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Singh A, Khanna T, Mahendru D, Kahlon J, Kumar V, Sohal A, Yang J. Insights into renal and urological complications of inflammatory bowel disease. World J Nephrol 2024; 13:96574. [PMID: 39351187 PMCID: PMC11439091 DOI: 10.5527/wjn.v13.i3.96574] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/01/2024] [Accepted: 07/15/2024] [Indexed: 09/19/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition characterized by immune-mediated inflammation in the gastrointestinal tract, which follows a relapsing and remitting course. Apart from affecting the gastrointestinal tract, IBD also has extra-intestinal manifestations (EIMs). While the etiology of extraintestinal manifestation remains unclear, it is theorized to be based on immunological responses influenced by genetic factors. Renal involvement is one of the EIMs observed in ulcerative colitis and Crohn's disease. The renal manifestations in IBD patients encompass a range of conditions including nephrolithiasis, amyloidosis, tubulointerstitial nephritis, glomerulonephritis (GN), obstructive pathologies, and chronic kidney disease (CKD). The incidence of CKD in IBD patients varies from 5%-15%. The decline in renal function can stem from various factors such as direct inflammatory damage to the kidneys leading to glomerular or tubular injury, or from complications like recurrent stones, amyloidosis, or GN. Additionally, nephrotoxic medications used in treating IBD, such as TNF-α inhibitors, calcineurin inhibitors, and aminosalicylates, can exacerbate the decline in renal function. Currently, there is a lack of consensus regarding these patients' screening and renal function monitoring. This review aims to assess the existing literature on the different renal complications among individuals with IBD, shedding light on their pathophysiology and management.
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Affiliation(s)
- Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Tejasvini Khanna
- Department of Medicine, Maulana Azad Medical College, New Delhi 110002, India
| | - Diksha Mahendru
- Department of Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Jasraj Kahlon
- Department of Internal Medicine, Abrazo Medical Center, Phoenix, AZ 85015, United States
| | - Vikash Kumar
- Department of Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, United States
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA 98105, United States
| | - Juliana Yang
- Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX 77555, United States
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Yu J, Wei X, Gao J, Wang C, Wei W. Role of cyclosporin A in the treatment of kidney disease and nephrotoxicity. Toxicology 2023; 492:153544. [PMID: 37164250 DOI: 10.1016/j.tox.2023.153544] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 05/12/2023]
Abstract
The clinical use of cyclosporin A (CsA) has led to significant advances and achievements in the field of transplantation and immune diseases. However, the nephrotoxicity of CsA is a major concern in current immunosuppression regimens. CsA causes abnormal kidney function while treating kidney disease, causing problems for clinicians and patients. Evidence of CsA nephrotoxicity is almost always present in transplant recipients after long-term CsA administration (up to 10 years), and similar phenomena occur with other calcineurin inhibitors. In this review, we summarize the mechanisms and influencing factors of CsA for the treatment of primary nephrotic syndrome. The mechanisms of CsA nephrotoxicity, clinical-pathological features, diagnosis, prevention strategies, and risk factors are summarized. We discuss the correlates and mechanisms of the switch between kidney disease prevention and nephrotoxicity of CsA to better understand the function of CsA in the kidney and to provide a basis for the prevention and treatment of CsA nephrotoxicity.
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Affiliation(s)
- Jun Yu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Mdicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China; Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China
| | - Xiao Wei
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China; Blood Purification Center, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Jinzhang Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Mdicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China; Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Mdicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China; Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; Key Laboratory of Anti-Inflammatory and Immune Mdicine, Ministry of Education, Hefei, China; Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, China; Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China.
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Schmucki K, Hofmann P, Fehr T, Inci I, Kohler M, Schuurmans MM. Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients. Transplantation 2023; 107:53-73. [PMID: 36508646 PMCID: PMC9746343 DOI: 10.1097/tp.0000000000004336] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) after lung transplantation is common and limits the survival of transplant recipients. The calcineurin inhibitors (CNI), cyclosporine A, and tacrolimus being the cornerstone of immunosuppression are key mediators of nephrotoxicity. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used in combination with reduced CNI dosage after lung transplantation. METHODS This systematic review examined the efficacy and safety of mTOR inhibitors after lung transplantation and explored their effect on kidney function. RESULTS mTOR inhibitors are often introduced to preserve kidney function. Several clinical trials have demonstrated improved kidney function and efficacy of mTOR inhibitors. The potential for kidney function improvement and preservation increases with early initiation of mTOR inhibitors and low target levels for both mTOR inhibitors and CNI. No defined stage of CKD for mTOR inhibitor initiation exists, nor does severe CKD preclude the improvement of kidney function under mTOR inhibitors. Baseline proteinuria may negatively predict the preservation and improvement of kidney function. Discontinuation rates of mTOR inhibitors due to adverse effects increase with higher target levels. CONCLUSIONS More evidence is needed to define the optimal immunosuppressive regimen incorporating mTOR inhibitors after lung transplantation. Not only the indication criteria for the introduction of mTOR inhibitors are needed, but also the best timing, target levels, and possibly discontinuation criteria must be defined more clearly. Current evidence supports the notion of nephroprotective potential under certain conditions.
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Affiliation(s)
- Katja Schmucki
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
| | - Patrick Hofmann
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
| | - Thomas Fehr
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Ilhan Inci
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Thoracic Surgery, Zurich University Hospital, Zurich, Switzerland
| | - Malcolm Kohler
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Macé M. Schuurmans
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
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4
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van Hoeve K, Hoffman I. Renal manifestations in inflammatory bowel disease: a systematic review. J Gastroenterol 2022; 57:619-629. [PMID: 35834005 DOI: 10.1007/s00535-022-01903-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023]
Abstract
As extra-intestinal manifestations (EIMs) are frequent in inflammatory bowel disease (IBD) and affect morbidity and sometimes even mortality, vigilance in the surveillance of EIMs and installing the appropriate treatment are essential. Data on renal manifestations in patients with IBD are however rare. Nevertheless, up to 5-15% of adult patients with IBD will develop chronic kidney disease over time. The pathophysiology of renal involvement in patients with IBD is complex and poorly understood, with a wide range of renal disorders affecting the glomeruli and/or the tubular structure. Furthermore, medication used to treat IBD can be potentially nephrotoxic and metabolic complication due to the disease itself can furthermore cause renal damage. The aim of this systematic review is to provide an overview of the existing data in literature on these renal manifestations and complications in patients with IBD.
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Affiliation(s)
- Karen van Hoeve
- Department of Paediatric Gastroenterology and Hepatology and Nutrition, University Hospitals Leuven, Herestraat 49. 3000 KU, Louvain, Belgium.
| | - Ilse Hoffman
- Department of Paediatric Gastroenterology and Hepatology and Nutrition, University Hospitals Leuven, Herestraat 49. 3000 KU, Louvain, Belgium
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2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-β1 and p-ERK1/2 Axis. Antioxidants (Basel) 2022; 11:antiox11081499. [PMID: 36009218 PMCID: PMC9405159 DOI: 10.3390/antiox11081499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 01/25/2023] Open
Abstract
The immunosuppressant cyclosporine A (CSA) has been linked to serious renal toxic effects. Although 2-methoxyestradiol (2ME) possesses a wide range of pharmacological abilities, it suffers poor bioavailability after oral administration. The purpose of this study was to evaluate the potential of 2ME loaded D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles to prevent CSA-induced nephrotoxicity in rats. A 2ME-TPGS was prepared and showed particle size of 44.3 ± 3.5 nm with good entrapment efficiency and spherical structures. Male Wistar rats were divided into 5 groups, namely: Control, Vehicle, CSA, CSA + 2ME-Raw, and CSA + 2ME-Nano. CSA was injected daily at a SC dose of 20 mg/kg. Both 2ME-Raw and 2ME-Nano were given daily at oral doses of 5 mg/kg. Treatments continued for three successive weeks. 2ME-TPGS exerted significant protective effects against CSA nephrotoxicity. This was evidenced in ameliorating deterioration of renal functions, attenuation of pathological changes in kidney tissues, exerting significant anti-fibrotic, antioxidant, and anti-inflammatory effects together with significant anti-apoptotic effects. Western blot analyses showed both 2ME-Raw and 2ME-Nano significantly inhibited protein expression of TGF-β1 and phospho-ERK (p-ERK). It was observed that 2ME-TPGS, in almost all experiments, exerted superior protective effects as compared with 2ME-Raw. In conclusion, 2ME loaded in a TPGS nanocarrier possesses significant protective activities against CSA-induced kidney injury in rats. This is attributable to 2ME anti-fibrotic, antioxidant, anti-inflammatory, and anti-apoptotic activities which are mediated at least partly by inhibition of TGF-β1/p-ERK axis.
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Drovandi S, Lugani F, Boyer O, La Porta E, Giordano P, Hummel A, Knebelmann B, Cornet J, Baujat G, Lipska-Ziętkiewicz BS, Ghiggeri GM, Caridi G, Angeletti A. Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review. J Clin Med 2022; 11:4423. [PMID: 35956038 PMCID: PMC9369440 DOI: 10.3390/jcm11154423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.
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Affiliation(s)
- Stefania Drovandi
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (S.D.); (E.L.P.); (P.G.); (G.M.G.)
| | - Francesca Lugani
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (F.L.); (G.C.)
| | - Olivia Boyer
- PHP, Service de Néphrologie Pédiatrique, Institut Imagine, Centre de Référence MARHEA, Hôpital Universitaire Necker-Enfants Malades, Université Paris Cité, 75015 Paris, France; (O.B.); (A.H.)
| | - Edoardo La Porta
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (S.D.); (E.L.P.); (P.G.); (G.M.G.)
| | - Paolo Giordano
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (S.D.); (E.L.P.); (P.G.); (G.M.G.)
| | - Aurélie Hummel
- PHP, Service de Néphrologie Pédiatrique, Institut Imagine, Centre de Référence MARHEA, Hôpital Universitaire Necker-Enfants Malades, Université Paris Cité, 75015 Paris, France; (O.B.); (A.H.)
| | - Bertrand Knebelmann
- Nephrology Department, Reference Center for Inherited Kidney Diseases (MARHEA), APHP, Necker Hospital, Paris University, 75015 Paris, France; (B.K.); (J.C.)
| | - Joséphine Cornet
- Nephrology Department, Reference Center for Inherited Kidney Diseases (MARHEA), APHP, Necker Hospital, Paris University, 75015 Paris, France; (B.K.); (J.C.)
| | - Genevieve Baujat
- Reference Centre for Constitutional Bone Diseases, Laboratory of Osteochondrodysplasia, INSERM UMR 1163, Imagine Institute, Université de Paris, 75015 Paris, France;
| | - Beata S. Lipska-Ziętkiewicz
- Rare Diseases Centre, Medical University of Gdansk, 80-210 Gdansk, Poland;
- Department of Biology and Medical Genetics, Clinical Genetics Unit, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (S.D.); (E.L.P.); (P.G.); (G.M.G.)
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (F.L.); (G.C.)
| | - Gianluca Caridi
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (F.L.); (G.C.)
| | - Andrea Angeletti
- Division of Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (S.D.); (E.L.P.); (P.G.); (G.M.G.)
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (F.L.); (G.C.)
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Kumar A, Bonnell LN, Eberlein M, Thomas CP. The U-shaped association of post-lung transplant mortality with pre-transplant eGFR underscores possible limitations of creatinine-based estimation equations for risk stratification. J Heart Lung Transplant 2022; 41:1277-1284. [DOI: 10.1016/j.healun.2022.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 05/10/2022] [Accepted: 05/30/2022] [Indexed: 12/01/2022] Open
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Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt/β-catenin and PPARγ signaling pathways. Life Sci 2021; 291:120259. [PMID: 34968469 DOI: 10.1016/j.lfs.2021.120259] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 11/24/2022]
Abstract
AIMS The nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/β-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. MATERIALS AND METHODS Rats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-β1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/β-catenin and E-cadherin), and PPARγ expression were evaluated. KEY FINDINGS CsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and β-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SIGNIFICANCE The down-regulation of Wnt/β-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.
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Nagao RJ, Marcu R, Shin YJ, Lih D, Xue J, Arang N, Wei L, Akilesh S, Kaushansky A, Himmelfarb J, Zheng Y. Cyclosporine Induces Fenestra-Associated Injury in Human Renal Microvessels In Vitro. ACS Biomater Sci Eng 2021; 8:196-207. [DOI: 10.1021/acsbiomaterials.1c00986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Ryan J. Nagao
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
| | - Raluca Marcu
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
- Kidney Research Institute, University of Washington, Seattle, Washington 98109, United States
| | - Yu Jung Shin
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
| | - Daniel Lih
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
- Kidney Research Institute, University of Washington, Seattle, Washington 98109, United States
| | - Jun Xue
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
| | - Nadia Arang
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington 98101, United States
| | - Ling Wei
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington 98101, United States
| | - Shreeram Akilesh
- Kidney Research Institute, University of Washington, Seattle, Washington 98109, United States
- Department of Pathology, University of Washington, Seattle, Washington 98195, United States
| | - Alexis Kaushansky
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington 98101, United States
- Department of Pediatrics, University of Washington, Seattle, Washington 98195, United States
| | - Jonathan Himmelfarb
- Kidney Research Institute, University of Washington, Seattle, Washington 98109, United States
- Department of Medicine, University of Washington, Seattle, Washington 98109, United States
| | - Ying Zheng
- Department of Bioengineering, University of Washington, Seattle, Washington 98195, United States
- Kidney Research Institute, University of Washington, Seattle, Washington 98109, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, United States
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10
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Improvement of renal function prior to liver transplantation is not associated with better long-term renal outcome or survival. Ann Hepatol 2021; 26:100559. [PMID: 34656773 DOI: 10.1016/j.aohep.2021.100559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/04/2021] [Accepted: 06/22/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Since MELD implementation renal impairment in liver transplant (LT) recipients has become of increasing importance. This is the first study evaluating the course of renal function immediately prior to LT as predictor for long-term renal and overall outcome. PATIENTS AND METHODS In this retrospective study, 226 adults undergoing LT at the University Medical Center Hamburg-Eppendorf (2011-2015) were included. The impact of renal function over a period of 3 months prior to LT compared to renal function at the day of LT on long-term renal outcome and survival was assessed. RESULTS According to GFR at day of LT renal function improved (≥1 CKD stage) in 64 patients (28%), remained stable in 144 (64%) or deteriorated in 18 (8%). Improvement of renal function prior to LT did neither significantly affect 90-day (13% vs. 14%, p = 0.83), nor 5-year post-LT mortality (35% vs. 41%, p = 0.57). 50 patients (22%) with hepatorenal syndrome (HRS) received terlipressin prior to LT, but only 18 (37%) showed prolonged stabilization of renal function (improvement ≥1 CKD stage). Response to terlipressin did neither improve 90-day (p=1), 5-year mortality (p = 0.52) nor long-term renal function (p = 0.843). Nevertheless, need for dialysis pre-LT (59% vs. 34%, p = 0.005) and post-LT (62% vs. 17%, p<0.001) was associated with increased 5-year mortality. CONCLUSIONS Improvement of renal function immediately prior to LT, either spontaneously or following terlipressin therapy, did neither ameliorate long-term renal outcome nor survival in LT recipients. Future studies need to clarify the impact of terlipressin in HRS on the transplant waiting time in LT candidates.
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Ponticelli C, Reggiani F, Moroni G. Old and New Calcineurin Inhibitors in Lupus Nephritis. J Clin Med 2021; 10:jcm10214832. [PMID: 34768354 PMCID: PMC8584552 DOI: 10.3390/jcm10214832] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/11/2021] [Accepted: 10/19/2021] [Indexed: 12/27/2022] Open
Abstract
Calcineurin inhibitors (CNIs) are drugs that inhibit calcineurin, a key phosphatase that dephosphorylates a transcription factor called the nuclear factor of activated T cells (NFAT), allowing its translocation into the nucleus of quiescent T cells. In the nucleus, NFAT activates interleukin 2, which stimulates the proliferation and differentiation of T-cells. CNIs can also stabilize the actin cytoskeleton of podocytes reducing proteinuria. Thanks to these characteristics, CNIs have been often used in the treatment of autoimmune diseases. However, the therapeutic index of CNIs is narrow, and their interactions with other drugs can increase toxicity or reduce efficacy. In lupus nephritis, cyclosporine and tacrolimus have been used both in induction and maintenance therapies. Observational studies and randomized controlled trials showed that both cyclosporine and tacrolimus can increase efficacy. Tolerance is satisfactory if low doses are used and the patient is carefully monitored. More recently, a new CNI, called voclosporin (VCS), has been approved by the Food and Drug Administration for use in lupus nephritis. VCS offers potential advantages over other CNIs. In two large multiethnic trials, VCS was not associated with adverse renal and metabolic events and obtained positive results despite a novel and rapid corticosteroid tapering regime.
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Affiliation(s)
- Claudio Ponticelli
- Nephrology Division, Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Correspondence:
| | - Francesco Reggiani
- Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Milan, Italy; (F.R.); (G.M.)
| | - Gabriella Moroni
- Nephrology and Dialysis Division, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Milan, Italy; (F.R.); (G.M.)
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Nagavally RR, Sunilkumar S, Akhtar M, Trombetta LD, Ford SM. Chrysin Ameliorates Cyclosporine-A-Induced Renal Fibrosis by Inhibiting TGF-β 1-Induced Epithelial-Mesenchymal Transition. Int J Mol Sci 2021; 22:ijms221910252. [PMID: 34638597 PMCID: PMC8508845 DOI: 10.3390/ijms221910252] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 01/27/2023] Open
Abstract
Cyclosporine A (CsA) is a nephrotoxicant that causes fibrosis via induction of epithelial-mesenchymal transition (EMT). The flavonoid chrysin has been reported to have anti-fibrotic activity and inhibit signaling pathways that are activated during EMT. This study investigated the nephroprotective role of chrysin in the prevention of CsA-induced renal fibrosis and elucidated a mechanism of inhibition against CsA-induced EMT in proximal tubule cells. Treatment with chrysin prevented CsA-induced renal dysfunction in Sprague Dawley rats measured by blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Chrysin inhibited CsA-induced tubulointerstitial fibrosis, characterized by reduced tubular damage and collagen deposition. In vitro, chrysin significantly inhibited EMT in LLC-PK1 cells, evidenced by inhibition of cell migration, decreased collagen expression, reduced presence of mesenchymal markers and elevated epithelial junction proteins. Furthermore, chrysin co-treatment diminished CsA-induced TGF-β1 signaling pathways, decreasing Smad 3 phosphorylation which lead to a subsequent reduction in Snail expression. Chrysin also inhibited activation of the Akt/ GSK-3β pathway. Inhibition of both pathways diminished the cytosolic accumulation of β-catenin, a known trigger for EMT. In conclusion, flavonoids such as chrysin offer protection against CsA-induced renal dysfunction and interstitial fibrosis. Chrysin was shown to inhibit CsA-induced TGF-β1-dependent EMT in proximal tubule cells by modulation of Smad-dependent and independent signaling pathways.
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Affiliation(s)
- Rohan Reddy Nagavally
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; (R.R.N.); (S.S.); (M.A.); (L.D.T.)
- Viatris Inc., 1000 Mylan Blvd, Canonsburg, PA 15317, USA
| | - Siddharth Sunilkumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; (R.R.N.); (S.S.); (M.A.); (L.D.T.)
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Mumtaz Akhtar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; (R.R.N.); (S.S.); (M.A.); (L.D.T.)
| | - Louis D. Trombetta
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; (R.R.N.); (S.S.); (M.A.); (L.D.T.)
| | - Sue M. Ford
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; (R.R.N.); (S.S.); (M.A.); (L.D.T.)
- Correspondence: ; Tel.: +1-71-8990-6220
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13
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Zmijewska AA, Zmijewski JW, Becker EJ, Benavides GA, Darley-Usmar V, Mannon RB. Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity. Am J Transplant 2021; 21:2964-2977. [PMID: 33724664 PMCID: PMC8429074 DOI: 10.1111/ajt.16561] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 02/11/2021] [Accepted: 03/01/2021] [Indexed: 01/25/2023]
Abstract
Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.
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Affiliation(s)
- Anna A. Zmijewska
- Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jaroslaw W. Zmijewski
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Eugene J. Becker
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gloria A. Benavides
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor Darley-Usmar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Roslyn B. Mannon
- Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama,Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama
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14
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Sarró E, Durán M, Rico A, Bou-Teen D, Fernández-Majada V, Croatt AJ, Nath KA, Salcedo MT, Gundelach JH, Batlle D, Bram RJ, Meseguer A. Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype. J Mol Cell Biol 2021; 12:499-514. [PMID: 32162654 PMCID: PMC7493029 DOI: 10.1093/jmcb/mjaa005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 01/29/2020] [Accepted: 03/06/2020] [Indexed: 11/23/2022] Open
Abstract
Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial–mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.
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Affiliation(s)
- Eduard Sarró
- Renal Physiopathology Group, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain
| | - Mónica Durán
- Renal Physiopathology Group, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain
| | - Ana Rico
- Renal Physiopathology Group, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain
| | - Diana Bou-Teen
- Cardiovascular Diseases Group, Vall d'Hebron Research Institute, 08035 Barcelona, Spain
| | - Vanesa Fernández-Majada
- Biomimetic Systems for Cell Engineering Laboratory, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Anthony J Croatt
- Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Karl A Nath
- Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Maria Teresa Salcedo
- Department of Pathology, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
| | - Justin H Gundelach
- Department of Pediatric and Adolescent Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.,Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Daniel Batlle
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Richard J Bram
- Department of Pediatric and Adolescent Medicine, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.,Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Anna Meseguer
- Renal Physiopathology Group, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute, 08035 Barcelona, Spain.,Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.,Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III-FEDER, 28040 Madrid, Spain
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15
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Castoldi G, Carletti R, Ippolito S, Colzani M, Barzaghi F, Stella A, Zerbini G, Perseghin G, Zatti G, di Gioia CRT. Sodium-glucose cotransporter 2 inhibition prevents renal fibrosis in cyclosporine nephropathy. Acta Diabetol 2021; 58:1059-1070. [PMID: 33760995 PMCID: PMC8272713 DOI: 10.1007/s00592-021-01681-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/25/2021] [Indexed: 01/06/2023]
Abstract
AIMS Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic drugs, are nephroprotective in case of diabetes, but whether a similar beneficial effect may be detectable also in case of chronic non-diabetic kidney diseases remains still unknown. The aim of this study was to evaluate the effects of empagliflozin, a SGLT-2 inhibitor, on the progression of cyclosporine nephropathy, in the absence of diabetes. METHODS Sprague Dawley rats (n = 27) have been fed with low-salt diet starting 10 days before the beginning and finished at the end of the experimental period. Cyclosporine-A (CsA, 15 mg/kg/day, intraperitoneal injection, n = 8) and CsA plus empagliflozin (Empa, 10 mg/kg/day, per os, n = 7) were administered for 4 weeks. The control groups were treated with placebo (Control, n = 7) or empagliflozin (Control + Empa, n = 5). Blood pressure (plethysmographic method) was measured at the beginning and at the end of the experimental period. At the end of the experimental protocol, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates (monocytes/macrophages), type I and type IV collagen expression, and tyrosine hydroxylase expression, used as marker of sympathetic nerve activity. RESULTS CsA-treated rats showed a significant increase (p < 0.01) in blood pressure, which was reduced by administration of empagliflozin (p < 0.05). CsA administration caused an increase in glomerular and tubulo-interstitial fibrosis (p < 0.05), renal inflammatory infiltrates (p < 0.05), type I and type IV collagen expression (p < 0.01), and tyrosine hydroxylase expression (p < 0.01) as compared to the control rats and control + Empa-treated rats. Treatment with empagliflozin in CsA-treated rats reduced glomerular (p < 0.01) and tubulo-interstitial fibrosis (p < 0.05), type I and type IV collagen expression (p < 0.01), inflammatory cell infiltration (p < 0.01) and tyrosine hydroxylase expression (p < 0.05), as compared to rats treated with CsA. CONCLUSION Empagliflozin administration caused a reduction in blood pressure in CsA-treated rats and showed a protective effect on CsA nephropathy by decreasing renal fibrosis, type I and type IV collagen expression, macrophage infiltration and tyrosine hydroxylase expression. These data suggest that empagliflozin promotes nephroprotection also in non-diabetic kidney disease.
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Affiliation(s)
- Giovanna Castoldi
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
| | - Raffaella Carletti
- Dipartimento Di Scienze Radiologiche, Oncologiche E Anatomopatologiche, Istituto Di Anatomia Patologica Sapienza Universita' Di Roma, Roma, Italy
| | - Silvia Ippolito
- Laboratorio Analisi Chimico Cliniche, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | - Massimiliano Colzani
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy
| | - Francesca Barzaghi
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy
| | - Andrea Stella
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy
| | - Gianpaolo Zerbini
- Unita' Complicanze del Diabete, Diabetes Research Institute, IRCCS Istituto Scientifico San Raffaele, Milano, Italy
| | - Gianluca Perseghin
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy
- Dipartimento Di Medicina Interna E Riabilitazione, Policlinico Di Monza, Monza, Italy
| | - Giovanni Zatti
- Dipartimento Di Medicina E Chirugia, Università Degli Studi Di Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy
- Clinica Ortopedica, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | - Cira R T di Gioia
- Dipartimento Di Scienze Radiologiche, Oncologiche E Anatomopatologiche, Istituto Di Anatomia Patologica Sapienza Universita' Di Roma, Roma, Italy
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16
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Prusinskas B, Ohlsson S, Kathemann S, Pilic D, Kampmann K, Büscher R, Paul A, Pape L, Hoyer PF, Lainka E. Role of Tacrolimus C/D Ratio in the First Year After Pediatric Liver Transplantation. Front Pediatr 2021; 9:659608. [PMID: 34150686 PMCID: PMC8206534 DOI: 10.3389/fped.2021.659608] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/27/2021] [Indexed: 12/17/2022] Open
Abstract
Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosuppressive therapy in pediatric liver transplantation (LTX). Adverse effects limit the use of CNI. In adults, calculating the individual TAC metabolism rate allows to estimate the transplant recipient's risk for therapy-associated complications. Methods: A retrospective, descriptive data analysis was performed in children who had undergone LTX in 2009-2017 and had received TAC twice daily in the first year after LTX. A weight-adjusted concentration/dose ratio (C/D ratio) was calculated [TAC trough level/(daily TAC dose/body weight)] every 3 months after LTX to estimate the average individual TAC metabolism rate. Depending on the C/D ratio, all patients were divided into two groups: fast metabolizers (FM) and slow metabolizers (SM). Clinical and laboratory parameters were analyzed as risk factors in both groups. Results: A total of 78 children (w 34, m 44, median age at LTX 2.4; 0.4-17.0 years) were enrolled in the study. FM (SM) had a mean C/D ratio of <51.83 (≥51.83) ng/ml/(mg/kg). FM were younger at the time of LTX (median age 1.7; 0.4-15.8 years) than SM (5.1, 0.4-17.0), p = 0.008. FM were more likely to have biliary atresia (20/39, 51%) compared to SM (11/39, 28%), p = 0.038, whereas SM were more likely to have progressive familial intrahepatic cholestasis (9/39, 23%) vs. in FM (1/39, 3%), p = 0.014. Epstein-Barr virus (EBV) infection occurred more frequently in FM (27/39, 69%) than SM (13/39, 33%), p = 0.002. Three FM developed post-transplant lymphoproliferative disorder. The annual change of renal function did not differ in both groups (slope FM 1.2 ± 0.6; SM 1.4 ± 0.8 ml/min/1.73 m2 per year, and p = 0.841). Conclusions: Calculation of individual, weight-adjusted TAC C/D ratio is a simple, effective, and cost-efficient tool for physicians to estimate the risk of therapy-associated complications and to initiate individual preventive adjustments after pediatric LTX. Lower TAC levels are tolerable in FM, especially in the presence of EBV infection, reduced renal function, or when receiving a liver transplant in the first 2 years of life.
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Affiliation(s)
- Benas Prusinskas
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
| | - Sinja Ohlsson
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
| | - Simone Kathemann
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
| | - Denisa Pilic
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
| | - Kristina Kampmann
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
| | - Rainer Büscher
- Department of Pediatrics II, Pediatric Nephrology and Kidney Transplantation, University Children's Hospital Essen, Essen, Germany
| | - Andreas Paul
- Department of General, Visceral, and Transplantation Surgery, University Medicine Essen, Essen, Germany
| | - Lars Pape
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
- Department of Pediatrics II, Pediatric Nephrology and Kidney Transplantation, University Children's Hospital Essen, Essen, Germany
| | - Peter F. Hoyer
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
- Department of Pediatrics II, Pediatric Nephrology and Kidney Transplantation, University Children's Hospital Essen, Essen, Germany
| | - Elke Lainka
- Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany
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17
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Liu B, Tan P. PPAR γ/TLR4/TGF-β1 axis mediates the protection effect of erythropoietin on cyclosporin A-induced chronic nephropathy in rat. Ren Fail 2020; 42:216-224. [PMID: 32090669 PMCID: PMC7054967 DOI: 10.1080/0886022x.2020.1729188] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/18/2019] [Accepted: 02/04/2020] [Indexed: 01/12/2023] Open
Abstract
Objective: Nephrotoxicity is the main side effect of cyclosporine A and finding an effective combating method is urgent. The present study investigates the improving effect of erythropoietin (EPO) on cyclosporine A induce renal injury in rats and further explores its possible mechanism.Methods: Recombinant adenovirus for expression of EPO was constructed and injected into kidney with multipoint. Levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were detected by kits. HE staining and Masson's trichrome staining were used to evaluate pathological changes. ELISA was performed to detect the levels of transforming growth factor (TGF)-β1, interleukin (IL)-1β, and IL-6 in serum. Levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in kidney were detected according to manufacturer's instruction. Western blotting was performed to observe the protein expression levels of peroxisome proliferator-activated receptor γ (PPAR γ), Toll-like receptor (TLR) 4, and TGF-β1.Results: Results showed that EPO overexpression in rat kidney could significantly improve renal injury and fibrosis, suppress the release of inflammatory factors and reduce oxidative stress induced by cyclosporine A. Western blotting results showed that EPO overexpression could up-regulate the expression of PPARγ and down-regulate the expression of TLR4 and TGF-β1. Interestingly, when PPARγ activity was inhibited by T0070907, an effective and specific PPARγ inhibitor, the therapeutic effect of EPO was significantly attenuated.Conclusion: Taken together, above results shown the protective effect of EPO on cyclosporine A-induced renal injury and confirmed that EPO's anti-inflammation and antioxidative stress involving the PPAR γ/TLR4/TGFβ1 axis.
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Affiliation(s)
- Bin Liu
- Department of Nephrology and Rheumatology, Chinese Medicine Hospital of Hainan Province, Haikou, China
| | - Ping Tan
- Department of Nephrology and Rheumatology, Chinese Medicine Hospital of Hainan Province, Haikou, China
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18
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Florens N, Dubourg L, Bitker L, Kalbacher E, Philit F, Mornex JF, Parant F, Guebre-Egziabher F, Juillard L, Lemoine S. Measurement of glomerular filtration rate in lung transplant recipients highlights a dramatic loss of renal function after transplantation. Clin Kidney J 2020; 13:828-833. [PMID: 33123359 PMCID: PMC7577765 DOI: 10.1093/ckj/sfaa053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/16/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) after lung transplantation (LT) is underestimated. The aim of the present study was to measure the loss of glomerular filtration rate (GFR) 1 year after LT and to identify the risk factors for developing Stage ≥3 CKD. METHODS LT patients in the University Hospital of Lyon had a pre- and post-transplantation measurement of their GFR (mGFR), and GFR was also estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS During the study period, 111 patients were lung transplant candidates, of which 91 had a pre-transplantation mGFR, and 29 had a mGFR at 1 year after LT. Six patients underwent maintenance haemodialysis after transplantation. Mean mGFR was 106 mL/min/1.73 m2 before LT and 58 mL/min/1.73 m2 1 year after LT (P < 0.05) with a mean loss of 48 mL/min/1.73 m2 per patient. The risk of developing Stage ≥3 CKD after LT was higher in patients with lower pre-LT mGFR (odds ratio for each 1 mL/min/1.73 m2 increase: 0.94, 95% confidence interval 0.88-0.99). Receiver operator characteristics curves for the sensitivity and specificity of eGFR and mGFR for the prediction of CKD Stage ≥3 after LT found that pre-LT mGFR of 101 mL/min/1.73 m2 and pre-LT eGFR of 124 mL/min/1.73 m2 were the optimal thresholds for predicting Stage ≥3 CKD after LT. CONCLUSION The present study underlines the value of mGFR in the pre-LT stage and found major renal function loss after LT, and consequently two-thirds of patients have Stage ≥3 CKD at 1 year. All patients with a pre-LT mGFR <90 mL/min/1.73 m2 warrant particular attention.
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Affiliation(s)
- Nans Florens
- Université de Lyon, CarMeN, INSERM U1060, INSA de Lyon, Université Claude Bernard Lyon 1, INRA U1397, Villeurbanne, France.,Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - Laurence Dubourg
- Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - Laurent Bitker
- Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - Emilie Kalbacher
- Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - François Philit
- Hospices Civils de Lyon, Hôpital L. Pradel, Bron, F-69500, France.,UMR754 INRA Université Lyon 1, Université de Lyon, Lyon, France
| | - Jean François Mornex
- Hospices Civils de Lyon, Hôpital L. Pradel, Bron, F-69500, France.,UMR754 INRA Université Lyon 1, Université de Lyon, Lyon, France
| | - François Parant
- Department of Pharmacology, Hospices Civils de Lyon, Hôpital Lyon Sud, Lyon, France
| | - Fitsum Guebre-Egziabher
- Université de Lyon, CarMeN, INSERM U1060, INSA de Lyon, Université Claude Bernard Lyon 1, INRA U1397, Villeurbanne, France.,Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - Laurent Juillard
- Université de Lyon, CarMeN, INSERM U1060, INSA de Lyon, Université Claude Bernard Lyon 1, INRA U1397, Villeurbanne, France.,Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
| | - Sandrine Lemoine
- Université de Lyon, CarMeN, INSERM U1060, INSA de Lyon, Université Claude Bernard Lyon 1, INRA U1397, Villeurbanne, France.,Hospices Civils de Lyon, Service de Néphrologie, Hôpital E. Herriot, Lyon, France
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19
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Ramírez-Bajo MJ, Martín-Ramírez J, Bruno S, Pasquino C, Banon-Maneus E, Rovira J, Moya-Rull D, Lazo-Rodriguez M, Campistol JM, Camussi G, Diekmann F. Nephroprotective Potential of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Murine Model of Chronic Cyclosporine Nephrotoxicity. Front Cell Dev Biol 2020; 8:296. [PMID: 32432111 PMCID: PMC7214690 DOI: 10.3389/fcell.2020.00296] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
Background Cell therapies and derived products have a high potential in aiding tissue and organ repairing and have therefore been considered as potential therapies for treating renal diseases. However, few studies have evaluated the impact of these therapies according to the stage of chronic kidney disease. The aim of this study was to evaluate the renoprotective effect of murine bone marrow mesenchymal stromal cells (BM-MSCs), their extracellular vesicles (EVs) and EVs-depleted conditioned medium (dCM) in an aggressive mouse model of chronic cyclosporine (CsA) nephrotoxicity in a preventive and curative manner. Methods After 4 weeks of CsA-treatment (75 mg/kg daily) mice developed severe nephrotoxicity associated with a poor survival rate of 25%, and characterized by tubular vacuolization, casts, and cysts in renal histology. BM-MSC, EVs and dCM groups were administered as prophylaxis or as treatment of CsA nephrotoxicity. The effect of the cell therapies was analyzed by assessing renal function, histological damage, apoptotic cell death, and gene expression of fibrotic mediators. Results Combined administration of CsA and BM-MSCs ameliorated the mice survival rates (6-15%), but significantly renal function, and histological parameters, translating into a reduction of apoptosis and fibrotic markers. On the other hand, EVs and dCM administration were only associated with a partial recovery of renal function or histological damage. Better results were obtained when used as treatment rather than as prophylactic regimen i.e., cell therapy was more effective once the damage was established. Conclusion In this study, we showed that BM-MSCs induce an improvement in renal outcomes in an animal model of CsA nephrotoxicity, particularly if the inflammatory microenvironment is already established. EVs and dCM treatment induce a partial recovery, indicating that further experiments are required to adjust timing and dose for better long-term outcomes.
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Affiliation(s)
- María José Ramírez-Bajo
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal (REDINREN), Madrid, Spain
| | - Javier Martín-Ramírez
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Stefania Bruno
- Dipartimento di Scienze Mediche, Università degli Studi di Torino, Centro di Biotecnologie Molecolari, Turin, Italy
| | - Chiara Pasquino
- Dipartimento di Scienze Mediche, Università degli Studi di Torino, Centro di Biotecnologie Molecolari, Turin, Italy
| | - Elisenda Banon-Maneus
- Red de Investigación Renal (REDINREN), Madrid, Spain.,Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal (REDINREN), Madrid, Spain
| | - Daniel Moya-Rull
- Red de Investigación Renal (REDINREN), Madrid, Spain.,Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain
| | - Marta Lazo-Rodriguez
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain
| | - Josep M Campistol
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal (REDINREN), Madrid, Spain.,Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain.,Departament de Nefrologia i Trasplantament Renal, ICNU, Hospital Clínic, Barcelona, Spain
| | - Giovanni Camussi
- Dipartimento di Scienze Mediche, Università degli Studi di Torino, Centro di Biotecnologie Molecolari, Turin, Italy
| | - Fritz Diekmann
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal (REDINREN), Madrid, Spain.,Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain.,Departament de Nefrologia i Trasplantament Renal, ICNU, Hospital Clínic, Barcelona, Spain
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20
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Schneidewind L. [Calcineurin inhibitors in kidney transplant patients: withdrawal or tapering?]. Urologe A 2020; 59:341-343. [PMID: 32055933 DOI: 10.1007/s00120-020-01146-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Laila Schneidewind
- Urologische Klinik und Poliklinik, Universitätsmedizin Rostock, Ernst-Heydemann-Str. 6, 18055, Rostock, Deutschland. .,UroEvidence@Deutsche Gesellschaft für Urologie, Berlin, Deutschland.
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21
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Hou L, Le G, Lin Z, Qian G, Gan F, Gu C, Jiang S, Mu J, Ge L, Huang K. Nontoxic concentration of ochratoxin A decreases the dosage of cyclosporine A to induce chronic nephropathy model via autophagy mediated by toll-like receptor 4. Cell Death Dis 2020; 11:153. [PMID: 32108135 PMCID: PMC7046648 DOI: 10.1038/s41419-020-2353-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 11/29/2022]
Abstract
Cyclosporine A (CsA) extracted from the products of fungal fermentation is used to develop a chronic nephropathy model. However, it has numerous side effects. Ochratoxin A (OTA) is a mycotoxin that induces renal injury. We developed a chronic nephropathy model to lessen the side effects of CsA by administration of nontoxic dosage of OTA, and investigated the underlying mechanism. C57BL/10 wild-type mice, toll-like receptor 4 (TLR4)-/- mice, and HK-2 cells were used in this study. The nontoxic dosage (0.25 mg/kg, qod) of OTA could significantly decrease the dosage of CsA from 30 to 20 mg/kg per day, and combination of them induced chronic nephropathy model and alleviated the side effects of onefold CsA in vivo, including cardiotoxicity, hepatotoxicity, and immunosuppression. The nontoxic concentration (0.5 μg/ml) of OTA could significantly decrease the concentration of CsA from 10 to 6 μg/ml that induced cytotoxicity, oxidative stress, and nephrotoxicity in vitro. Nontoxic concentration of OTA and low dosage of CsA activated TLR4 and autophagy. These toxic effects induced by OTA and CsA could be reversed by knockdown of TLR4 and autophagy inhibitor 3-methyladenine in vitro. Furthermore, the renal injury and autophagy induced by OTA and CsA could be attenuated in TLR4-/- mice. It suggested that a chronic nephropathy model had been successfully developed by administration of nontoxic concentration of OTA and low dosage of CsA via TLR4-mediated autophagy. The side effects of current model were significantly lesser than those of the previous model induced by onefold CsA. It provided a new tool for exploring the pathogenesis and treatment of chronic kidney disease.
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Affiliation(s)
- Lili Hou
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Guannan Le
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Ziman Lin
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Gang Qian
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Cong Gu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Shuai Jiang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Jiaxin Mu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Lei Ge
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China.
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China.
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu Province, China.
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22
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Raza Z, Naureen Z. Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights. Nefrologia 2019; 40:12-25. [PMID: 31735377 DOI: 10.1016/j.nefro.2019.06.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 05/29/2019] [Accepted: 06/07/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-α and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.
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Affiliation(s)
- Zohaib Raza
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.
| | - Zainab Naureen
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
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23
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Nanmoku K, Shinzato T, Kubo T, Shimizu T, Yagisawa T. Conversion to Everolimus in Kidney Transplant Recipients With Calcineurin Inhibitor-Induced Nephropathy: 3 Case Reports. Transplant Proc 2019; 51:1424-1427. [PMID: 31060742 DOI: 10.1016/j.transproceed.2019.01.131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/28/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs), which remain the most important immunosuppressants in kidney transplant recipients, are a major cause of renal dysfunction due to CNI-induced nephropathy. However, a safe and effective CNI-sparing protocol is yet to be established. Herein, we report a case series of kidney transplant recipients experiencing CNI nephropathy, whose renal function is improved after conversion from CNIs to everolimus. CASES The 3 kidney transplant recipients included in this study were diagnosed with CNI arteriolopathy by episode biopsy between 9 months and 11 years after transplantation. All patients received triple immunosuppressive therapy consisting of CNI (tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. All allografts were transplanted from elderly living donors to ABO-compatible and donor-specific antibody-negative recipients. All allograft biopsy specimens exhibited CNI arteriolopathy with alternative quantitative criteria for hyaline arteriolar thickening (aah score: 2 or 3), according to the Banff classification; however, histopathologic assessment did not show any evidence of allograft rejection. Conversely, total dose and blood concentrations of CNIs were within appropriate ranges. After conversion from CNIs to everolimus (1.5 mg/day, twice daily; trough level, 3-5 ng/mL), serum creatinine levels returned to baseline levels measured before the diagnosis of CNI arteriolopathy. In all patients, renal allograft function remained stable, with no evidence of donor-specific antibodies, 1 year after conversion from CNIs to everolimus. CONCLUSION Conversion from CNIs to everolimus can safely and effectively improve renal function in kidney transplant recipients experiencing CNI-induced nephropathy.
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Affiliation(s)
- Koji Nanmoku
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan.
| | - Takahiro Shinzato
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Taro Kubo
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Toshihiro Shimizu
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Takashi Yagisawa
- Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
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Turunç V, Açıkgöz S, Dheir H. Early Switch to Mammalian Target of Rapamycin Inhibitors Is a Sustainable Treatment Approach in Renal Transplant Recipients: 7-Year Results. Transplant Proc 2019; 51:1070-1073. [DOI: 10.1016/j.transproceed.2019.01.098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/21/2019] [Indexed: 10/27/2022]
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Ponticelli C, Glassock RJ. Prevention of complications from use of conventional immunosuppressants: a critical review. J Nephrol 2019; 32:851-870. [PMID: 30927190 DOI: 10.1007/s40620-019-00602-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 03/21/2019] [Indexed: 01/08/2023]
Abstract
Synthetic immunosuppressive drugs are largely used in immune-related renal diseases and in kidney transplantation. Most of these drugs have a low therapeutic index (the ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective), which means that the drug should be dosed carefully and the patient monitored frequently. In this review, we consider the categories of synthetic immunosuppressive agents more frequently and conventionally used in clinical nephrology: glucocorticoids, Aalkylating agents (cyclophosphamide, chlorambucil), purine synthesis inhibitors (azathioprine, mycophenolate salts) and calcineurin inhibitors (cyclosporine, tacrolimus). For each category the possible side effects will be reviewed, the general and specific measures to prevent or treat the adverse events will be suggested, and the more common mistakes that may increase the risk of toxicity will be described. However, the efficacy and safety of immunosuppressive agents depend not only on the pharmacologic characteristics of single drugs but can be influenced also by the clinical condition and genetic characteristics of the patient, by the typology and severity of the underlying disease and by the interaction with other concomitantly used drugs.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, Istituto Scientifico Ospedale Maggiore, Milan, Italy.
- , Via Ampere 126, 20131, Milan, Italy.
| | - Richard J Glassock
- The David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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26
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Vasa recta hyalinosis reflects severe arteriolopathy in renal allografts. Clin Exp Nephrol 2019; 23:799-806. [PMID: 30734165 DOI: 10.1007/s10157-019-01709-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 01/28/2019] [Indexed: 10/27/2022]
Abstract
AIM We examined the clinicopathologic significance of hyalinosis in the vasa recta in the medulla of allograft kidney biopsies. METHOD We analyzed biopsy specimens from January 2010 to December 2015, obtained from both the cortex and medulla (including the vasa recta) ≥ 1 year after living-donor kidney transplantation. We excluded biopsy specimens from recipients who had undergone transplantation due to diabetic nephropathy or who had diabetes mellitus after transplantation. We evaluated hyaline arteriolopathy in the cortex using the aah score determined by the Banff 2007 classification. RESULT Among 381 biopsy specimens obtained from 248 transplant recipients ≥ 1 year after transplantation, 36 specimens obtained from 34 recipients showed vasa recta hyalinosis (VRH) in the medulla. Among these 36 specimens, 17 had a score of aah3, 16 had a score of aah2, and 3 had a score of aah1. The incidence of VRH was 1.9% at ≥ 1 to < 4 years, 7.1% at ≥ 4 to < 8 years, and 50.0% at ≥ 8 years. The aah scores and the proportion of hyalinosis in the arteriolar media among all muscular arterioles in the cortex were significantly higher in the VRH group at ≥ 8 years in the late-phase biopsy (P < 0.01). The graft survival was worse in the VRH group (P = 0.024), although there was no significant difference in the graft survival between the ≥ aah2 and < aah2 groups at ≥ 8 years in the late-phase biopsy (P = 0.159). CONCLUSION VRH in renal allografts reflects severe arteriolopathy of the cortex. VRH in the late-phase biopsy may be a prognostic factor for graft survival.
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Oguchi H, Sakai K, Yamaguchi Y, Mikami T, Nemoto T, Ohashi Y, Kawamura T, Muramatsu M, Itabashi Y, Shinoda K, Hyodo Y, Takahashi Y, Kawaguchi Y, Onishi H, Hamasaki Y, Shibuya K, Shishido S. Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts. Nephrology (Carlton) 2018; 23 Suppl 2:58-62. [PMID: 29968404 DOI: 10.1111/nep.13275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 11/30/2022]
Abstract
AIM The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed ≥1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed ≥1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at ≥1 to <4 years, 18.5% at ≥4 to <8 years, and 54.1% at ≥8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained ≥8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group ≥8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION IHA in renal allografts is associated with severe arteriolopathy.
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Affiliation(s)
- Hideyo Oguchi
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Ken Sakai
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | | | - Tetuo Mikami
- Department of Pathology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Tetsuo Nemoto
- Department of Surgical Pathology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yasushi Ohashi
- Department of Nephrology, Sakura Medical Center, Toho University, Chiba, Japan
| | - Takeshi Kawamura
- Department of Nephrology, Sakura Medical Center, Toho University, Chiba, Japan
| | - Masaki Muramatsu
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yoshihiro Itabashi
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Kazunobu Shinoda
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yoji Hyodo
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Takahashi
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yuki Kawaguchi
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Hiroka Onishi
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yuko Hamasaki
- Department of Pediatric Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Kazutoshi Shibuya
- Department of Surgical Pathology, Toho University Faculty of Medicine, Tokyo, Japan
| | - Seiichiro Shishido
- Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan
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Benway CJ, Iacomini J. Defining a microRNA-mRNA interaction map for calcineurin inhibitor induced nephrotoxicity. Am J Transplant 2018; 18:796-809. [PMID: 28925592 DOI: 10.1111/ajt.14503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 08/21/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023]
Abstract
Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)-messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine-induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we isolated RNAs associated with Argonaute 2 in the RNA-induced silencing complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs. CsA causes specific changes in miRNAs and mRNAs associated with RISC, thereby altering post-transcriptional regulation of gene expression. Pathway enrichment analysis identified canonical pathways regulated by miRNAs specifically following CsA treatment. RNA-seq performed on total RNA indicated that only a fraction of total miRNAs and mRNAs are actively targeted in the RISC, indicating that PAR-CLIP more accurately defines meaningful targeting interactions. Our data also revealed a role for miRNAs in calcineurin-independent regulation of JNK and p38 MAPKs caused by targeting of MAP3K1. Together, our data provide a novel resource and unique insights into molecular pathways regulated by miRNAs in CIN. The gene pathways and miRNAs defined may represent novel targets to reduce calcineurin induced nephrotoxicity.
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Affiliation(s)
- Christopher J Benway
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
| | - John Iacomini
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.,Tufts University School of Medicine, Boston, MA, USA
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29
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Abstract
BACKGROUND Calcineurin inhibitors (CNIs) are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders, such as steroid-resistant nephrotic syndrome, steroid-dependent nephrotic syndrome, and frequent relapse nephrotic syndrome. Although CNIs remain the most effective available immunosuppressant agent, there is clinical concern regarding possible long-term nephrotoxicity. This concern is especially significant in children who have a longer life expectancy and greater growth rate. DATA SOURCES In this review, we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity. PubMed, Elsevier, and Tompson ISI Web of Knowledge were searched for identifying relevant papers. RESULTS Clinical research supports the presence of CNI-related nephrotoxicity. However, some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity, especially because the pathological lesions typically associated with long-term CNI use are nonspecific. Many researchers have focused on early markers of CNI nephrotoxicity, and the methods that may help prevent and manage nephrotoxicity. CONCLUSIONS Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy, and developing alternative treatments. CNI-mediated nephrotoxicity should always be taken seriously in clinic.
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Affiliation(s)
- Fei Liu
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian-Hua Mao
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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30
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Koppelstaetter C, Kern G, Leierer G, Mair SM, Mayer G, Leierer J. Effect of cyclosporine, tacrolimus and sirolimus on cellular senescence in renal epithelial cells. Toxicol In Vitro 2018; 48:86-92. [PMID: 29309803 DOI: 10.1016/j.tiv.2018.01.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 01/02/2018] [Accepted: 01/04/2018] [Indexed: 01/09/2023]
Abstract
INTRODUCTION In transplantation medicine calcineurin inhibitors (CNI) still represent the backbone of immunosuppressive therapy. The nephrotoxic potential of the CNI Cyclosporine A (CsA) and Tacrolimus (FK506) is well recognized and CNI not only have been linked with toxicity, but also with cellular senescence which hinders parenchymal tissue regeneration and thus may prime kidneys for subsequent insults. To minimize pathological effects on kidney grafts, alternative immunosuppressive agents like mTOR inhibitors or the T-cell co-stimulation blocker Belatacept have been introduced. METHODS We compared the effects of CsA, FK506 and Sirolimus on the process of cellular senescence in different human renal tubule cell types (HK2, RPTEC). Telomere length (by real time PCR), DNA synthesis (by BrdU incorporation), cell viability (by Resazurin conversion), gene expression (by RT-PCR), protein (by western blotting), Immuncytochemistry and H2O2 production (by Amplex Red® conversion) were evaluated. RESULTS DNA synthesis was significantly reduced when cells were treated with cyclosporine but not with tacrolimus and sirolimus. Resazurin conversion was not altered by all three immunosuppressive agents. The gene expression as well as protein production of the cell cycle inhibitor p21 (CDKN1A) but not p16 (CDKN2A) was significantly induced by cyclosporine compared to the other two immunosuppressive agents when determined by western blotting an immuncytochemistry. Relative telomere length was reduced and hydrogen peroxide production increased after treatment with CsA but not with FK506 or sirolimus. CONCLUSION In summary, renal tubule cells exposed to CsA show clear signs of cellular senescence where on the contrary the second calcineurin inhibitor FK506 and the mTOR inhibitor sirolimus are not involved in such mechanisms. Chronic renal allograft dysfunction could be in part triggered by cellular senescence induced by immunosuppressive medication and the choice of drug could therefore influence long term outcome. Tacrolimus and Sirolimus are equally effective in avoiding cellular senescence compared to cyclosporine at least in parts due to a lack of induction of reactive oxygen species.
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Affiliation(s)
| | - Georg Kern
- Department of Physiology, Medical University Innsbruck, Austria
| | - Gisela Leierer
- Division of Genetic Epidemiology, Medical University Innsbruck, Austria
| | - Sabine Maria Mair
- Department of Internal Medicine II; Infectious Diseases, Medical University Innsbruck, Austria
| | - Gert Mayer
- Department of Internal Medicine IV Nephrology, Medical University Innsbruck, Austria
| | - Johannes Leierer
- Department of Internal Medicine IV Nephrology, Medical University Innsbruck, Austria
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Evaluation of Immunosuppressive Therapy Use for Tracheal Transplantation with Trachea-Mimetic Bellows Scaffolds in a Rabbit Model. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5205476. [PMID: 29226141 PMCID: PMC5684528 DOI: 10.1155/2017/5205476] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 09/10/2017] [Indexed: 11/28/2022]
Abstract
The objective of this study was to evaluate the use of immunosuppressive therapy with high-dose cyclosporine, high-dose azathioprine, and a combination of low-dose cyclosporine and azathioprine after tracheal reconstruction by using a trachea-mimetic graft of polycaprolactone (PCL) bellows-type scaffold in a rabbit model. Twenty-four healthy New Zealand white rabbits were used in the study. All underwent circumferential tracheal replacement using tissue-engineered tracheal graft, prepared from PCL bellows scaffold reinforced with silicone ring, collagen hydrogel, and human turbinate mesenchymal stromal cell (hTMSC) sheets. The control group (Group 1) received no medication. The three experimental groups were given daily cyclosporine intramuscular doses of 10 mg/kg (Group 2), azathioprine oral doses of 5 mg/kg (Group 3), and azathioprine oral doses of 2.5 mg/kg plus cyclosporine intramuscular doses of 5 mg/kg (Group 4) for 4 weeks or until death. Group 1 had longer survival times compared to Group 2 or Group 3. Each group except for Group 1 experienced decreases in amount of nutrition and weight loss. In addition, compared with the other groups, Group 2 had significantly increased serum interleukin-2 and interferon-γ levels 7 days after transplantation. The results of this study showed that the administration of cyclosporine and/or azathioprine after tracheal transplantation had no beneficial effects. Furthermore, the administration of cyclosporine had side effects, including extreme weight loss, respiratory distress, and diarrhea. Therefore, cyclosporine and azathioprine avoidance may be recommended for tracheal reconstruction using a native trachea-mimetic graft of PCL bellows-type scaffold in a rabbit model.
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Karpe KM, Talaulikar GS, Walters GD. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database Syst Rev 2017; 7:CD006750. [PMID: 28730648 PMCID: PMC6483545 DOI: 10.1002/14651858.cd006750.pub2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. OBJECTIVES This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment-related side effects (hypertension, hyperlipidaemia) and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Specialised Register to 11 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA All randomised controlled trials (RCTs) where drug regimens containing CNI were compared to alternative drug regimens (CNI withdrawal, tapering or low dose) in the post-transplant period were included, without age or dosage restriction. DATA COLLECTION AND ANALYSIS Two authors independently assessed studies for eligibility, risk of bias, and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included 83 studies that involved 16,156 participants. Most were open-label studies; less than 30% of studies reported randomisation method and allocation concealment. Studies were analysed as intent-to-treat in 60% and all pre-specified outcomes were reported in 54 studies. The attrition and reporting bias were unclear in the remainder of the studies as factors used to judge bias were reported inconsistently. We also noted that 50% (47 studies) of studies were funded by the pharmaceutical industry.We classified studies into four groups: CNI withdrawal or avoidance with or without substitution with mammalian target of rapamycin inhibitors (mTOR-I); and low dose CNI with or without mTOR-I. The withdrawal groups were further stratified as avoidance and withdrawal subgroups for major outcomes.CNI withdrawal may lead to rejection (RR 2.54, 95% CI 1.56 to 4.12; moderate certainty evidence), may make little or no difference to death (RR 1.09, 95% CI 0.96 to 1.24; moderate certainty), and probably slightly reduces graft loss (RR 0.85, 95% CI 0.74 to 0.98; low quality evidence). Hypertension was probably reduced in the CNI withdrawal group (RR 0.82, 95% CI 0.71 to 0.95; low certainty), while CNI withdrawal may make little or no difference to malignancy (RR 1.10, 95% CI 0.93 to 1.30; low certainty), and probably makes little or no difference to cytomegalovirus (CMV) (RR 0.87, 95% CI 0.52 to 1.45; low certainty)CNI avoidance may result in increased acute rejection (RR 2.16, 95% CI 0.85 to 5.49; low certainty) but little or no difference in graft loss (RR 0.96, 95% CI 0.79 to 1.16; low certainty). Late CNI withdrawal increased acute rejection (RR 3.21, 95% CI 1.59 to 6.48; moderate certainty) but probably reduced graft loss (RR 0.84, 95% CI 0.72 to 0.97, low certainty).Results were similar when CNI avoidance or withdrawal was combined with the introduction of mTOR-I; acute rejection was probably increased (RR 1.43; 95% CI 1.15 to 1.78; moderate certainty) and there was probably little or no difference in death (RR 0.96; 95% CI 0.69 to 1.36, moderate certainty). mTOR-I substitution may make little or no difference to graft loss (RR 0.94, 95% CI 0.75 to 1.19; low certainty), probably makes little of no difference to hypertension (RR 0.86, 95% CI 0.64 to 1.15; moderate), and probably reduced the risk of cytomegalovirus (CMV) (RR 0.60, 95% CI 0.44 to 0.82; moderate certainty) and malignancy (RR 0.69, 95% CI 0.47 to 1.00; low certainty). Lymphoceles were increased with mTOR-I substitution (RR 1.45, 95% CI 0.95 to 2.21; low certainty).Low dose CNI combined with mTOR-I probably increased glomerular filtration rate (GFR) (MD 6.24 mL/min, 95% CI 3.28 to 9.119; moderate certainty), reduced graft loss (RR 0.75, 95% CI 0.55 to 1.02; moderate certainty), and made little or no difference to acute rejection (RR 1.13 ; 95% CI 0.91 to 1.40; moderate certainty). Hypertension was decreased (RR 0.98, 95% CI 0.80 to 1.20; low certainty) as was CMV (RR 0.41, 95% CI 0.16 to 1.06; low certainty). Low dose CNI plus mTOR-I makes probably makes little of no difference to malignancy (RR 1.22, 95% CI 0.42 to 3.53; low certainty) and may make little of no difference to death (RR 1.16, 95% CI 0.71 to 1.90; moderate certainty). AUTHORS' CONCLUSIONS CNI avoidance increased acute rejection and CNI withdrawal increases acute rejection but reduced graft loss at least over the short-term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short-term. The use of mTOR-I reduced CMV infections but increased the risk of acute rejection. These conclusions must be tempered by the lack of long-term data in most of the studies, particularly with regards to chronic antibody-mediated rejection, and the suboptimal methodological quality of the included studies.
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Affiliation(s)
- Krishna M Karpe
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
| | - Girish S Talaulikar
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
| | - Giles D Walters
- Canberra HospitalRenal ServicesYamba DriveGarranACTAustralia2605
- Australian National University Medical SchoolActonACTAustralia2601
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Calcineurin Inhibitor Nephrotoxicity Through the Lens of Longitudinal Histology: Comparison of Cyclosporine and Tacrolimus Eras. Transplantation 2017; 100:1723-31. [PMID: 27306529 DOI: 10.1097/tp.0000000000001243] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The contribution of calcineurin inhibitors (CNI) nephrotoxicity to progressive kidney transplant injury remains debated, with little long-term data from the modern tacrolimus (TAC) era using lower doses. METHODS This longitudinal cohort study evaluated histological evidence of CNI nephrotoxicity from normal donor kidneys of successful kidney-pancreas transplant recipients during cyclosporine (CSA) and TAC eras, analyzed by intention-to-treat. RESULTS From 200 patients, 1622 adequate prospective protocol (84.3%) and indication (15.7%) kidney biopsies yielded 8.1 ± 4.1 samples per patient, over 7.4 ± 4.4 years posttransplant. The TAC era demonstrated less rejection and reduced early immune-mediated tubular damage, compared with CSA (P < 0.001). The incidences of acute mild arteriolopathy, striped interstitial fibrosis, glomerular congestion, and tubular microcalcification were all greater with CSA (hazard ratios of 1.70, 9.35, and 3.78, respectively) and maximal within the first posttransplant year, compared with TAC-treated patients (P < 0.001). However, the 1-, 5-, and 10-year prevalence moderate arteriolar hyalinosis was similar: CSA was 5.4%, 38.4%, and 79.1%; and TAC was 4.3%, 33.6% and 77.2%, respectively (P = NS). Morphometric measurement demonstrated lumenal narrowing from inwards collapse of hyalinized arteriolar walls unable to maintain its structural integrity. Severe hyalinosis was calculated to reduce arteriolar blood flow to 20 ± 34% of normal. Severity of arteriolar hyalinosis correlated with contemporaneous glomerulosclerosis (r = 0.44, P < 0.001), and subsequent progression in 1356 sequential biopsy pairs, consistent with glomerular ischemia. CONCLUSIONS Tacrolimus-based therapy appeared superior to the CSA era, with less early CNI nephrotoxicity and fewer rejection episodes, but comparable chronic arteriolar toxicity. Calcineurin inhibitors are imperfect long-term maintenance immunosuppressive agents because of frequent and irreversible chronic toxicity.
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Jin M, Lv P, Chen G, Wang P, Zuo Z, Ren L, Bi J, Yang CW, Mei X, Han D. Klotho ameliorates cyclosporine A–induced nephropathy via PDLIM2/NF-kB p65 signaling pathway. Biochem Biophys Res Commun 2017; 486:451-457. [DOI: 10.1016/j.bbrc.2017.03.061] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 03/14/2017] [Indexed: 12/27/2022]
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González-Parra E, Daudén E, Carrascosa J, Olveira A, Botella R, Bonanad C, Rivera R. Kidney Disease and Psoriasis. A New Comorbidity? ACTAS DERMO-SIFILIOGRAFICAS 2016. [DOI: 10.1016/j.adengl.2016.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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González-Parra E, Daudén E, Carrascosa J, Olveira A, Botella R, Bonanad C, Rivera R. Enfermedad renal y psoriasis. ¿Una nueva comorbilidad? ACTAS DERMO-SIFILIOGRAFICAS 2016; 107:823-829. [DOI: 10.1016/j.ad.2016.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 05/19/2016] [Accepted: 05/29/2016] [Indexed: 10/21/2022] Open
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Angiotensin type-2 (AT-2)-receptor activation reduces renal fibrosis in cyclosporine nephropathy: evidence for blood pressure independent effect. Biosci Rep 2016; 36:BSR20160278. [PMID: 27679859 PMCID: PMC5293591 DOI: 10.1042/bsr20160278] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 08/26/2016] [Accepted: 09/26/2016] [Indexed: 02/06/2023] Open
Abstract
Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague–Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (P<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P<0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (P<0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases.
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Schachtner T, Stein M, Reinke P. Kidney transplant recipients after nonrenal solid organ transplantation show low alloreactivity but an increased risk of infection. Transpl Int 2016; 29:1296-1306. [PMID: 27638250 DOI: 10.1111/tri.12856] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 07/29/2016] [Accepted: 09/04/2016] [Indexed: 12/13/2022]
Abstract
The number of kidney transplant recipients (KTRs) after nonrenal solid organ transplantation (SOT) has increased to almost 5%. Knowledge on patient and allograft outcomes, infections, and alloreactivity, however, remains scarce. We studied 40 KTRs after nonrenal SOT. Seven hundred and twenty primary KTRs and 119 repeat KTRs were used for comparison. Samples were collected pretransplantation, at +1, +2, and +3 months post-transplantation. Alloreactive and CMV-specific T cells were measured by interferon-γ ELISPOT assay. Patient survival in KTRs after SOT, primary and repeat KTRs was comparable. While death-censored allograft survival was comparable between KTRs after SOT and primary KTRs, KTRs after SOT showed superior 5-year death-censored allograft survival of 92.5% compared to 81.2% in repeat KTRs. Interestingly, KTRs after SOT show less preformed panel-reactive antibodies, frequencies of alloreactive T cells, and acute rejections compared to repeat KTRs. KTRs after SOT, however, show higher incidences of EBV viremia and PTLD, sepsis, and death from sepsis. Impaired CMV-specific cellular immunity was associated with more CMV replication compared to repeat KTRs. Our results suggest comparable patient and allograft outcomes in KTRs after SOT and primary KTRs. The observed low alloreactivity may contribute to excellent allograft outcomes. Caution should be taken in KTRs after SOT regarding infectious complications due to overimmunosuppression.
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Affiliation(s)
- Thomas Schachtner
- Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany.,Berlin-Brandenburg Center of Regenerative Therapies (BCRT), Berlin, Germany.,Charité and Max-Delbrück Center, Berlin Institute of Health (BIH), Berlin, Germany
| | - Maik Stein
- Berlin-Brandenburg Center of Regenerative Therapies (BCRT), Berlin, Germany
| | - Petra Reinke
- Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany.,Berlin-Brandenburg Center of Regenerative Therapies (BCRT), Berlin, Germany
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Cippà PE, Grebe SO, Fehr T, Wüthrich RP, Mueller TF. Altitude and arteriolar hyalinosis after kidney transplantation. Nephrology (Carlton) 2016; 21:782-4. [PMID: 26823025 DOI: 10.1111/nep.12734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/12/2016] [Accepted: 01/22/2016] [Indexed: 11/27/2022]
Abstract
The kidney is very susceptible to hypoxic injury. Calcineurin inhibitors (CNIs) induce vasoconstriction and might reduce renal tissue oxygenation. We aimed to investigate if the synergistic deleterious effects of CNI-treatment and hypoxia of high altitude living might accelerate the development of arteriolar hyalinosis in kidney allografts. We stratified all patients who received a kidney graft from 2000 to 2010 in our centre (n = 477) in three groups according to the residential elevation (below 400, between 400 to 600 and above 600 m above sea level) and we retrospectively re-evaluated all transplant biopsies performed during follow-up, specifically looking at the degree of arteriolar hyalinosis, the hallmark of chronic CNI nephrotoxicity. Living at high altitude was markedly associated with a higher degree of arteriolar hyalinosis (P < 0.001). Haemoglobin levels confirmed the functional relevance of different arterial oxygenation among the groups (P = 0.01). Thus, patients living at high altitude seem to be more susceptible to the development of arteriolar hyalinosis after kidney transplantation.
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Affiliation(s)
- Pietro E Cippà
- Division of Nephrology, University Hospital Zurich, Switzerland
| | | | - Thomas Fehr
- Department of Internal Medicine, Cantonal Hospital Graubuenden, Chur, Switzerland
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Lin NC, Wang HK, Yeh YC, Liu CP, Loong CC, Tsai HL, Chen CY, Chin T, Liu C. Minimization or withdrawal of immunosuppressants in pediatric liver transplant recipients. J Pediatr Surg 2015; 50:2128-33. [PMID: 26377868 DOI: 10.1016/j.jpedsurg.2015.08.043] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 08/24/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND We aimed to minimize the dose of tacrolimus in pediatric patients undergoing liver transplantation prospectively. METHODS Pediatric liver transplant recipients with stable graft function >1year (transplant at <1year of age), or 2years (transplant at >1year of age) post transplant were screened. After baseline graft biopsy, patients were enrolled into our protocol for elective tacrolimus dose reduction. Patients were assessed by liver function test and protocol biopsy during and after tacrolimus dose reduction. RESULTS From January 2011 to December 2012, 16 patients were recruited, of whom 15 completed follow-up at a mean 40.75±5.98months. Six patients were preliminarily weaned off tacrolimus, and five remained tacrolimus-free for more than 2years. Of the 10 patients who were not weaned off tacrolimus, six experienced seven episodes of clinical rejection. Five patients had a reduction in tacrolimus dosage to an undetectable trough level, another five to a trough level <4ng/ml, including one patient who was off the study. At the last patient visit, all of the patients had normal liver function test results with no graft loss. Three patients had low-grade graft fibrosis. The patients with metabolic liver disease (p=0.039) and who were recruited earlier after transplantation (p=0.028) were more likely to be weaned off tacrolimus. CONCLUSION Tacrolimus withdrawal is feasible in select pediatric liver transplant recipients, and long-term follow-up for these patients is suggested.
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Affiliation(s)
- Niang-Cheng Lin
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Hsin-Kai Wang
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Chia-Pei Liu
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Che-Chuan Loong
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Hsin-Lin Tsai
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Cheng-Yen Chen
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Taiwai Chin
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | - Chinsu Liu
- Divisions of Pediatric Surgery, and Transplantation Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Taipei, Taiwan.
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Malvezzi P, Rostaing L. The safety of calcineurin inhibitors for kidney-transplant patients. Expert Opin Drug Saf 2015; 14:1531-46. [DOI: 10.1517/14740338.2015.1083974] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Yuan J, Benway CJ, Bagley J, Iacomini J. MicroRNA-494 promotes cyclosporine-induced nephrotoxicity and epithelial to mesenchymal transition by inhibiting PTEN. Am J Transplant 2015; 15:1682-91. [PMID: 25854542 DOI: 10.1111/ajt.13161] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 12/11/2014] [Indexed: 01/25/2023]
Abstract
A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. In this study, we examined whether microRNAs play a role in cyclosporine-induced nephrotoxicity. Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of microRNA mmu-miR-494 (miR-494). Similarly, tubular epithelial cell epithelial-mesenchymal transition (EMT) induced by CsA toxicity resulted in the upregulation of microRNA-494 and a decrease in PTEN levels in vitro. miR-494 directly targeted Pten and negatively regulated its expression. Preventing Pten targeting by miR-494 was sufficient to prevent CsA induced EMT. Knockdown of miR-494 prevented the downregulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Thus, miR-494 plays a major role in promoting CsA induced nephrotoxicity through its ability to target Pten thereby contributing to EMT. We suggest that manipulating miR-494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.
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Affiliation(s)
- J Yuan
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA
| | - C J Benway
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.,Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA
| | - J Bagley
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA
| | - J Iacomini
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA.,Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA
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Essiz D, Sozmen M, Sudagidan M, Devrim AK. Phosphodiesterase type 5 inhibition attenuates cyclosporine A induced nephrotoxicity in mice. Biotech Histochem 2014; 90:167-78. [PMID: 25420893 DOI: 10.3109/10520295.2014.976270] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
We investigated the renal protective effects of phophodiesterase type 5 (PDE5) inhibitors in mice with cyclosporine A (CyA; a calcineurin phosphatase inhibitor) induced nephrotoxicity. Fifty male mice were divided into five groups of 10. Group 1 received no treatment, group 2 received only saline orally, group 3 received 30 mg/kg/day CyA by subcutaneous injection, group 4 received only 30 mg/kg/day vardenafil orally, and group 5 received 30 mg/kg/day CyA by subcutaneous injection and 30 mg/kg/day vardenafil orally. At 28 days, platelet-derived growth factor A (PDGF-A) and C (PDGF-C), transforming growth factor-beta 1 (TGF-β1), cyclo-oxygenase 1 and 2 (COX-1 and COX-2), and P glycoprotein (Pgp) expression levels were measured in the renal tissues. In addition, expressions of COX-1 and COX-2 genes were determined using real-time PCR. PDE5 inhibitor administration ameliorated decreased PDGF-A and C, TGF-β1, COX-1 and -2, and Pgp expression levels by modulation of cyclic guanosine monophosphate (cGMP) activity in kidneys. The relative expressions of COX-1 and COX-2 genes to GAPDH revealed that the maximum increase was obtained in the group treated with CyA and vardenafil for both COX-1 and COX-2 genes. Our study revealed that long term oral treatment with vardenafil protects kidneys from CyA induced nephrotoxicity. We showed that long term oral treatment with PDE5 prevents pathological kidney changes caused by CyA induced nephrotoxicity.
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Affiliation(s)
- D Essiz
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Kirikkale University , 71450, Kirikkale
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Wormser C, Mariano A, Holmes ES, Aronson LR, Volk SW. Post-transplant malignant neoplasia associated with cyclosporine-based immunotherapy: prevalence, risk factors and survival in feline renal transplant recipients. Vet Comp Oncol 2014; 14:e126-e134. [DOI: 10.1111/vco.12120] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 09/10/2014] [Accepted: 09/11/2014] [Indexed: 01/20/2023]
Affiliation(s)
- C. Wormser
- Department of Surgery; University of Pennsylvania; Philadelphia Pennsylvania USA
| | - A. Mariano
- Department of Clinical Sciences; Tufts University; North Grafton Massachusetts USA
| | - E. S. Holmes
- Veterinary Specialty Hospital of the Carolinas; Cary North Carolina USA
| | - L. R. Aronson
- Department of Surgery; University of Pennsylvania; Philadelphia Pennsylvania USA
| | - S. W. Volk
- Department of Surgery; University of Pennsylvania; Philadelphia Pennsylvania USA
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Different effects of tacrolimus and cyclosporine on PDGF induction and chronic allograft injury: Evidence for improved kidney graft outcome. Transpl Immunol 2014; 31:145-51. [DOI: 10.1016/j.trim.2014.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Revised: 08/18/2014] [Accepted: 08/18/2014] [Indexed: 11/18/2022]
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Joo DJ, Yang CW, Jeong HJ, Lim BJ, Huh KH, Chung BH, Choi YJ, Kang SW, Kim YS. Sirolimus conversion efficacy for graft function improvement and histopathology in renal recipients with mild to moderate renal insufficiency. J Korean Med Sci 2014; 29:1069-76. [PMID: 25120315 PMCID: PMC4129197 DOI: 10.3346/jkms.2014.29.8.1069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 04/30/2014] [Indexed: 11/20/2022] Open
Abstract
This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.
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Affiliation(s)
- Dong Jin Joo
- The Research Institute for Transplantation, Severance Hospital, Yonsei University Health System, Seoul, Korea
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Chul Woo Yang
- Department of Internal Medicine, Seoul St. Mary Hospital, The Catholic University of Korea, Seoul, Korea
| | - Hyeon Joo Jeong
- The Research Institute for Transplantation, Severance Hospital, Yonsei University Health System, Seoul, Korea
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu Ha Huh
- The Research Institute for Transplantation, Severance Hospital, Yonsei University Health System, Seoul, Korea
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Byung Ha Chung
- Department of Internal Medicine, Seoul St. Mary Hospital, The Catholic University of Korea, Seoul, Korea
| | - Yeong Jin Choi
- Department of Pathology, Seoul St. Mary Hospital, The Catholic University of Korea, Seoul, Korea
| | - Shin-Wook Kang
- The Research Institute for Transplantation, Severance Hospital, Yonsei University Health System, Seoul, Korea
- Department of Internal Medicine, Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Yu Seun Kim
- The Research Institute for Transplantation, Severance Hospital, Yonsei University Health System, Seoul, Korea
- Department of Transplantation Surgery, Severance Hospital, Yonsei University Health System, Seoul, Korea
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Carlos CP, Sonehara NM, Oliani SM, Burdmann EA. Predictive usefulness of urinary biomarkers for the identification of cyclosporine A-induced nephrotoxicity in a rat model. PLoS One 2014; 9:e103660. [PMID: 25072153 PMCID: PMC4114979 DOI: 10.1371/journal.pone.0103660] [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: 03/30/2014] [Accepted: 07/03/2014] [Indexed: 01/13/2023] Open
Abstract
The main side effect of cyclosporine A (CsA), a widely used immunosuppressive drug, is nephrotoxicity. Early detection of CsA-induced acute nephrotoxicity is essential for stop or minimize kidney injury, and timely detection of chronic nephrotoxicity is critical for halting the drug and preventing irreversible kidney injury. This study aimed to identify urinary biomarkers for the detection of CsA-induced nephrotoxicity. We allocated salt-depleted rats to receive CsA or vehicle for 7, 14 or 21 days and evaluated renal function and hemodynamics, microalbuminuria, renal macrophage infiltration, tubulointerstitial fibrosis and renal tissue and urinary biomarkers for kidney injury. Kidney injury molecule-1 (KIM-1), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibronectin, neutrophil gelatinase-associated lipocalin (NGAL), TGF-β, osteopontin, and podocin were assessed in urine. TNF-α, IL-6, fibronectin, osteopontin, TGF-β, collagen IV, alpha smooth muscle actin (α -SMA) and vimentin were assessed in renal tissue. CsA caused early functional renal dysfunction and microalbuminuria, followed by macrophage infiltration and late tubulointerstitial fibrosis. Urinary TNF-α, KIM-1 and fibronectin increased in the early phase, and urinary TGF-β and osteopontin increased in the late phase of CsA nephrotoxicity. Urinary biomarkers correlated consistently with renal tissue cytokine expression. In conclusion, early increases in urinary KIM-1, TNF-α, and fibronectin and elevated microalbuminuria indicate acute CsA nephrotoxicity. Late increases in urinary osteopontin and TGF-β indicate chronic CsA nephrotoxicity. These urinary kidney injury biomarkers correlated well with the renal tissue expression of injury markers and with the temporal development of CsA nephrotoxicity.
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Affiliation(s)
- Carla Patrícia Carlos
- Division of Nephrology, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil
- Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Nathália Martins Sonehara
- Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Sonia Maria Oliani
- Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University, São José do Rio Preto, SP, Brazil
| | - Emmanuel A. Burdmann
- Division of Nephrology, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil
- LIM 12, Division of Nephrology, University of São Paulo Medical School, São Paulo, SP, Brazil
- * E-mail:
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Hamon J, Jennings P, Bois FY. Systems biology modeling of omics data: effect of cyclosporine a on the Nrf2 pathway in human renal cells. BMC SYSTEMS BIOLOGY 2014; 8:76. [PMID: 24964791 PMCID: PMC4089556 DOI: 10.1186/1752-0509-8-76] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 06/04/2014] [Indexed: 01/10/2023]
Abstract
Background Incorporation of omic data streams for building improved systems biology models has great potential for improving their predictions of biological outcomes. We have recently shown that cyclosporine A (CsA) strongly activates the nuclear factor (erythroid-derived 2)-like 2 pathway (Nrf2) in renal proximal tubular epithelial cells (RPTECs) exposed in vitro. We present here a quantitative calibration of a differential equation model of the Nrf2 pathway with a subset of the omics data we collected. Results In vitro pharmacokinetic data on CsA exchange between cells, culture medium and vial walls, and data on the time course of omics markers in response to CsA exposure were reasonably well fitted with a coupled PK-systems biology model. Posterior statistical distributions of the model parameter values were obtained by Markov chain Monte Carlo sampling in a Bayesian framework. A complex cyclic pattern of ROS production and control emerged at 5 μM CsA repeated exposure. Plateau responses were found at 15 μM exposures. Shortly above those exposure levels, the model predicts a disproportionate increase in cellular ROS quantity which is consistent with an in vitro EC50 of about 40 μM for CsA in RPTECs. Conclusions The model proposed can be used to analyze and predict cellular response to oxidative stress, provided sufficient data to set its parameters to cell-specific values. Omics data can be used to that effect in a Bayesian statistical framework which retains prior information about the likely parameter values.
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Affiliation(s)
| | | | - Frederic Y Bois
- Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France.
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Cyclosporin in cell therapy for cardiac regeneration. J Cardiovasc Transl Res 2014; 7:475-82. [PMID: 24831573 DOI: 10.1007/s12265-014-9570-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 04/21/2014] [Indexed: 12/19/2022]
Abstract
Stem cell therapy is a promising strategy in promoting cardiac repair in the setting of ischemic heart disease. Clinical and preclinical studies have shown that cell therapy improves cardiac function. Whether autologous or allogeneic cells should be used, and the need for immunosuppression in non-autologous settings, is a matter of debate. Cyclosporin A (CsA) is frequently used in preclinical trials to reduce cell rejection after non-autologous cell therapy. The direct effect of CsA on the function and survival of stem cells is unclear. Furthermore, the appropriate daily dosage of CsA in animal models has not been established. In this review, we discuss the pros and cons of the use of CsA on an array of stem cells both in vitro and in vivo. Furthermore, we present a small collection of data put forth by our group supporting the efficacy and safety of a specific daily CsA dosage in a pig model.
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Bechstein WO, Paczek L, Wramner L, Squifflet JP, Zygmunt AJ. A comparative, randomized trial of concentration-controlled sirolimus combined with reduced-dose tacrolimus or standard-dose tacrolimus in renal allograft recipients. Transplant Proc 2014; 45:2133-40. [PMID: 23953523 DOI: 10.1016/j.transproceed.2013.03.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/27/2013] [Accepted: 03/06/2013] [Indexed: 12/24/2022]
Abstract
BACKGROUND The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. METHODS One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. RESULTS Demographic variables were similar between groups. At 6 months, mean (± standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P = .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P = .095). CONCLUSIONS The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.
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