sirolimus 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

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

Persistent nephrotic syndrome that does not respond to treatment may cause progression to kidney failure. We designed a therapeutic protocol with sirolimus for this group of patients. We conducted a prospective, interventional, time series, cohort study lasting 20 months. Thirteen patients were enrolled, with a mean age of 10 years (range: 8-18 years old) with steroid-resistant primary nephrotic syndrome and a histological diagnosis of focal and segmental glomerulosclerosis. We administered sirolimus 3.6mg/m2/day. The duration of this regimen was 12 months in responsive patients. The protocol's efficacy was assessed according to reduction of proteinuria (3 response levels: total, partial, or no response). Severity of histological renal damage and mean time from clinical diagnosis to protocol initiation were also assessed. Nine of 13 patients responded to the treatment with sirolimus, and mean progression time and the severity of histological renal damage influenced response to therapy. We believe that sirolimus is a valid treatment option in patients with steroid-resistant nephrotic syndrome, even though this regimen probably requires an earlier treatment.

Topics: Adolescent; Adrenal Cortex Hormones; Child; Cohort Studies; Drug Resistance; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Male; Nephrotic Syndrome; Prospective Studies; Proteinuria; Remission Induction; Sirolimus; Treatment Outcome

To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy.

Topics: Adult; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; In Vitro Techniques; Kidney Diseases; Male; Middle Aged; Proteinuria; Sirolimus

Calcineurin inhibitors are effective therapy for steroid-resistant focal segmental glomerulosclerosis (FSGS) but are associated with significant morbidity and nephrotoxicity. Sirolimus is a novel immunosuppressive agent that is structurally related to tacrolimus but demonstrates no long-term nephrotoxicity. For determination of the efficacy of sirolimus in reducing proteinuria, a prospective, open-label trial was conducted of 21 patients with idiopathic, steroid-resistant FSGS. A complete response was defined as <300 mg protein/24 h after 6 mo, whereas a partial response was defined as a 50% reduction in baseline proteinuria. After 6 mo of therapy, sirolimus induced complete remission in four (19%) of 21 patients and partial remissions in eight (38%). Among sirolimus-responsive patients, 6 mo of therapy decreased proteinuria from a mean of 8.8 +/- 1.7 to 2.1 +/- 0.5 g/24 h (P = 0.0003). In responsive patients, GFR was maintained (45 +/- 6 versus 47 +/- 7 ml/min per 1.73 m2 at 6 mo) throughout the study, whereas nonresponders tended to decrease (31 +/- 4 versus 28 +/- 5 ml/min per 1.73 m2). Using dextran sieving analysis, complete or partial response was associated with an increase in the glomerular ultrafiltration coefficient (K(f), 7 +/- 1. versus 8 +/- 0.9 units at 6 mo; P < 0.05). Glomerular permselectivity and K(f) tended to decrease in nonresponders (8.2 +/- 1.9 versus 6.2 +/- 1.3 units at 6 mo; P = 0.07). Patients with complete remission had a higher GFR (45 +/- 6 versus 31 +/- 4 ml/min per 1.73 m2) at the end of 6 mo compared with nonresponders. In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased K(f) in patients with steroid-resistant FSGS.

Topics: Adult; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Prospective Studies; Sirolimus

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood.. To investigate the role of the UPS in podocytes, mice were generated that had deletion of. Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.

Topics: Aging; Animals; Apoptosis; Autophagy; Bortezomib; Cells, Cultured; Glomerulosclerosis, Focal Segmental; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Podocytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Aggregates; Renal Insufficiency, Chronic; Sirolimus; Ubiquitination

Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.

Topics: Albuminuria; Animals; Cell Proliferation; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Sclerosis; Signal Transduction; Sirolimus; Thy-1 Antigens; TOR Serine-Threonine Kinases

Podocyte loss is one of the determining factors for the progression toward glomerulosclerosis. Podocyte is terminally differentiated and does not typically proliferate following injury and loss. However, recent evidence suggested that during renal injury, podocyte could re-enter the cell cycle, sensitizing the cells to injury and death, but the molecular mechanisms underlying it, as well as the cell fate determination still remained unclear. Here, using NPHS2 Cre; mT/mG transgenic mice and primary podocytes isolated from the mice, we investigated the effect of mammalian target of rapamycin complex 1 (mTORC1)/4E-binding protein 1 (4E-BP1) signaling pathway on cell cycle re-entry and apoptosis of podocyte induced by adriamycin. It was found that podocyte cell cycle re-entry could be induced by adriamycin as early as the 1st week in vivo and the 2nd hour in vitro, accompanied with 4E-BP1 activation and was followed by podocyte loss or apoptosis from the 4th week in vivo or the 4th hour in vitro. Importantly, targeting 4E-BP1 activation by the RNA interference of 4E-BP1 or pharmacologic rapamycin (inhibitor of mTORC1, blocking mTORC1-dependent phosphorylation of its substrate 4E-BP1) treatment was able to inhibit the increases of PCNA, Ki67, and the S-phase fraction of cell cycle in primary podocyte during 2-6 h of adriamycin treatment, and also attenuated the following apoptotic cell death of podocyte detected from the 4th hour, suggesting that 4E-BP1 could be a regulator to manipulate the amount of cell cycle re-entry provided by differentiated podocyte, and thus regulate the degree of podocyte apoptosis, bringing us a new potential podocyte-protective substance that can be used for therapy.

Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cells, Cultured; Down-Regulation; Doxorubicin; Glomerulosclerosis, Focal Segmental; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phosphorylation; Podocytes; Signal Transduction; Sirolimus

Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both

Topics: Animals; Disease Progression; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Parietal epithelial cell (PEC) response to glomerular injury may underlie a common pathway driving fibrogenesis following podocyte loss that typifies several glomerular disorders. Although the mammalian target of rapamycin (mTOR) pathway is important in cell homeostasis, little is known of the biological role or impact of reducing mTOR activity on PEC response following podocyte depletion, nor in the aging kidney. The purpose of these studies was to determine the impact on PECs of reducing mTOR activity following abrupt experimental depletion in podocyte number, as well as in a model of chronic podocyte loss and sclerosis associated with aging. Podocyte depletion was induced by an anti-podocyte antibody and rapamycin started at day 5 until death at day 14 Reducing mTOR did not lead to a greater reduction in podocyte density, despite greater glomerulosclerosis. However, mTOR inhibition lead to an increase in PEC density and PEC-derived crescent formation. Additionally, markers of epithelial-to-mesenchymal transition (platelet-derived growth factor receptor-β, α-smooth muscle actin, Notch-3) and PEC activation (CD44, collagen IV) were further increased by mTOR reduction. Aged mice treated with rapamycin for 1, 2, and 10 wk before death at 26.5 mo (≈75-yr-old human age) had increased the number of glomeruli with a crescentic appearance. mTOR inhibition at either a high or low level lead to changes in PEC phenotype, indicating PEC morphology is sensitive to changes mediated by global mTOR inhibition.

Topics: Aging; Animals; Cell Count; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Glomerulus; Male; Mice; Podocytes; Sirolimus; TOR Serine-Threonine Kinases

The clinical and pathological experience with sirolimus is limited at this time. In this study, we report severe isometric vacuolization of the proximal tubules after sirolimus therapy in two kidney transplant patients. Patient 1 is a hepatitis C virus-positive, 30-year-old African American man who had end-stage renal disease (ESRD) of unknown etiology. Patient 2 is a 62-year-old white woman with ESRD due to unknown etiology. Both patients were initially placed on tacrolimus, mycophenolic acid, and prednisone immunosuppressive therapy. These patients were switched to sirolimus at 1 and 5 month posttransplant, respectively, due to the development of new-onset hyperglycemia and an elevated serum creatinine. Both patients presented with acute renal failure and high sirolimus levels at 5 years (patient 1) and 10 months posttransplant (patient 2). Biopsies of their kidney transplants showed widespread isometric tubular cytoplasmic vacuolization and severe arterial hyalinosis. Acute renal insufficiency improved after sirolimus dose reduction. In this case report, we introduce a new morphological appearance after sirolimus therapy of isometric cytoplasmic vacuolization of the renal tubules and severe arterial hyalinosis, similar to that seen in calcineurin inhibitor induced tubular toxicity.

Topics: Adult; Cadaver; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Sirolimus; Time Factors; Tissue Donors

Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis.. Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection.. Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration.. Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy. The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.

Topics: Albuminuria; Animals; Antibiotics, Antineoplastic; Body Weight; Chemokine CCL5; Collagen Type I; Disease Models, Animal; Doxorubicin; Fibrosis; Gene Expression; Glomerulosclerosis, Focal Segmental; Immunosuppressive Agents; Kidney; Male; Mice; Mice, Inbred BALB C; Severity of Illness Index; Sirolimus; Survival Rate

A 58-year-old man with advanced renal cell carcinoma developed grade 3 proteinuria (8.5 g/24 h) without microscopic hematuria or renal insufficiency five days after temsirolimus infusion. Kidney biopsy revealed ischemic glomeruli and focal segmental glomerulosclerosis lesion. Proteinuria level decreased to 2.80 g per day two weeks after temsirolimus withdrawal. Clinicians should be aware to this complication.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Glomerulosclerosis, Focal Segmental; Humans; Kidney Neoplasms; Male; Middle Aged; Proteinuria; Sirolimus

Corticosteroids and/or cyclosporine constitute the present therapeutic approach for patients with focal segmental glomerulosclerosis (FSGS). The high incidence of side effects for the former and risk of nephrotoxicity combined with the high relapse rate after discontinuation for the latter render their use problematic. Results concerning the role of rapamycin in the treatment of patients with FSGS are conflicting. We describe results for 3 patients treated with a combination of low-dose steroids and rapamycin for FSGS, focusing on the importance of maintaining low drug (rapamycin) levels by using a twice-daily regimen.

Topics: Adult; Drug Therapy, Combination; Female; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Sirolimus

In this study we tested the hypothesis that sirolimus (a target of rapamycin inhibitor that attenuates intrinsic renal and immune cell proliferation) reduces glomerular hypertrophy and tubular epithelial cell (TEC) proliferation, and attenuates the progression of renal scarring and dysfunction, in a non-immune initiated model of focal segmental glomerulosclerosis (FSGS).. Adult male Wistar rats with adriamycin nephropathy (AN) were stratified into two groups, according to proteinuria on day 12, and received either vehicle (dimethylsulphoxide) or sirolimus (0.1 mg/kg) by daily subcutaneous injection, from day 14 until day 49 (n = 8 each). Control animals were also examined (n = 3 each).. Sirolimus did not affect the progression of proteinuria, renal dysfunction, hypercholesterolaemia, body weight or alter intraluminal cast formation in AN. Sirolimus prevented the increase in kidney enlargement in AN, and attenuated glomerular capillary tuft expansion, glomerulosclerosis and periglomerular myofibroblast accumulation. In the tubulointerstitium, sirolimus attenuated tubular dilatation, TEC proliferation and interstitial fibrosis. This was accompanied by a reduction in renal cortical TGF-beta1, but peritubular myofibroblast accumulation and renal inflammation (glomerular and interstitial ED-1 and CD3-positive cell accumulation), were unaffected.. The anti-renotrophic properties of sirolimus were correlated with a reduction in renal scarring in AN. These data suggest that sirolimus has renoprotective effects when administered during the early stages of an FSGS pattern of chronic renal injury.

Topics: Animals; Antibiotics, Antineoplastic; Body Weight; Cell Proliferation; Disease Progression; Doxorubicin; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Diseases; Male; Nephrotic Syndrome; Rats; Rats, Wistar; Sirolimus

Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.

Topics: Adult; Biopsy; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Sirolimus

Mutations in the NPHS2 gene, which encodes podocin, are associated with steroid-resistant nephrotic syndrome in childhood. Renal histology frequently presents focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria in patients affected by homozygous or compound heterozygous NPHS2 mutation is encountered rarely (1-2%) compared to 30% recurrence in nonhereditary FSGS. We report on a pediatric kidney transplant recipient with NPHS2-associated nephrotic syndrome and FSGS, who developed biopsy-proven recurrence of FSGS 10 years post-transplant in temporal association with conversion from cyclosporin A (CsA)- to sirolimus (SRL)-based immunosuppression, due to histological evidence of severe CsA-induced nephrotoxicity. Reswitch of the immunosuppressive regimen from SRL to CsA led to a noticeable decrease of proteinuria and to stabilization of graft function. We conclude that patients with hereditary FSGS are not entirely protected from post-transplant recurrence of proteinuria, even in the long term. The close temporal relationship of FSGS recurrence with CsA withdrawal and conversion to SRL suggests that caution should be exercised in the use of CsA-free immunosuppression also in patients with NPHS2-associated FSGS.

Topics: Adolescent; Cyclosporine; Female; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Transplantation; Living Donors; Membrane Proteins; Mutation; Nephrotic Syndrome; Proteinuria; Recurrence; Renal Insufficiency; Risk Factors; Sirolimus; Time Factors

Topics: Creatinine; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Proteinuria; Sirolimus; Treatment Failure

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) is frequent after the first kidney transplantation (KT), but a recurrence that only occurred after the second KT has never been reported. Although cyclosporine reduces proteinuria and prolongs graft survival in patients with recurrent glomerulosclerosis, the effectiveness of sirolimus for this condition is still not known. We report, for the first time as far as we know, the case of a 35-year-old black male patient who experienced a recurrence of FSGS, 10 days after a second KT, although no recurrence had occurred after the first. Cyclosporine treatment led to a decrease in proteinuria, whereas mycophenolate mofetil and angiotensin-converting enzyme inhibitor had no effect. Cyclosporine was replaced by sirolimus as treatment for chronic allograft nephropathy 24 months after KT. Nephrotic syndrome, which reappeared 3 weeks after the switch, was cured by cyclosporine re-introduction. The absence of FSGS recurrence after the first graft does not totally preclude its recurrence after the second. This observation points to the effectiveness of cyclosporine for the recurrence of FSGS and indicates that sirolimus should be given with caution in such cases.

Topics: Adult; Cyclosporine; Drug Resistance; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Recurrence; Retreatment; Sirolimus; Treatment Outcome

Topics: Aged; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Liver Transplantation; Male; Podocytes; Proteinuria; Sarcoma, Kaposi; Sirolimus; Vascular Endothelial Growth Factor A

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

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

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

Topics: Animals; Body Weight; Cyclosporine; Disease Models, Animal; Everolimus; Glomerulosclerosis, Focal Segmental; Graft Rejection; Hypertrophy; Immunosuppressive Agents; Kidney Transplantation; Organ Size; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus

Chronic rejection remains the most frequent cause of renal graft loss over the long term. However, effective treatment of this process is not yet available. SDZ-RAD (40-O-[2-hydroxyethyl]-rapamycin) is a new, orally active rapamycin derivative with potent immunosuppressive activity. We have examined the effects of SDZ-RAD in a well-established model of chronic renal allograft rejection in rats.. Kidneys of Fisher (F334) rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. To suppress an initial episode of acute rejection, rats were briefly treated with low doses of cyclosporine for the first 10 days. Thereafter they received either SDZ-RAD (0.5 mg/kg(day) or vehicle. At 24 weeks, functional evaluations were performed, kidneys were harvested, and histological, immunohistological, and reverse transcription-polymerase chain reaction evaluations were performed.. Animals treated with SDZ-RAD developed lower proteinuria and less glomerulosclerosis as compared with controls. Additionally SDZ-RAD reduced the infiltration of macrophages and lymphocytes and the expression of intercellular adhesion molecule-1, laminin, and fibronectin. Furthermore, we observed a reduced expression of growth factor mRNA (transforming growth factor-beta and platelet-derived growth factor-AA) in these animals.. Our results demonstrated that SDZ-RAD effectively ameliorates chronic renal allograft rejection in rats, probably mediated by suppression of growth factors.

Topics: Animals; Cyclosporine; Everolimus; Glomerulosclerosis, Focal Segmental; Graft Rejection; Growth Substances; Immunohistochemistry; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney; Kidney Transplantation; Male; Polymerase Chain Reaction; Rats; Rats, Inbred F344; Rats, Inbred Lew; RNA, Messenger; Sirolimus; Transplantation, Homologous