sirolimus and Nephritis

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens.. This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL).. Mean TAC concentrations were 6.0 ± 2.4 ng/mL and 5.8 ± 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043-5.267; P = 0.039) were associated with inferior renal function at 24 months.. In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months.

Topics: Adult; Atrophy; Biomarkers; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Drug Substitution; Female; Fibrosis; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Nephritis; Odds Ratio; Proteinuria; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo.. In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated.. hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals.. Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin.

Topics: Adenine; Animals; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Biomarkers; Cell Differentiation; Cell Line; Cisplatin; Epithelial Cells; Exosomes; Female; Fetus; Fibroblasts; Gene Expression; Humans; Mesenchymal Stem Cells; Microtubule-Associated Proteins; Nephritis; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Sirolimus; Umbilical Cord

Conversion from calcineurin inhibitor (CNI) to mTOR inhibitors may reduce and even halt the progression of chronic allograft dysfunction (CAD) which is the most important cause of renal allograft loss. We aimed to investigate the effects of conversion from CNI to everolimus on parameters of fibrosis, inflammation, glomerulotubular damage and vascular functions in renal transplant recipients.. Fifteen stable renal transplant recipients who were under CNI treatment (male/female 13/2, mean age 41 ± 10 years) were enrolled and switched to everolimus. Serum and urinary transforming growth factor-β (TGF-β), urinary neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1) were measured as markers of fibrosis, tubular damage and inflammation. As parameters of vascular functions, pulse wave velocity (PWV), augmentation index (AIx), serum asymmetric dimethyl-arginine and fibroblast growth factor-23 (FGF-23) were measured. All these measurements were repeated at the 3rd month of conversion.. Estimated GFR (52 ± 7-57 ± 11 ml/min/l.73 m(2), p = 0.02) (was increased after conversion to everolimus. However, serum uric acid levels were significantly decreased (6.21 ± 1.21-5.50 ± 1.39 mg/dL, p = 0.01). Serum TGF-β levels (8727 ± 2897-1943 ± 365 pg/mL, p = 0.03) and urinary NGAL levels (26 ± 10-12 ± 2 ng/mg creatinine, p = 0.05) were significantly decreased. However, urinary MCP-1, FGF-23, PWV and AIx did not change. Urinary TGF-β was associated with urinary NGAL (r = 0.62, p = 0.01), urinary MCP-1 (r = 0.68, p = 0.005) and proteinuria (r = 0.50, p = 0.05).. Conversion from CNI to everolimus resulted in significant decreases of serum TGF-β and urinary NGAL which may represent less fibrosis and tubular damage. Association of urinary TGF-β with NGAL and MCP-1 suggests that tubular damage, fibrosis and inflammation may act together for progression of CAD.

Topics: Acute-Phase Proteins; Adult; Calcineurin Inhibitors; Chemokine CCL2; Everolimus; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Lipocalin-2; Lipocalins; Male; Middle Aged; Nephritis; Proto-Oncogene Proteins; Pulse Wave Analysis; Renal Artery; Risk Factors; Sirolimus; Transforming Growth Factor beta; Transplant Recipients

Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4(+) T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.

Topics: Animals; Gene Expression Regulation; Immunity, Innate; Inflammation Mediators; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Nephritis; Platelet Endothelial Cell Adhesion Molecule-1; Proteinuria; RNA, Messenger; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

To evaluate the effects of sirolimus (SRL) on renal injury in rats with bile duct ligation.. A total of 21 male Sprague-Dawley rats weighing 220-260 g were used. Group 1 (Sham-control, n=7) rats were undergone laparotomy alone and bile duct was just dissected from the surrounding tissue. Group 2 rats (BDL/Untreated, n=7) were subjected to bile duct ligation and no drug was applied. Group 3 rats (BDL/SRL, n =7) received a daily dose of sirolimus (0.5 mg·day(-1) x kg(-1) dissolved 1 ml in saline) by orogastric tube for 14 days after BDL. At the end of the two-week period, biochemical and histological evaluation were processed.. AST, ALT, AP and TB levels values were decreased in group 3 when compared to group 2. There was no significant difference in serum levels of BUN and creatinine among all the experimental groups. Histological evaluation of the liver of BDL/Untreated group rats demonstrated marked portal fibrosis and signs of major bile duct obstruction with prominent portal and lobular inflammation. In BDL/SRL group, moderate damage was seen. Tubular injury scores were higher in the BDL subgroups; however, group 3 rats showed considerably fewer lesions in the tubules and interstitium compared to the group 2 rats. In group 2 animals, in the epithelial cells of proximal tubules presented vacuoles and hydropic changes, atrophy and inflammatory cell infiltrate in the medullar interstitium.. Sirolimus decreased tubulointerstitial lesions in kidney induced by bile duct ligation in rats. The improve effects of sirolimus on renal morphology can be due to improved liver function or due to direct action on the kidney.

Topics: Acute Kidney Injury; Animals; Bile Ducts; Disease Models, Animal; Kidney; Ligation; Male; Nephritis; Random Allocation; Rats; Rats, Sprague-Dawley; Sirolimus

Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice.. Six-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies.. Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES.. We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.

Topics: Albuminuria; Animals; Autoimmunity; Chemokine CCL5; Female; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Nephritis; Sirolimus; Splenomegaly

Rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) protein kinase, is a well-known immunosuppressive agent. In this issue, Wu and colleagues report that rapamycin significantly attenuates renal interstitial fibrosis in obstructive nephropathy. Besides its inhibition of renal inflammation, rapamycin is able to block tubular epithelial-mesenchymal transition, thereby shedding new light on the mechanism of its antifibrotic actions.

Topics: Chronic Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Nephritis; Sirolimus