sirolimus 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

Sirolimus is an important immunosuppressive drug in renal transplantation but contains numerous side effects. In this study, we describe a case of renal transplant recipient treated with sirolimus who developed pericardial effusion associated with interstitial pneumonia. An extensive search for alternative causes were all negative, and all symptoms disappeared after sirolimus interruption. Therefore, this case demonstrates that sirolimus can cause pericardial effusion possibly through a proinflammatory mechanism.

Topics: Diagnosis, Differential; Drug Substitution; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pericardial Effusion; Postoperative Complications; Sirolimus; Transplant Recipients; Treatment Outcome

A 68-year-old man who underwent living-unrelated kidney transplantation from his spousal donor was immunosuppressed with tacrolimus and mycophenolate mofetil. Despite his uneventful clinical course, protocol biopsy at 2 years post transplant showed de novo CNI tubulotoxicity despite low tacrolimus exposure. Everolimus was added in order to discontinue TACER. However, prominent proteinuria impeded continuation of everolimus since biopsy showed diffuse glomerular endocapillary proliferation without C4d deposition. No donor-specific antibody was detected. Pulse steroids were given and proteinuria returned to normal with histological reversal.

Topics: Aged; Everolimus; Glomerulonephritis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Proteinuria; Sirolimus

The use of targeted therapies is increasing in the treatment of cancer. Monoclonal antibodies and tyrosine kinase inhibitors are the most commonly used but other classes such as mTOR inhibitors are increasingly prescribed. These treatments are often given in the long term in metastatic and maintenance treatments. It is therefore important to monitor the occurrence of immediate toxicities but also later and cumulative toxicities. Renal toxicities of targeted therapies are most often due to structural damages of the nephron. The anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor (VEGFR) have renal side effects since growth factor receptors are expressed in the kidney. The toxicity of molecules such as bortezomib, erlotinib and lapatinib are less known. The approvals by the Food and Drugs Administration (FDA) and European Medicines Agency (EMA) of sorafenib, sunitinib and temsirolimus were based on studies of less than 3,000 patients. In this context, there is little data on their acute and chronic tolerance, including on the kidneys. This short review synthesizes the physiopathological hypotheses, early diagnosis and treatment of renal toxicity of major targeted therapies available in 2011.

Topics: Antibodies, Monoclonal; Benzenesulfonates; Boronic Acids; Bortezomib; Erlotinib Hydrochloride; Glomerulonephritis; Humans; Indoles; Kidney; Kidney Tubules; Lapatinib; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrazines; Pyridines; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib

Late spontaneous kidney graft decapsulation with fluid collection is a rare condition with only a few cases reported in the literature. Common causes of renal allograft rupture include acute rejection, acute tubular necrosis, renal vein thrombosis, and trauma. Sirolimus related late spontaneous decapsulation has not been reported in the past. Interestingly, sirolimus may promote lymphocele formation in renal transplant recipients, including those presenting with chronic hepatitis B or C. Herein, we report a case of late spontaneous decapsulation with subcapsular hematoma formation developing 12 years after receipt of a cadaveric allograft. The patient was infected with both hepatitis B and C viruses. Cyclosporine was replaced by sirolimus for maintenance therapy because of chronic rejection and acute deterioration of renal function. He presented to the hospital at 9 months after sirolimus inception because of a sudden onset of pain and swelling over the kidney graft. Magnetic resonance imaging found the capsule to be stripped from the kidney by a collection of liquefied hematomas. A laparoscopic fenestration was performed by creation of a peritoneal window adjacent to the renal allograft. When patients have chronic hepatitis, tacrolimus might be a better choice than sirolimus.

Topics: Bowman Capsule; Cadaver; Creatinine; Glomerulonephritis; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Magnetic Resonance Imaging; Male; Renal Artery; Sirolimus; Tissue Donors; Ultrasonography

The antiproliferative immunosuppressant everolimus adversely affects the acute reversible anti-Thy1 nephritis model. We hypothesized that everolimus treatment started after the acute proliferative phase could even be beneficial in the chronic anti-Thy1 nephritis model in the rat.. Chronic anti-Thy1 nephritis was induced by injection of the monoclonal antibody 1-22-3 in 20 male Sprague-Dawley rats 7 days after uninephrectomy. Two weeks after disease induction, rats were randomly treated with either everolimus or vehicle for 14 weeks. Changes in progression of renal disease were investigated by immunohistochemistry and real-time PCR 16 weeks after disease induction.. During chronic anti-Thy1 nephritis, the formation of focal segmental glomerulosclerosis lesions, the degree of interstitial fibrosis as well as the increase in proteinuria over 14 weeks was ameliorated by everolimus treatment. Increased glomerular hypertrophy observed in the vehicle-treated rats was completely prevented in the everolimus-treated nephritic rats. Increased glomerular fibronectin mRNA and protein as well as the renal influx of monocytes/macrophages was significantly reduced in the everolimus group. Everolimus reduced the pro-angiogenic factor vascular endothelial growth factor (VEGF) and VEGF mRNA in glomeruli, while the transforming growth factor-beta signaling pathway was not affected.. 'Late' start of everolimus treatment demonstrates beneficial effects on the time course of chronic anti-Thy1 nephritis.

Topics: Animals; Chronic Disease; Everolimus; Glomerulonephritis; Isoantibodies; Male; Protein Kinases; Rats; Rats, Sprague-Dawley; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Topics: Adult; Female; Glomerulonephritis; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prednisone; Reoperation; Sarcoma, Kaposi; Secondary Prevention; Sirolimus

Everolimus is a potent immunosuppressant used in renal transplant therapy, but its effects on renal endothelial cell regeneration after injury are unknown. The effects of an everolimus therapy were investigated in a model of renal thrombotic microangiopathy (TMA) with specific endothelial cell (EC) injury in the rat in vivo as well as in glomerular ECs in vitro.. During the early regenerative phase (day 3) of the renal microvascular injury model in vivo, everolimus inhibited glomerular EC proliferation by up to 60% compared with vehicle-treated rats, whereas apoptosis was not different in these groups. This decreased EC proliferation was associated with an enhanced deposition of fibrin in everolimus treated animals on day 3. In cultured glomerular endothelial cells, everolimus effectively and dose dependently inhibited cellular proliferation. This anti-proliferative effect was associated with a reduced phosphorylation of the p70S6 kinase and reduction of the pro-angiogenic factor VEGF in glomeruli in vivo and in cultured podocytes in vitro.. Despite the prolonged EC repair and in contrast to the anti-Thy1 nephritis model, everolimus therapy did not disturb the long-term repair reaction in this thrombotic microangiopathy model.. Everolimus is anti-proliferative for glomerular EC in vitro and in vivo and does not seem to have detrimental long-term effects in experimental renal TMA, when only the glomerular endothelium, but not the mesangium is severely injured.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Everolimus; Glomerular Mesangium; Glomerulonephritis; Immunohistochemistry; Immunosuppressive Agents; Kidney Glomerulus; Male; Mice; Phosphorylation; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Thrombosis; Vascular Endothelial Growth Factor A

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

Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered.

Topics: Aneurysm; Animals; Apoptosis; Capillaries; Cell Division; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Everolimus; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Immunosuppressive Agents; Isoantibodies; Kidney Glomerulus; Kidney Transplantation; Male; Mesangial Cells; Rats; Rats, Sprague-Dawley; Sirolimus; Vascular Endothelial Growth Factor A

The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has been related to the KS herpesvirus and the permissive effect of immunosuppressive therapy. Calcineurin inhibitors are the cornerstone of immunosuppression in organ transplantation, although they could promote tumor progression. In contrast, sirolimus, a new immunosuppressive agent, exhibits potent antitumor activity. We postulated that conversion from cyclosporine to sirolimus in patients with KS could favor regression of KS lesions without increasing the risk of graft rejection. Two renal transplant recipients with KS underwent conversion from cyclosporine to sirolimus. Both patients showed complete regression of KS lesions and excellent clinical and functional results. Sirolimus offers a new and promising approach to the management of posttransplantation KS and probably to other types of malignancies in organ transplant recipients.

Topics: Aged; Antibiotics, Antineoplastic; Cyclosporine; Diabetic Nephropathies; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Sarcoma, Kaposi; Sirolimus

Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, non-nephrotoxic immunosuppression. We report, however, on four kidney-transplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2-9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Creatine; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Proteinuria; Sirolimus; Time Factors; Treatment Outcome

This report describes the preclinical pharmacological profile of the new rapamycin analog, SDZ RAD, i.e., 40-O-(2-hydroxyethyl)-rapamycin.. The pharmacological effects of SDZ RAD were assessed in a variety of in vitro and in vivo models, which included an autoimmune disease model as well as kidney and heart allotransplantation models using different rat strain combinations.. SDZ RAD has a mode of action that is different from that of cyclosporine or FK506. In contrast to the latter, SDZ RAD inhibits growth factor-driven cell proliferation in general, as demonstrated for the in vitro cell proliferation of a lymphoid cell line and of vascular smooth muscle cells. SDZ RAD is immunosuppressive in vitro as demonstrated by the inhibition of mouse and human mixed lymphocyte reactions and the inhibition of antigen-driven proliferation of human T-cell clones. The concentrations needed to achieve 50% inhibition in all of these assays fall into the subnanomolar range. SDZ RAD is effective in the in vivo models when given by the oral route in doses ranging between 1 mg/kg/day and 5 mg/kg/day. When compared with rapamycin, the in vitro activity of SDZ RAD is generally about two to three times lower; however, when administered orally, SDZ RAD is at least as active in vivo as rapamycin.. In conclusion, SDZ RAD is a new, orally active rapamycin-derivative that is immunosuppressive and that efficiently prevents graft rejection in rat models of allotransplantation. SDZ RAD has therefore been selected for development for use in combination with cyclosporine A to prevent acute and chronic rejection after solid organ allotransplantation.

Topics: Abdomen; Administration, Oral; Animals; Carrier Proteins; Cell Division; DNA-Binding Proteins; Dose-Response Relationship, Drug; Everolimus; Glomerulonephritis; Graft Rejection; Graft vs Host Reaction; Growth Inhibitors; Growth Substances; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Kidney Transplantation; Mercuric Chloride; Polyenes; Protein Binding; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Wistar; Sirolimus; Tacrolimus Binding Proteins; Transplantation, Heterotopic; Transplantation, Homologous

Topics: Animals; Autoimmune Diseases; Cyclosporine; Drug Evaluation, Preclinical; Female; Glomerulonephritis; Immunosuppressive Agents; Mercuric Chloride; Polyenes; Proteinuria; Rats; Rats, Inbred BN; Sirolimus; Splenomegaly; Weight Loss