whether FK506 is available for therapy of mesangial proliferative GN.. The effects of daily treatments of FK506 from day -5 and from day +1 of Thy 1.1 GN induction on glomerular alterations were analyzed.. FK506 treatment with 1.0 and 0.3 mg/kg body weight (BW) daily from day 1 to day 4 significantly reduced the glomerular expression of mRNA for interferon-gamma (IFN-gamma; 1.0 mg/kg BW FK506, 32.4% to the placebo group, P < 0.01) and IL-2 (55.6%, P < 0.01) on day 5. FK506 treatment from day -5 of GN induction reduced proteinuria and glomerular alteration in a dose-dependent manner. Although no side effects were detected in rats with 0.3 mg/kg BW of FK506 treatment from day +1, the treatment also ameliorated proteinuria (day 14, 3.7 +/- 0.89 vs. 19.8 +/- 12.3 mg/100 g BW/day P < 0.05) and glomerular alterations [total cell number, 63.1 +/- 3.1 vs. 80.2 +/- 7.4, P < 0.01; matrix expansion, 0.90 +/- 0.30 vs. 1.34 +/- 0.27, P < 0.05; alpha-smooth muscle actin (alphaSMA) expression; 1.20 +/- 0.12 vs. 1.96 +/- 0.29, P < 0.01] on day 14.. Th1 cytokines may play an important role in the development of mesangial proliferative glomerulonephritis, and could be targets for therapy. FK506 might be available for clinical use.

Topics: Animals; Antibodies, Monoclonal; Cytokines; Dose-Response Relationship, Drug; Female; Glomerulonephritis; Immunosuppressive Agents; Kidney Glomerulus; Proteinuria; Rats; Rats, Wistar; Tacrolimus; Th1 Cells; Thy-1 Antigens; Time Factors

Proximal tubular cholesterol levels rise within 18 hours of diverse forms of acute renal tubular injury (eg, myoglobinuria, ischemia/reperfusion, urinary tract obstruction). These increments serve to protect against further bouts of tubular attack (so-called "acquired cytoresistance"). Whether these cholesterol increments are merely transitory, or persist into the maintenance phase of acute renal failure (ARF), has not been previously defined. Furthermore, whether subacute/insidious tubular injury [eg, cyclosporine A (CSA), tacrolimus toxicity], nontubular injury (eg, acute glomerulonephritis), or physiological stress (eg, mild dehydration) impact renal cholesterol homeostasis have not been addressed. This study sought to resolve these issues. Male CD-1 mice were subjected to glycerol-induced ARF. Renal cortical-free cholesterol (FC) and cholesterol ester (CE) levels were determined 3, 5, 7, or 14 days later, and the values contrasted to prevailing blood-urea nitrogen concentrations. The impact of 40 minutes of unilateral renal ischemia plus reflow (3 to 6 days) on mouse cortical FC/CE content was also assessed. Additionally, FC/CE levels were measured in rat renal cortex either 10 days after CSA or tacrolimus therapy, or 48 hours after induction of nephrotoxic serum nephritis. Finally, the impact of overnight dehydration on mouse renal cortical/medullary FC/CE profiles was determined. Compared to sham-treated animals, glycerol, CSA, tacrolimus, ischemia-reperfusion, and nephrotoxic serum each induced dramatic CE +/- FC elevations, rising as much as 10x control values. In the glycerol model, striking correlations (r

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cholesterol; Cholesterol Esters; Cyclosporine; Dehydration; Glomerulonephritis; Glycerol; Ischemia; Kidney; Kidney Cortex; Kidney Medulla; Kidney Tubules; Male; Mice; Nephritis; Rats; Rats, Sprague-Dawley; Reperfusion; Tacrolimus

Mercuric-chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway rats. The effects of a new immunosuppressant FK 506 on this model of glomerulonephritis were studied. Brown Norway rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/ week). Rats developed proteinuria at day 7, which reached a plateau level at day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed a strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Coadministration of FK 506 (1 mg/kg s.c. daily) prevented the appearance of proteinuria at day 14 (621.4 +/- 30.5 vs. 2.2 +/- 2.7 mg/day) and the morphological lesions. These findings suggest that FK 506 could be useful for the therapy of certain types of human glomerulonephritis.

Topics: Animals; Autoimmune Diseases; Blood Proteins; Disinfectants; Dose-Response Relationship, Drug; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Male; Mercuric Chloride; Microscopy, Electron; Rats; Tacrolimus; Urine

Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway (BN) rats. The effects of a new immunosuppressant, FK 506, on this model of glomerulonephritis were studied. BN rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/week). FK 506 was inoculated subcutaneously daily from day 15 to day 28. Animals were divided into 4 groups: group 1, rats were treated with normal saline alone and sacrificed on day 28; group 2, rats were treated with HgCl2 alone and sacrificed on day 14; group 3, rats were treated with HgCl2 alone and sacrificed on day 28, and group 4, rats were treated with HgCl2 and FK 506 (from day 15 to day 28) and sacrificed on day 28. Rats developed proteinuria by day 7, which reached a plateau level by day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Treatment with FK 506 (1 mg/kg s.c. daily) resulted in a remarkable reduction in proteinuria on day 28 (493.5 +/- 48.3 vs. 24.4 +/- 13.5 mg/day) and an improvement in the morphological lesions. These findings suggest that FK 506 could be useful in the treatment of some human glomerulonephritides.

Topics: Animals; Autoimmune Diseases; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney; Kidney Function Tests; Male; Mercuric Chloride; Microscopy, Electron; Proteinuria; Rats; Rats, Inbred BN; Tacrolimus

Living renal transplantation (Tx) was carried out on a 41-year-old male undergoing hemodialysis for a six-month period because of end-stage renal failure due to chronic glomerulonephritis. Tacrolimus (FK 506) was used as one of immunosuppressants. The graft worked immediately after Tx. However, his blood sugar level rose extremely high and use of insulin (IS) was required. At the second postoperative day, 0.3 mg/kg/day of FK506 was administered and the trough level (TL) was as high as 65 ng/ml. The serum IS level decreased from the pre-Tx value of 22 microU/ml to 12 microU/ml. With decrease in the dose of FK506, the TL was normalized, and the dose of IS could be decreased. FK506 has been reported to inhibit IS secretion. Therefore, we must be careful to evaluate the blood glucose level in the use of FK506 for patients with poor glucose tolerance.

Topics: Adult; Chronic Disease; Diabetes Mellitus; Glomerulonephritis; Glucose Intolerance; Humans; Kidney Transplantation; Male; Renal Dialysis; Tacrolimus; Transplantation, Homologous

FK506 is a recently-developed immunosuppressive drug. The aim of the present work was to investigate the effects of FK506 in experimental autoimmune glomerulonephritis (active Heymann nephritis) in rats. Active Heymann nephritis was induced in female Lewis rats by two immunizations with the homologous brush border vesicles (BBVs) at day 0 and day 28 (groups I, II, V, and VI). Rats of groups III and IV received the third immunization at day 56. In rats of groups I and III, FK506 was injected (1 mg/kg/day IM) from day 0 for 14 days. In rats of groups II and IV, significant proteinuria was observed (group II, 112.8 mg/16 hours; group IV, 55.4 mg/16 hours) at the time the rats were killed (day 84). Coarse subepithelial immune deposits (IDs) were found in these rats. In contrast, urinary protein excretion remained within normal range (less than 3.0 mg/16 hours) in groups I and III rats, and tiny subepithelial IDs were only occasionally seen. Circulating anti-BBV antibody levels were markedly lower in group I and III rats than in those of groups II and IV during the period between day 14 and day 56. To investigate the effects of FK506 on the proteinuric rats, FK506 (1 mg/kg/day, IM) was administered every day for 2 weeks beginning on day 56 (group V).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibodies; Creatine; Disease Models, Animal; Female; Glomerulonephritis; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Microvilli; Proteinuria; Rats; Rats, Inbred Lew; Tacrolimus

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

The aim of the present work was to study the effects of a new immunosuppressive drug, FK506, in accelerated nephrotoxic serum glomerulonephritis. Glomerulonephritis was induced in female Wistar rats by the preimmunization with normal rabbit IgG (Day-4) and the subsequent intravenous injection of rabbit anti-GBM serum (Day 0). Without treatment with FK506, rats developed proteinuria at Day 6 and onward. Rat anti-rabbit IgG was strongly detected at Day 6 and the titer was maintained through Day 20. Moderate hypercellularity and focal crescent formation were observed at Day 20. Rats injected intramuscularly with 0.3 or 1 mg/kg of FK506 did not develop proteinuria and the anti-rabbit IgG titer was much less or was undetectable throughout the experiments. These data suggest that FK506 is effective in the present model of glomerulonephritis.

Topics: Animals; Anti-Bacterial Agents; Creatinine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Kidney; Proteinuria; Rats; Rats, Inbred Strains; Tacrolimus