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Gao C, Chen ZY, Ma L, Gou SJ. A liver transplant patient developed renal injury on tacrolimus and experienced worsening renal function and rhabdomyolysis after switching to sirolimus: a case report. BMC Nephrol 2024; 25:445. [PMID: 39627758 PMCID: PMC11616183 DOI: 10.1186/s12882-024-03874-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 11/20/2024] [Indexed: 12/06/2024] Open
Abstract
Renal impairment and rhabdomyolysis are rare in transplant patients receiving sirolimus. We report the case of a 54-year-old male who underwent liver transplantation and was initially treated with tacrolimus, mycophenolate mofetil, and glucocorticoids for immunosuppression. After the development of renal dysfunction, tacrolimus was replaced with sirolimus. However, one month after taking sirolimus, the patient's renal function continued to deteriorate, and rhabdomyolysis developed one and a half months later. Serum analysis indicated high sirolimus concentration, whereas renal histopathology revealed acute tubular injury and interstitial arteriopathy. After reducing the dosage of sirolimus, the patient's creatine kinase levels returned to normal, and renal function improved. Two years after discharge, the patient's renal function had recovered. This case highlights the importance of monitoring sirolimus blood concentrations in clinical practice, because elevated drug concentrations can lead to renal dysfunction and rhabdomyolysis as adverse reactions. Further investigations into the pathogenic mechanisms of sirolimus-induced renal dysfunction and rhabdomyolysis may contribute to clinical practice.
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Affiliation(s)
- Chang Gao
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China
- Department of Nephrology, Sichuan Second Hospital of traditional Chinese medicine, Chengdu, 610000, China
| | - Zhi-Yu Chen
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Liang Ma
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Shen-Ju Gou
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China.
- Department of Nephrology, West China Tianfu Hospital of Sichuan University, Chengdu, 610200, China.
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Hoff U, Markmann D, Nieminen-Kelhä M, Budde K, Hegner B. Low-dose rapamycin does not impair vascular integrity and tubular regeneration after kidney transplantation in rats. Sci Rep 2021; 11:16270. [PMID: 34381142 PMCID: PMC8358014 DOI: 10.1038/s41598-021-95790-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/16/2021] [Indexed: 11/23/2022] Open
Abstract
mTOR inhibitors offer advantages after kidney transplantation including antiviral and antitumor activity besides facilitating low calcineurin inhibitor exposure to reduce nephrotoxicity. Concerns about adverse effects due to antiproliferative and antiangiogenic properties have limited their clinical use particularly early after transplantation. Interference with vascular endothelial growth factor (VEGF)-A, important for physiologic functioning of renal endothelial cells and tubular epithelium, has been implicated in detrimental renal effects of mTOR inhibitors. Low doses of Rapamycin (loading dose 3 mg/kg bodyweight, daily doses 1.5 mg/kg bodyweight) were administered in an allogenic rat kidney transplantation model resulting in a mean through concentration of 4.30 ng/mL. Glomerular and peritubular capillaries, tubular cell proliferation, or functional recovery from preservation/reperfusion injury were not compromised in comparison to vehicle treated animals. VEGF-A, VEGF receptor 2, and the co-receptor Neuropilin-1 were upregulated by Rapamycin within 7 days. Rat proximal tubular cells (RPTC) responded in vitro to hypoxia with increased VEGF-A and VEGF-R1 expression that was not suppressed by Rapamycin at therapeutic concentrations. Rapamycin did not impair proliferation of RPTC under hypoxic conditions. Low-dose Rapamycin early posttransplant does not negatively influence the VEGF network crucial for recovery from preservation/reperfusion injury. Enhancement of VEGF signaling peritransplant holds potential to further improve outcomes.
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Affiliation(s)
- Uwe Hoff
- Department of Nephrology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Denise Markmann
- Nieren- und Dialysezentrum Schöneberg-Tempelhof, Berlin, Germany
| | - Melina Nieminen-Kelhä
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Björn Hegner
- Department of Nephrology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
- Vitanas Hospital for Geriatric Medicine, Berlin, Germany.
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Hall G, Lane BM, Khan K, Pediaditakis I, Xiao J, Wu G, Wang L, Kovalik ME, Chryst-Stangl M, Davis EE, Spurney RF, Gbadegesin RA. The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes. J Am Soc Nephrol 2018; 29:2110-2122. [PMID: 30002222 PMCID: PMC6065096 DOI: 10.1681/asn.2017121338] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 05/31/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. METHODS We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLNR431C and ANLNG618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLNWT ) or ANLNR431C . RESULTS Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLNR431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLNR431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLNR431C -expressing podocytes. Inhibition of mTOR, GSK-3β, Rac1, or calcineurin ameliorated the effects of ANLNR431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. CONCLUSIONS The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.
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Affiliation(s)
- Gentzon Hall
- Departments of Pediatrics and
- Duke Molecular Physiology Institute, Durham, North Carolina; and
- Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Brandon M Lane
- Departments of Pediatrics and
- Duke Molecular Physiology Institute, Durham, North Carolina; and
| | - Kamal Khan
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina
| | - Igor Pediaditakis
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina
| | - Jianqiu Xiao
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina
| | - Guanghong Wu
- Departments of Pediatrics and
- Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Liming Wang
- Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Maria E Kovalik
- Departments of Pediatrics and
- Duke Molecular Physiology Institute, Durham, North Carolina; and
- Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Megan Chryst-Stangl
- Departments of Pediatrics and
- Duke Molecular Physiology Institute, Durham, North Carolina; and
| | - Erica E Davis
- Departments of Pediatrics and
- Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina
| | - Robert F Spurney
- Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Rasheed A Gbadegesin
- Departments of Pediatrics and
- Duke Molecular Physiology Institute, Durham, North Carolina; and
- Medicine, Duke University School of Medicine, Durham, North Carolina
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4
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Shah M, Shankar A, Gee I, Nash K, Hoare M, Gibbs P, Davies S, Alexander GJM. A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. Aliment Pharmacol Ther 2015; 41:379-92. [PMID: 25496225 DOI: 10.1111/apt.13049] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/05/2014] [Accepted: 11/21/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus. AIM To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis. METHODS A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%). RESULTS Patients switched to sirolimus had improved survival (P < 0.001) and slower progression to cirrhosis (P = 0.001). In patients with HCC (n = 91), sirolimus duration rather than strategy was an independent predictor of survival (P = 0.001) and extended time to HCC recurrence (33 vs. 16 months). Patients switched for renal dysfunction showed improvement in serum creatinine (140-108 μmol/L, P = 0.001). Those remaining on CNI-therapy were more likely to develop post-transplant diabetes (P = 0.03). CONCLUSION These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome.
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Affiliation(s)
- M Shah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK
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Mathis AS, Egloff G, Ghin HL. Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies. World J Transplant 2014; 4:57-80. [PMID: 25032096 PMCID: PMC4094953 DOI: 10.5500/wjt.v4.i2.57] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 03/25/2014] [Accepted: 05/14/2014] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.
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Sereno J, Rodrigues-Santos P, Vala H, Rocha-Pereira P, Alves R, Fernandes J, Santos-Silva A, Carvalho E, Teixeira F, Reis F. Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model. Int J Mol Sci 2014; 15:8979-97. [PMID: 24853130 PMCID: PMC4057770 DOI: 10.3390/ijms15058979] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/05/2014] [Accepted: 05/13/2014] [Indexed: 01/16/2023] Open
Abstract
Cyclosporin A (CsA), a calcineurin inhibitor, remain the cornerstone of immunosuppressive regimens, regardless of nephrotoxicity, which depends on the duration of drug exposure. The mechanisms and biomarkers underlying the transition from CsA-induced renal dysfunction to nephrotoxicity deserve better elucidation, and would help clinical decisions. This study aimed to clarify these issues, using a rat model of short- and long-term CsA (5 mg/kg bw/day) treatments (3 and 9 weeks, respectively). Renal function was assessed on serum and urine; kidney tissue was used for histopathological characterization and gene and/or protein expression of markers of proliferation, fibrosis and inflammation. In the short-term, creatinine and blood urea nitrogen (BUN) levels increased and clearances decreased, accompanied by glomerular filtration rate (GFR) reduction, but without kidney lesions; at that stage, CsA exposure induced proliferating cell nuclear antigen (PCNA), transforming growth factor beta 1 (TGF-β1), factor nuclear kappa B (NF-κβ) and Tumor Protein P53 (TP53) kidney mRNA up-regulation. In the long-term treatment, renal dysfunction data was accompanied by glomerular and tubulointerstitial lesions, with remarkable kidney mRNA up-regulation of the mammalian target of rapamycin (mTOR) and the antigen identified by monoclonal antibody Ki-67 (Mki67), accompanied by mTOR protein overexpression. Transition from CsA-induced renal dysfunction to nephrotoxicity is accompanied by modification of molecular mechanisms and biomarkers, being mTOR one of the key players for kidney lesion evolution, thus suggesting, by mean of molecular evidences, that early CsA replacement by mTOR inhibitors is indeed the better therapeutic choice to prevent chronic allograft nephropathy.
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Affiliation(s)
- José Sereno
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
| | - Paulo Rodrigues-Santos
- Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal.
| | - Helena Vala
- Agrarian School of Viseu (ESAV), Polytechnic Institute of Viseu, Viseu 3500-606, Portugal.
| | | | - Rui Alves
- University Nephrology Unit, Faculty of Medicine, University of Coimbra, Coimbra 3004-504, Portugal.
| | - João Fernandes
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
| | - Alice Santos-Silva
- Biochemistry Department, Pharmacy Faculty, Porto University, Porto 4050-313, Portugal.
| | - Eugénia Carvalho
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
| | - Frederico Teixeira
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
| | - Flávio Reis
- Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal.
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Abstract
Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.
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Affiliation(s)
- Christina Nguyen
- Division of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
| | - Ron Shapiro
- Division of Transplant Surgery, UPMC Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, United States
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8
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Serum and renal tissue markers of nephropathy in rats under immunosuppressive therapy: cyclosporine versus sirolimus. Transplant Proc 2013; 45:1149-56. [PMID: 23622648 DOI: 10.1016/j.transproceed.2013.02.085] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cyclosporin (CsA) has been progressively replaced by other drugs with putatively fever side effects, including nephrotoxicity and hypertension. Sirolimus (SRL) is one of the main options for management of kidney transplant patients in the post-CsA era. It shows identical efficacy with apparently less cardiorenal side effects than CsA. However, doubts remain concerning the mechanisms of putative renoprotection by SRL as well as the best serum and/or tissue markers for nephropathy, as assessed in this study employing CsA- and SRL-treated rats. Three groups (n = 6) were treated orally during a 6-week protocol: control (vehicle); CsA (5 mg/kg body weight per day Sandimmun Neoral); SRL (1 mg/kg body weight per day Rapamune). Blood pressure and heart rate were assessed with a "tail cuff". Renal dysfunction and morphology were characterized using serum creatinine and blood urea nitrogen (BUN) levels as well as hematoxylin and eosin and periodic acid Schiff staining, respectively. We examined serum concentrations of interleukin (IL)-2, IL-1β, high-sensitivity C-reactive protein, tumor necrosis factor TNF-α, and vascular endothelial growth factor and kidney mRNA expression of interleukin-1β (IL-1β), tumor protein 53 (TP53), mammalian target of rapamycin (mTOR) and proliferating cell nuclear antigen (PCNA), as well as markers of lipid peroxidation in the kidney and serum. Both CsA and SRL induced significant increases in systolic and diastolic blood pressure, but only CsA caused tachycardia. CsA-treated rats also displayed increased serum creatinine and BUN levels, accompanied by mild renal lesions, which were almost absent among SRL-treated rats, which presented hyperlipidemic and hyperglycemic profiles. CsA-induced nephrotoxicity was accompanied by kidney overexpression of inflammatory and proliferative mRNA markers (IL-1β, mTOR and PCNA), which were absent among SRL group. In conclusion, the antiproliferative and antifibrotic character of SRL may explain its less nephrotoxic profile. Renal over expression of mTOR in the CsA-treated group, associated with renal dysfunction and structural damage, reinforces the potential beneft of SRL as a strategy to reduce CsA-evoked nephrotoxicity.
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Menon MC, Murphy B. Maintenance immunosuppression in renal transplantation. Curr Opin Pharmacol 2013; 13:662-71. [PMID: 23731524 DOI: 10.1016/j.coph.2013.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/03/2013] [Indexed: 12/28/2022]
Abstract
The need to maintain allograft recipients on immunosuppression is nearly universal. Immunosuppressive agents used in organ transplantation target one or more steps of the host alloimmune response, specifically processes related to CD4-positive T lymphocytes. Calcineurin-inhibitor based steroid-containing regimens have been the mainstay of maintenance immunosuppression over the last two decades. Newer agents have shown efficacy in this role in recent trials with comparable allograft and patient outcomes. These agents have permitted calcineurin-inhibitor minimization and steroid-sparing strategies in selected groups of patients.
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Affiliation(s)
- Madhav C Menon
- Ichan School of Medicine at Mount Sinai, New York, United States
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Fidan K, Kandur Y, Sozen H, Gonul İ, Dalgic A, Söylemezoğlu O. How Often Do We Face Side Effects of Sirolimus in Pediatric Renal Transplantation? Transplant Proc 2013; 45:185-9. [DOI: 10.1016/j.transproceed.2012.08.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 08/11/2012] [Accepted: 08/30/2012] [Indexed: 10/27/2022]
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Halleck F, Duerr M, Waiser J, Huber L, Matz M, Brakemeier S, Liefeldt L, Neumayer HH, Budde K. An evaluation of sirolimus in renal transplantation. Expert Opin Drug Metab Toxicol 2012; 8:1337-56. [PMID: 22928953 DOI: 10.1517/17425255.2012.719874] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. AREAS COVERED The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. EXPERT OPINION Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.
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Affiliation(s)
- Fabian Halleck
- Department of Nephrology, Charité Universitätsmedizin, Berlin, Germany.
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12
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Everolimus as primary immunosuppression in kidney transplantation: experience in conversion from calcineurin inhibitors. Transplantation 2012; 93:398-405. [PMID: 22245871 DOI: 10.1097/tp.0b013e31823ffd0e] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion. METHODS Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival. RESULTS Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion. CONCLUSIONS Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.
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Shing CM, Fassett RG, Brown L, Coombes JS. The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats. Transpl Int 2012; 25:337-46. [PMID: 22239125 DOI: 10.1111/j.1432-2277.2011.01420.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week-old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus-treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.
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Affiliation(s)
- Cecilia M Shing
- School of Human Life Sciences, University of Tasmania, Launceston, Australia.
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14
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del Carmen Rial M, Abbud-Filho M, Torres Gonçalves R, Martinez-Mier G, Montero C, Raffaele P, Toledo Solares M, Alberú J. Individualizing Early Use of Sirolimus in Renal Transplantation. Transplant Proc 2010; 42:4518-25. [DOI: 10.1016/j.transproceed.2010.10.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 10/07/2010] [Indexed: 12/30/2022]
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15
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Low-Dose Calcineurin Inhibitor Regimen Combined With Mammalian Target of Rapamycin Inhibitors Preserves Kidney Functions in Renal Transplant Recipients Without Allograft Nephropathy. Transplant Proc 2010; 42:3513-6. [DOI: 10.1016/j.transproceed.2010.08.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Revised: 06/04/2010] [Accepted: 08/26/2010] [Indexed: 11/22/2022]
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Conversion to sirolimus for chronic allograft nephropathy and calcineurin inhibitor toxicity and the adverse effects of sirolimus after conversion. Transplant Proc 2010; 41:2789-93. [PMID: 19765436 DOI: 10.1016/j.transproceed.2009.07.094] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use. MATERIALS AND METHODS We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration. RESULTS At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia. CONCLUSION Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.
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Witzke O, Viklicky O, Türk TR, Lutz J, Wilde B, Willenberg I, Vitko S, Heemann U. Conversion to sirolimus of patients with chronic allograft nephropathy—a retrospective analysis of outcome and influencing factors. Langenbecks Arch Surg 2009; 394:1073-8. [DOI: 10.1007/s00423-008-0435-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 10/31/2008] [Indexed: 11/30/2022]
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Outcomes With Conversion From Calcineurin Inhibitors to Sirolimus After Renal Transplantation in the Context of Steroid Withdrawal or Steroid Continuation. Transplantation 2009; 88:684-92. [DOI: 10.1097/tp.0b013e3181b27d44] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Reis F, Parada B, Teixeira de Lemos E, Garrido P, Dias A, Piloto N, Baptista S, Sereno J, Eufrásio P, Costa E, Rocha-Pereira P, Santos-Silva A, Figueiredo A, Mota A, Teixeira F. Hypertension Induced by Immunosuppressive Drugs: A Comparative Analysis Between Sirolimus and Cyclosporine. Transplant Proc 2009; 41:868-73. [DOI: 10.1016/j.transproceed.2009.02.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Liew A, Chiang GSC, Vathsala A. Factors associated with proteinuria in renal transplant recipients treated with sirolimus. Transpl Int 2009; 22:313-22. [DOI: 10.1111/j.1432-2277.2008.00801.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Therapeutic effect of Tripterygium wilfordii on proteinuria associated with sirolimus in renal transplant recipients. Transplant Proc 2009; 40:3474-8. [PMID: 19100416 DOI: 10.1016/j.transproceed.2008.07.140] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2008] [Accepted: 07/23/2008] [Indexed: 11/20/2022]
Abstract
Sirolimus (SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after renal transplantation. Nevertheless, the occurrence of proteinuria has recently been recognized among patients on SRL-based therapy. The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii Hook F. (T II) on proteinuria associated with SRL in renal transplant recipients. According to accepting T II, 36 recipients were divided into 2 groups: T II group (n = 21) and valsartan group (n = 15). The T II group was administered 1 mg/kg/d, and the valsartan group, 80 mg twice per day for 12 months. Efficiency was then evaluated. Complete remission: proteinuria decreased by >50%; partial remission: proteinuria decreased by 20% to 50%; ineffective: proteinuria decreased by <20%. Upon 12-month follow-up, the total effective rates in the T II group and the valsartan group were 95.2% and 86.7% (P < .05), respectively. Twenty of 21 patients with proteinuria in the T II group were negative at 3-month follow-up with disappearance of edema. There were some adverse events that had greater incidence rates in the valsartan group compared with the T II group, such as hyperkalemia (26.7% vs 4.8%). We concluded that the application of T II markedly reduced proteinuria associated with SRL in renal transplant patients.
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Vollenbröker B, George B, Wolfgart M, Saleem MA, Pavenstädt H, Weide T. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am J Physiol Renal Physiol 2008; 296:F418-26. [PMID: 19019920 DOI: 10.1152/ajprenal.90319.2008] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The immunosuppressive mammalian target of rapamycin (mTOR) inhibitors can cause proteinuria, especially in kidney and heart transplanted patients. Podocytes play a major role in establishing the selective permeability of the blood-urine filtration barrier. Damage of these cells leads to proteinuria, a hallmark of most glomerular diseases. Interestingly, podocyte damage and focal segmental glomerulosclerosis can occur after treatment with an mTOR inhibitor in some transplant patients. To investigate the mechanisms of mTOR inhibitor-induced podocyte damage, we analyzed the effect of rapamycin on mTOR signaling and cellular function in human podocytes. We found that prolonged rapamycin treatment reduced the expression of total mTOR, which correlates with diminished levels of mTOR phosphorylation at Ser(2448) and Ser(2481). In addition, treatment with rapamycin reduced rictor expression and mTORC2 formation, resulting in a reduced phosphorylation of protein kinase B at Ser(473). The expression level of the slit-diaphragm proteins nephrin and transient receptor potential cation channel 6 as well as the cytoskeletal adaptor protein Nck significantly decreased. Moreover, rapamycin reduced cell adhesion and cell motility, which was accompanied by an enhanced formation of dot-like actin-rich structures. Our data provide new molecular insights explaining which pathways and molecules are affected in podocytes by an imbalanced mTOR function because of rapamycin treatment.
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Affiliation(s)
- Beate Vollenbröker
- UKM, Medizinische Klinik und Poliklinik D, Abteilung: Molekulare Nephrologie, Domagkstr. 3a, D-48149 Münster, Germany
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Letavernier E, Bruneval P, Vandermeersch S, Perez J, Mandet C, Belair MF, Haymann JP, Legendre C, Baud L. Sirolimus interacts with pathways essential for podocyte integrity. Nephrol Dial Transplant 2008; 24:630-8. [PMID: 18927120 DOI: 10.1093/ndt/gfn574] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND The specific mTor inhibitor sirolimus has been implicated in the pathogenesis of renal glomerular lesions and nephrotic syndrome appearance after transplantation. Podocyte injury and focal segmental glomerulosclerosis have been related to sirolimus therapy in some patients but the pathways underlying these lesions remain hypothetical. METHODS To go further in the comprehension of these mechanisms, primary cultures of human podocytes were exposed to therapeutic-range concentrations of sirolimus. RESULTS Cell viability was not affected after 2 days' exposure to the drug but changes in cell phenotype and cytoskeleton reorganization were observed. We also evidenced that vascular endothelial growth factor (VEGF) synthesis and Akt phosphorylation were decreased by sirolimus addition. We did not observe any loss of podocyte differentiation markers with the notable exception of WT1, a transcription factor essential for maintaining podocyte integrity. WT1 gene and protein expression in podocytes were decreased in a dose-dependent manner after incubation with sirolimus. CONCLUSION Taken together, these data suggest that sirolimus could impair pathways essential for podocyte integrity and therefore predisposes to glomerular injury.
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Affiliation(s)
- Emmanuel Letavernier
- INSERM, U702 and Université Pierre et Marie Curie-Paris 6, UMRS702, Paris, France.
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mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev (Orlando) 2008; 22:125-30. [PMID: 18631865 DOI: 10.1016/j.trre.2007.12.001] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.
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Weintraub L, Li L, Kambham N, Alexander S, Concepcion W, Miller K, Wong C, Salvatierra O, Sarwal M. Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant 2008; 12:541-9. [PMID: 18564305 DOI: 10.1111/j.1399-3046.2007.00847.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 +/- 22 to 59.38 +/- 28.6 mL/min/1.73 m(2) (p = 0.04) at six months and 57.46 +/- 31.1 mL/min/1.73 m(2) (p = 0.02) at 12 months post-withdrawal. Forty-one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 +/- 1.0 to 1.71 +/- 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI-based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.
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Affiliation(s)
- Lauren Weintraub
- Department of Pediatrics, Stanford University, Stanford, CA, USA.
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Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation 2008; 84:956-64. [PMID: 17989600 DOI: 10.1097/01.tp.0000284808.28353.2c] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg. METHODS To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant. RESULTS Despite 4-fold higher CD4+CD25high Treg counts (22.1+/-12.2% vs. 5.7+/-4.2% of CD3+CD4+ T cells), SRL-treated patients, compared to CsA-treated patients, had a significantly higher tubular C4d staining score (1.1+/-0.6 vs. 0.2+/-0.3, P<0.01), with nonsignificant trends to higher chronic allograft damage index score (5.6+/-2.4 vs. 3.7+/-3.3), faster GFR (-2.92+/-0.33 vs. -0.28+/-0.44 ml/min/1.73 m2 per year), and RPF (-10.80+/-5.45 vs. -1.86+/-3.09 ml/min/1.73 m2 per year) decline, and more clinical proteinuria (n=6 vs. 4). There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each cohort. CONCLUSIONS These data suggest that, despite enhanced Treg expression, low-dose SRL combined to alemtuzumab induction and MMF-based steroid-free maintenance therapy, does not appreciably protect renal transplant recipients from chronic allograft injury and dysfunction.
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The mTOR Inhibitor Everolimus Induces Proteinuria and Renal Deterioration in the Remnant Kidney Model in the Rat. Transplantation 2007; 84:1492-9. [DOI: 10.1097/01.tp.0000282866.92367.99] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Worldwide, more than 250,000 individuals who have received a liver, heart, lung, or intestinal transplant are living longer. Twenty percent to 25% of these recipients experience perioperative acute renal failure, with 10% to 15% requiring renal replacement therapy. Chronic kidney disease (CKD) is also highly prevalent, affecting 30% to 50% of the nonrenal organ transplant population with an annual end-stage renal disease risk of 1.5% to 2.0%. Both acute renal failure and CKD contribute to increased morbidity and premature mortality. The dominant causative factor for renal disorders seen in nonrenal transplant recipients are the calcineurin inhibitors (CNI) and rapamycin analogues, which singly or in combination lead to a variety of nephrotoxic injury. However, 25% to 30% of nonrenal transplant recipients with CKD have other conditions such as hypertension, focal segmental glomerulosclerosis, diabetes mellitus, and hepatitis C infection as the principal underlying cause. Management strategies for renal disease in the nonrenal transplant recipients include the following: (1) delayed introduction of CNI after graft implantation, (2) withdrawal or minimization of long-term CNI therapy, (3) timely use of an appropriate dialysis modality, and (4) expeditious introduction of supportive measures such as anemia management, phosphate binding therapy, and dietary modification. Compared with maintenance dialysis, kidney transplantation reduces long-term mortality by 60% to 70% in nonrenal transplant recipients with end-stage renal disease.
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Affiliation(s)
- Akinlolu O Ojo
- Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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Campbell MS, Rai J, Kozin E, Bloom RD, Markmann JF, Olthoff KM, Shaked A, Rajender Reddy K. Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation. Clin Transplant 2007; 21:377-84. [PMID: 17488388 DOI: 10.1111/j.1399-0012.2006.00653.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus-based and calcineurin inhibitor-based immunosuppression. We retrospectively studied 79 patients converted to sirolimus-based immunosuppression and 100 control subjects continued on calcineurin inhibitor-based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine > or =2.0 mg/dL. Cohorts were compared using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post-OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus-based immunosuppression was associated with a 1.8 (0.8-4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8-4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.
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Affiliation(s)
- Mical S Campbell
- Division of Gastroenterology, Penn Liver Transplant Center, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
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Morales J, Fierro A, Benavente D, Zehnder C, Ferrario M, Contreras L, Herzog C, Buckel E. Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria. Transplant Proc 2007; 39:591-3. [PMID: 17445551 DOI: 10.1016/j.transproceed.2006.12.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.
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Affiliation(s)
- J Morales
- Unidad de Trasplante, Clinica Las Condes, Santiago, Chile.
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Fiocchi R, Iacovoni A, Sebastiani R, Fontana A, Gandolfi L, Gamba A. Possible Role of Everolimus in Improving Renal Function in Long-Term Heart Transplantation. Transplant Proc 2007; 39:1967-9. [PMID: 17692667 DOI: 10.1016/j.transproceed.2007.07.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Patient survival after heart transplantation has improved dramatically since the availability of calcineurine inhibitor (CNIs); the number of long-term patients is progressively increasing. However, in these patients, nephrotoxicity of CNIs has been largely responsible for the progressive development of renal dysfunction. Since impaired renal function is an important issue that reduces long-term patient survival, it is important to develop strategies to improve renal function while maintaining immunologic safety to preserve graft function. Everolimus is an mTOR inhibitor sirolimus analogue, that has proved, to be highly efficacious to prevent acute myocardial rejection and reduce the severity of cardiac allograft vasculopathy in de novo HTx patients. There is reasonable evidence that, in long term heart transplanted patients, renal function may improve when everolimus is administered associated with a progressive reduction of CNIs. So far there is no evidence to identify which patient may benefit from this therapeutic approach. Indeed everolimus alone may be equally effective to prevent rejection and improve renal function when CNIs are completely discontinued, but data are still lacking on the risks, dosages and side effects of this type of immunosuppression. Ongoing clinical studies will provide further guidance about the possibility to halt or reduce the progression of renal impairment in long term heart transplant patients.
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Affiliation(s)
- R Fiocchi
- Cardiovascular Department Heart Transplant Center, Ospedali Riuniti di Bergamo, Italy.
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Abdurrahman Z, Sarwal M, Millan M, Robertson S, Filler G. Sirolimus is not always responsible for new-onset proteinuria after conversion for chronic allograft nephropathy. Pediatr Transplant 2007; 11:336-9. [PMID: 17430494 DOI: 10.1111/j.1399-3046.2006.00670.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
An eight-yr-old combined liver and kidney transplant recipient for hyperoxaluria type I developed significant proteinuria and hypertension after conversion of a Tacrolimus, MMF, and corticosteroids-based immunosuppression to Sirolimus, low-dose Tacrolimus, and corticosteroids six and a half yr after the transplant for chronic allograft nephropathy. There was only one class I HLA match and the recipient had multiple blood exposures prior to transplantation. The patient was treated with combined hemodialysis and peritoneal dialysis while awaiting transplantation to reduce the oxalate load. A renal biopsy revealed a de novo transplant glomerulopathy that was associated with specific HLA antibodies unrelated to the donor (HLA DR 17 and 18). After reintroduction of MMF, these antibodies became undetectable and the proteinuria completely resolved. We hypothesize that HLA antibodies may cause transplant glomerulopathy even if they are not donor-specific. Their production appears more susceptible to MMF therapy. A thorough work-up of new-onset proteinuria after conversion to Sirolimus should be performed, including an immunological work-up and a renal biopsy.
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Affiliation(s)
- Zainab Abdurrahman
- Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, QC, Canada
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Franco AFV, Martini D, Abensur H, Noronha IL. Proteinuria in Transplant Patients Associated With Sirolimus. Transplant Proc 2007; 39:449-52. [PMID: 17362756 DOI: 10.1016/j.transproceed.2007.01.038] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 +/- 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 +/- 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.
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Affiliation(s)
- A F V Franco
- Laboratory of Molecular and Cellular Nephrology, University of São Paulo, São Paulo, Brazil.
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Halimi JM, Buchler M, Al-Najjar A, Laouad I, Chatelet V, Marlière JF, Nivet H, Lebranchu Y. Urinary albumin excretion and the risk of graft loss and death in proteinuric and non-proteinuric renal transplant recipients. Am J Transplant 2007; 7:618-25. [PMID: 17217438 DOI: 10.1111/j.1600-6143.2007.01665.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Microalbuminuria and macroalbuminuria constitute risk factors for ESRD and death in non-transplanted populations. Whether microalbuminuria (especially in non-proteinuric patients) and macroalbuminuria constitute risk factors for graft loss and death is presently unknown in renal transplantation. METHODS We retrospectively assessed the association between urinary albumin excretion (UAE) and ESRD and death in renal transplantation. RESULTS UAE was measured in 616 (397 proteinuric; 219 non-proteinuric patients) renal transplant recipients. They were grafted for 62 months (range: 6-192). During the 40 months (3.7-99) thereafter, 31 patients underwent dialysis and 32 died. Microalbuminuria (vs. normoalbuminuria) and macroalbuminuria (vs. microalbuminuria) were powerful risk factors for graft loss [OR: 14.25 (2.88-52.3) and 16.41 (7.46-36.0), respectively, both p < 0.0001], even after adjustments on renal function and diabetes. Among the 219 non-proteinuric patients, microalbuminuria (vs. normoalbuminuria) was a significant risk factor for graft loss [OR: 23.09 (1.93-276.4), p = 0.0132]. Both microalbuminuria (vs. normoalbuminuria) [OR: 5.55 (2.43-12.66), p < 0.0001] and macroalbuminuria (vs. microalbuminuria) [OR: 4.12 (1.65-10.29), p = 0.0024] were predictive of death. CONCLUSIONS Microalbuminuria and macroalbuminuria are powerful independent predictors of ESRD and death. Microalbuminuria is a risk factor for graft loss even in non-proteinuric patients. UAE provides additional information on renal and patient prognosis as compared to proteinuria and renal function.
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Affiliation(s)
- J-M Halimi
- François Rabelais University, Department of Nephrology and Clinical Immunology, CHU Tours, Tours, France.
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Letavernier E, Bruneval P, Mandet C, Duong Van Huyen JP, Péraldi MN, Helal I, Noël LH, Legendre C. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol 2007; 2:326-33. [PMID: 17699432 DOI: 10.2215/cjn.03751106] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- Emmanuel Letavernier
- Service de Transplantation Adulte Hôpital Necker, 149 rue de Sèvres 75743 Paris, France
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Abstract
Sirolimus is a potent immunosuppressant drug with a novel mechanism of action. It inhibits the mammalian target of rapamycin (mTOR) and blocks the cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus is widely used as a maintenance immunosuppressive agent in organ transplantation. Also, a potentially benefit of this valuable drug in some immunologic and malignant diseases is currently under scrutiny.Classical side effects: hematological (anaemia, leucopenia, thrombocytopenia), hypercholesterolemia, arthralgias, extremity oedema and impaired wound healing have been frequently associated with the use of sirolimus. Additionally with its increased use, transplant professionals are encountering a variety of previously unreported and potentially more severe side effects.Here, we review the most recent data on sirolimus unexpected side effects (with an emphasis on pulmonary and renal toxicity), its use in renal transplantation and its new potential therapeutic indications (chronic glomerulopathies, polycystic kidney disease, different types of cancer). A brief description of the current knowledge of sirolimus therapeutic drug monitoring, methods of analysis, pharmacokinetics and drug interactions with calcineurin inhibitors is also included.
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Affiliation(s)
- Irina Buhaescu
- Dialysis and Renal Transplantation Center, Parhon University Hospital, Iasi, Romania.
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Abstract
Pancreas and islet transplant recipients are monitored using various metabolic and imaging methods. The inaccessibility of the transplanted whole pancreas and of the isolated islets poses specific problems (eg, all assessment techniques are indirect). Although successful pancreas transplantation typically restores normal glucose homeostasis, islet transplantation into the liver does not completely normalize islet hormone secretion and glucose metabolism. Development of better testing strategies, such as direct islet imaging, will significantly advance the field.
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Affiliation(s)
- Emily C Dy
- Diabetes Branch, National Institutes of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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