sirolimus and Nephrotic-Syndrome

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

Danshen injection (DSI) is an agent extracted from the Salvia miltiorrhiza Bunge, a natural drug commonly used to alleviate kidney diseases. However, the material basis and therapeutic effects of DSI on nephrotic syndrome (NS) remain unclear.. To investigate the material basis of DSI and the therapeutic effects and underlying mechanisms of NS.. NS models were established using adriamycin-induced BALB/c mice and lipopolysaccharide-induced mouse podocytes (MPC-5). Following DSI and prednisone administration, kidney coefficients, 24 h urine protein, blood urea nitrogen, and serum creatinine levels were tested. Histomorphology was observed by periodic acid-Schiff staining and hematoxylin and eosin staining of the kidney sections. The glomerular basement membrane and autophagosomes of the kidneys were observed using transmission electron microscopy. Nephrin and desmin levels in the glomeruli were tested using immunohistochemistry. The viability of MPC-5 cells was tested using cell counting kit-8 after chloroquine and rapamycin administration in combination with DSI. The in vivo and in vitro protein levels of phosphatidylinositol 3-kinase (PI3K), AKT, phosphorylated AKT (Ser473), mammalian target of rapamycin (mTOR), microtubule-associated protein light chain 3 (LC3), beclin1, cleaved caspase-3, and caspase-3 were detected using western blotting.. Our results showed that DSI contained nine main components: caffeic acid, danshensu, lithospermic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, salvianolic acid C, salvianolic acid D, and 3, 4-Dihydroxybenzaldehyde. In in vivo studies, the NS mice showed renal function and pathological impairment. Podocytes were damaged, with decreased levels of autophagy and apoptosis, accompanied by inhibition of the PI3K/AKT/mTOR signaling. DSI administration resulted in improved renal function and pathology in NS mice, with the activation of autophagy and PI3K/AKT/mTOR signaling in the kidneys. Additionally, podocytes were less damaged and intracellular autophagosomes were markedly increased. In vitro studies have shown that DSI activated MPC-5 autophagy and reduced apoptosis via the PI3K/AKT/mTOR pathway.. Collectively, this study demonstrated that DSI activated podocyte autophagy and reduced apoptosis via the PI3K/AKT/mTOR signaling, ultimately attenuating NS. Our study clarified the main components of DSI and elucidated its therapeutic effects and potential mechanisms for NS, providing new targets and agents for the clinical treatment of NS.

Topics: Animals; Autophagy; Beclin-1; Caspase 3; Chloroquine; Creatinine; Desmin; Doxorubicin; Eosine Yellowish-(YS); Hematoxylin; Lipopolysaccharides; Mammals; Mice; Microtubule-Associated Proteins; Nephrotic Syndrome; Periodic Acid; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Podocytes; Prednisone; Proto-Oncogene Proteins c-akt; Salvia miltiorrhiza; Sirolimus; TOR Serine-Threonine Kinases

A 22-year-old manpresented as a refractory nephrotic syndrome with edema and proteinuria for more than one year. Physical examination revealed facial steatadenomas and periungual fibromas. Images were characterized by hamartomatous lesions in multiple organs, including the central nervous system, heart, lungs, liver, and kidneys. Gene tests verified TSC2 mutation and confirmed the diagnosis of tuberous sclerosis complex. The APOL1 mutation was positive in this patient, which indicated the possibility of steroid-resistant focal segmental glomerulonephritis. Thus, he was treated with sirolimus. Renal angiomyolipoma was shrunk, but proteinuria was not relieved (24h unine protein>10 g) and eventually led into renal insufficiency. Nondialytic therapy was initiated consequently. Losartan 50 mg/d was used to control proteinuria under the close watch of serum creatinine. A recent phone call on October 2018 failed to reachthe patient. Therefore, the follow-up information was not updated.. 患者男性，22岁。因水肿、蛋白尿1年余就诊，考虑为难治性肾病综合征。体检发现患者面部皮脂腺瘤、甲周纤维瘤，影像学显示中枢神经系统、心脏、肺、肝脏、肾脏等多系统受累，基因检查为TSC2基因突变，诊断结节性硬化症。基因检测同时发现APOL1基因突变，提示患者同时存在糖皮质激素抵抗型的局灶节段性肾小球硬化症的可能性。使用西罗莫司治疗，治疗初期肾脏血管平滑肌瘤体积缩小，但尿蛋白始终未缓解（24 h尿蛋白>10 g），最终仍发展为肾功能不全，开始非透析治疗，包括监测血压、血糖和血脂，餐中嚼服碳酸钙500 mg、3次/d，瑞舒伐他汀20 mg/d，补充维生素B(1)（10 mg/d）和叶酸（10 mg/d），使用氯沙坦50 mg/d控制尿蛋白并监测血肌酐变化。2018年10月电话随访未联系到患者，未能获得治疗近况。.

Topics: Angiomyolipoma; Apolipoprotein L1; Creatinine; Female; Glomerulonephritis, IGA; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Losartan; Male; Mutation; Nephrotic Syndrome; Proteinuria; Sirolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Young Adult

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Topics: Biopsy; Child; Diagnosis, Differential; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymph Nodes; Lymphadenopathy; Lymphatic Metastasis; Male; Nephrotic Syndrome; Sarcoma, Kaposi; Sirolimus

The mammalian target of rapamycin inhibitors sirolimus and everolimus are immunosuppressive drugs for kidney transplant patients, but adverse events may include proteinuria. The purpose of this study was to compare the effects of sirolimus and everolimus on creatinine clearance and proteinuria after kidney transplant.. This study was a prospective evaluation period of 50 patients (age, 16-65 y) who had kidney transplant. There were 25 patients who used sirolimus and 25 patients who used everolimus. Evaluation at the beginning mTOR and end of the evaluation period included complete blood count, blood pressure, serum creatinine level, creatinine clearance, and proteinuria level in a 24-hour urine collection.. Mean creatinine clearance at the beginning and end of the evaluation period was significantly less in the everolimus than sirolimus group. There was no significant change in creatinine clearance from the beginning to end of the evaluation period in either the sirolimus or everolimus group. Mean proteinuria at the beginning and end of the evaluation period was similar between the sirolimus and everolimus groups. Both groups had a significant increase in mean proteinuria from beginning to end of the evaluation period, but the increase in proteinuria was similar for the sirolimus and everolimus groups (difference not significant).. In kidney transplant recipients, sirolimus and everolimus are associated with a similar level of increased mean proteinuria.

Topics: Adolescent; Adult; Aged; Biomarkers; Creatinine; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Proteinuria; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

AIHA is a rare and serious complication of solid organ transplantation. Herein, we report four cases of warm or mixed AIHA in pediatric patients following combined liver, small bowel and pancreas transplant. The hemolysis was refractory to multiple treatment modalities including steroids, rituximab, IVIG, plasmapheresis, cytoxan, discontinuation of prophylactic penicillin, and a change in immunosuppression from tacrolimus to cyclosporine. All patients had resolution or marked improvement of hemolysis after discontinuation of maintenance of CNI and initiation of sirolimus immunosuppression. One patient developed nephrotic syndrome but responded to a change in immunosuppression to everolimus. Three of the four patients continue on immunosuppression with sirolimus or everolimus without further hemolysis, evidence of rejection or medication side effects. Based on our experience and review of similar cases in the literature, we have proposed a treatment algorithm for AIHA in the pediatric intestinal transplant patient population that recommends an early change in immunosuppressive regimen from CNIs to sirolimus therapy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Murine-Derived; Calcineurin; Cyclophosphamide; Cyclosporine; Everolimus; Female; Hemolysis; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestines; Liver Transplantation; Male; Medical Records; Nephrotic Syndrome; Pancreas Transplantation; Penicillins; Plasmapheresis; Retrospective Studies; Rituximab; Sirolimus; Steroids; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation; Treatment Outcome

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria and excessive fluid retention. The effects of early versus late treatment with low or high doses of oral everolimus, a mammalian target of rapamycin inhibitor, on proteinuria in NS have not been previously described.. The effects of early treatment (2 days prior to NS induction) versus late treatment (beginning 2 weeks following the establishment of NS) with a low (20 mg/L) or high (100 mg/L) dose of everolimus for 5-7 weeks on proteinuria and nephrin/podocin abundance were assessed in male adult SD rats with adriamycin-induced NS.. Adriamycin caused a significant increase in daily and cumulative proteinuria throughout the experimental period. Early, and to a lesser extent late treatment, with a low dose of everolimus, significantly decreased both daily and cumulative proteinuria and improved renal function. The anti-proteinuric effects of low-dose everolimus were associated with restoration of the disruptive glomerular nephrin/podocin abundance. In contrast, administration of a high dose of everolimus resulted in a decrease in proteinuria in NS rats, subsequently to deterioration of renal function.. Early, and to a lesser extent late treatment, with a low but not a high dose of everolimus is effective in reducing proteinuria in nephrotic rats. The mechanism may be via nephrin/podocin protection.

Topics: Animals; Antibiotics, Antineoplastic; Cytoprotection; Doxorubicin; Everolimus; Immunoenzyme Techniques; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Male; Membrane Proteins; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus

This study reports initial results of the development of the SIAM, a non-adherence risk assessment system for tacrolimus and sirolimus for the pediatric kidney transplant population. Forty-eight youths between 10 and 25 yr of age diagnosed with chronic kidney disease or a kidney transplant used an electronic pill bottle (EM; time stamps each bottle opening) to dispense their medication for at least 30 days or until their next clinic appointment. Youth also completed a self-report adherence measure, and standard deviations were calculated for the last four medication serum trough levels obtained for each patient. Estimation models were developed for each medication (i.e., SIAM(TACRO) and SIAM(SIRO) ) to assign weights to these clinically available adherence measures (self-report and trough levels) for the calculation of a non-adherence risk composite score. SIAM(TACRO) models included both self-report and tacrolimus trough levels and significantly predicted EM. For sirolimus, the model predictive of adherence as measured by EM consisted of the standard deviation of sirolimus trough levels only (SIAM(SIRO) ). Non-adherence risk can be effectively assessed using clinically available assessment tools. However, the best methods for using self-report and trough levels to predict non-adherence likely differ based on the medication for which adherence is being assessed.

Topics: Adolescent; Adult; Child; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Linear Models; Logistic Models; Male; Medication Adherence; Nephrotic Syndrome; Risk Assessment; Self Report; Sirolimus; Tacrolimus; Young Adult

Podocytes are terminally differentiated post-mitotic cells similar to neurons, and their damage leads to nephrotic syndrome, which is characterized by massive proteinuria associated with generalized edema. A recent functional genetic approach has identified the pathological relevance of several mutated proteins in glomerular podocytes to the mechanism of proteinuria in hereditary nephrotic syndrome. In contrast, the pathophysiology of acquired primary nephrotic syndrome, including minimal change disease, is still largely unknown. We recently demonstrated the possible linkage of an energy-consuming process in glomerular podocytes to the mechanism of proteinuria. Puromycin aminonucleoside nephrosis, a rat model of minimal change disease, revealed the activation of the unfolded protein response (UPR) in glomerular podocytes to be a cause of proteinuria. The pretreatment of puromycin aminonucleoside rat podocytes and cultured podocytes with the mammalian target of rapamycin (mTOR) inhibitor everolimus further revealed that mTOR complex 1 consumed energy, which was followed by UPR activation. In this paper, we will review nutritional transporters to summarize the energy uptake process in podocytes and review the involvement of the UPR in the pathogenesis of glomerular diseases. We will also present additional data that reveal how mTOR complex 1 acts upstream of the UPR. Finally, we will discuss the potential significance of targeting the energy metabolism of podocytes to develop new therapeutic interventions for acquired nephrotic syndrome.

Topics: AMP-Activated Protein Kinases; Animals; Energy Metabolism; Everolimus; Glucose Transport Proteins, Facilitative; Immunosuppressive Agents; Membrane Transport Proteins; Nephrotic Syndrome; Podocytes; Proteinuria; Rats; Sirolimus; TOR Serine-Threonine Kinases; Unfolded Protein Response

A common situation presented in any clinical facility is a woman with swelling and redness of the breast. Diagnosis upon suspicion is often mastitis or inflammatory breast cancer, which are popular and well-known diseases of the breast. However, there is one main differential diagnosis which has to be taken into consideration: lymphedema of the breast. Twenty patients with internal diseases presented in our Breast Care Unit over a 4-year period with breast-affecting lymphedema. The patients suffered from cardiac failure, nephrotic syndrome, liver failure, lymphadenopathy, and central vein occlusion. Additionally, we identified 5 patients with a history of organ transplantation and under immunosupressive medication with sirolimus or everolimus. These mTor inhibitors are known to have unwanted side effects such as unilateral or bilateral upper/lower extremity peripheral edema or facial/eyelid edema, but as we know, isolated lymphedema of the breast represents a previously unreported complication.

Topics: Adult; Aged; Aged, 80 and over; Breast; Diagnosis, Differential; Everolimus; Female; Heart Failure; Humans; Immunosuppressive Agents; Liver Failure; Lymphatic Diseases; Lymphedema; Middle Aged; Nephrotic Syndrome; Sirolimus; Tissue Transplantation; TOR Serine-Threonine Kinases; Vascular Diseases

Topics: Adolescent; Adrenal Cortex Hormones; Drug Resistance; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; 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

Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

Topics: Anemia, Hemolytic, Autoimmune; Child, Preschool; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

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