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Kanbay M, Copur S, Mizrak B, Mallamaci F, Zoccali C. Mineralocorticoid receptor antagonists in kidney transplantation. Eur J Clin Invest 2024; 54:e14206. [PMID: 38578116 DOI: 10.1111/eci.14206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/16/2024] [Accepted: 03/19/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND The fundamental role of the renin-angiotensin-aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre-clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin-angiotensin-aldosterone system blockage, along with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. METHODS In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology. RESULTS The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non-nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre-clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia-reperfusion injury, proteinuria, or calcineurin inhibitor-mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions. CONCLUSION Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large-scale randomized clinical trials with long-term follow-up data.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Internal Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Internal Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Berk Mizrak
- Department of Internal Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Francesca Mallamaci
- Nephrology, Dialysis and Transplantation Unit Azienda Ospedaliera "Bianchi-Melacrino-Morelli" & CNR-IFC, Institute of Clinical Physiology, Research Unit of Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Reggio Calabria, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Associazione Ipertensione Nefrologia Trapianto Renal (IPNET), Reggio Calabria, Italy
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Li Y, Tang Y, Lin T, Song T. Risk factors and outcomes of IgA nephropathy recurrence after kidney transplantation: a systematic review and meta-analysis. Front Immunol 2023; 14:1277017. [PMID: 38090563 PMCID: PMC10713786 DOI: 10.3389/fimmu.2023.1277017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023] Open
Abstract
Background IgA nephropathy may recur in patients receiving kidney transplantation due to IgA nephropathy induced renal failure. The risk factors for recurrence are still at issue. The aim of this study was to conduct a systematic review and meta-analysis to assess risk factors and outcomes for IgA nephropathy recurrence. Methods We used PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, CNKI, WanFang, VIP and CBM to search for relevant studies published in English and Chinese. Cohort or case-control studies reporting risk factors or outcomes for IgA nephropathy recurrence were included. Results Fifty-eight studies were included. Compare to no recurrence group, those with IgAN recurrence had younger age (mean difference [MD]=-4.27 years; risk ratio [RR]=0.96), younger donor age (MD=-2.19 years), shorter time from IgA nephropathy diagnosis to end stage renal disease (MD=-1.84 years; RR=0.94), shorter time on dialysis (MD=-3.14 months), lower human leukocyte-antigen (HLA) mismatches (MD=-0.11) and HLA-DR mismatches (MD=-0.13). HLA-B46 antigen (RR=0.39), anti-IL-2-R antibodies induction (RR=0.68), mycophenolate mofetil (RR=0.69), and pretransplant tonsillectomy (RR=0.43) were associated with less IgAN recurrence. Of note, male recipient gender (RR=1.17), related donor (RR=1.53), retransplantation (RR=1.43), hemodialysis (RR=1.68), no induction therapy (RR=1.73), mTOR inhibitor (RR=1.51), angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (RR=1.63) were risk factors for IgAN recurrence. Recurrence increased the risk of graft loss (RR=2.19). Conclusions This study summarized the risk factors for recurrence of IgA nephropathy after kidney transplantation. Well-designed prospective studies are warranted for validation. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=377480, identifier CRD42022377480.
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Affiliation(s)
- Yue Li
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
- Transplant Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yangming Tang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
- Transplant Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Lin
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
- Transplant Center, West China Hospital, Sichuan University, Chengdu, China
| | - Turun Song
- Department of Urology, West China Hospital, Sichuan University, Chengdu, China
- Transplant Center, West China Hospital, Sichuan University, Chengdu, China
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Kaur G, Wright K, Mital P, Hibler T, Miranda JM, Thompson LA, Halley K, Dufour JM. Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells. Cell Transplant 2021; 29:963689720947102. [PMID: 32841048 PMCID: PMC7564626 DOI: 10.1177/0963689720947102] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The acute cell-mediated immune response presents a significant barrier to
xenotransplantation. Immune-privileged Sertoli cells (SC) can prolong the
survival of co-transplanted cells including xenogeneic islets, hepatocytes, and
neurons by protecting them from immune rejection. Additionally, SC survive as
allo- and xenografts without the use of any immunosuppressive drugs suggesting
elucidating the survival mechanism(s) of SC could be used to improve survival of
xenografts. In this study, the survival and immune response generated toward
neonatal pig SC (NPSC) or neonatal pig islets (NPI), nonimmune-privileged
controls, was compared after xenotransplantation into naïve Lewis rats without
immune suppression. The NPSC survived throughout the study, while NPI were
rejected within 9 days. Analysis of the grafts revealed that macrophages and T
cells were the main immune cells infiltrating the NPSC and NPI grafts. Further
characterization of the T cells within the grafts indicated that the NPSC grafts
contained significantly more cluster of differentiation 4 (CD4) and cluster of
differentiation 8 (CD8) regulatory T cells (Tregs) at early time points than the
NPI grafts. Additionally, the presence of increased amounts of interleukin 10
(IL-10) and transforming growth factor (TGF) β and decreased levels of tumor
necrosis factor (TNF) α and apoptosis in the NPSC grafts compared to NPI grafts
suggests the presence of regulatory immune cells in the NPSC grafts. The NPSC
expressed several immunoregulatory factors such as TGFβ, thrombospondin-1
(THBS1), indoleamine-pyrrole 2,3-dioxygenase, and galectin-1, which could
promote the recruitment of these regulatory immune cells to the NPSC grafts. In
contrast, NPI grafts had fewer Tregs and increased apoptosis and inflammation
(increased TNFα, decreased IL-10 and TGFβ) suggestive of cytotoxic immune cells
that contribute to their early rejection. Collectively, our data suggest that a
regulatory graft environment with regulatory immune cells including CD4 and
CD8 Tregs in NPSC grafts could be attributed to the prolonged survival of the
NPSC xenografts.
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Affiliation(s)
- Gurvinder Kaur
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Medical Education, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Kandis Wright
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Payal Mital
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Taylor Hibler
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Jonathan M Miranda
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Lea Ann Thompson
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Katelyn Halley
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Jannette M Dufour
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Medical Education, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
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Peng Z, Xian W, Sun H, Li E, Geng L, Tian J. Efficacy and Safety of a Quadruple Regimen Compared with Triple Regimens in Patients with Mycophenolic Acid-Related Gastrointestinal Complications After Renal Transplantation: A Short-Term Single-Center Study. Ann Transplant 2020; 25:e919875. [PMID: 32107364 PMCID: PMC7065508 DOI: 10.12659/aot.919875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background At present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation. Material/Methods Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups. Results Compared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced. Conclusions This quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.
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Affiliation(s)
- Zhiguo Peng
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
| | - Wanhua Xian
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
| | - Huaibin Sun
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
| | - Engang Li
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
| | - Lina Geng
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
| | - Jun Tian
- Department of Organ Transplantation, Qilu Hospital of Shan Dong University, Jinan, Shandong, China (mainland)
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Sirolimus and mTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation. Drug Saf 2020; 42:813-825. [PMID: 30868436 DOI: 10.1007/s40264-019-00810-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to mechanisms hypothesized to cause adverse events and their management strategies.
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Recomendaciones para el uso de everolimus en trasplante renal de novo: falsas creencias, mitos y realidades. Nefrologia 2017; 37:253-266. [DOI: 10.1016/j.nefro.2016.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/15/2016] [Accepted: 11/16/2016] [Indexed: 12/16/2022] Open
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Ventura-Aguiar P, Campistol JM, Diekmann F. Safety of mTOR inhibitors in adult solid organ transplantation. Expert Opin Drug Saf 2016; 15:303-19. [PMID: 26667069 DOI: 10.1517/14740338.2016.1132698] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) are a class of immunosuppressive drugs approved for solid organ transplantation (SOT). By inhibiting the ubiquitous mTOR pathway, they present a peculiar safety profile. The increased incidence of serious adverse events in early studies halted the enthusiasm as a kidney sparing alternative to calcineurin inhibitors (CNI). AREAS COVERED Herein we review mTOR inhibitors safety profile for adult organ transplantation, ranging from acute side effects, such as lymphoceles, delayed wound healing, or cytopenias, to long-term ones which increase morbidity and mortality, such as cancer risk and metabolic profile. Infection, proteinuria, and cutaneous safety profiles are also addressed. EXPERT OPINION In the authors' opinion, mTOR inhibitors are a safe alternative to standard immunosuppression therapy with CNI and mycophenolate/azathioprine. Mild adverse events can be easily managed with an increased awareness and close monitoring of trough levels. Most serious side effects are dose- and organ-dependent. In kidney and heart transplantation mTOR inhibitors may be safely used as either low-dose de novo or through early-conversion. In the liver, conversion 4 weeks post-transplantation may reduce long-term chronic kidney disease secondary to calcineurin nephrotoxicity, without increasing hepatic artery/portal vein thrombosis.
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Affiliation(s)
- Pedro Ventura-Aguiar
- a Department of Nephrology and Renal Transplantation , Hospital Clínic , Villarroel, 170, E-08036 Barcelona , Spain
| | - Josep Maria Campistol
- a Department of Nephrology and Renal Transplantation , Hospital Clínic , Villarroel, 170, E-08036 Barcelona , Spain.,b August Pi i Sunyer Biomedical Research Institute (IDIBAPS) , University of Barcelona , Barcelona , Spain
| | - Fritz Diekmann
- a Department of Nephrology and Renal Transplantation , Hospital Clínic , Villarroel, 170, E-08036 Barcelona , Spain
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Neale J, Smith AC. Cardiovascular risk factors following renal transplant. World J Transplant 2015; 5:183-95. [PMID: 26722646 PMCID: PMC4689929 DOI: 10.5500/wjt.v5.i4.183] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/19/2015] [Accepted: 09/25/2015] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients (RTRs) remain at an increased risk of fatal and non-fatal cardiovascular (CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease (CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Non-traditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.
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Álamo JM, Olivares C, Barrera L, Marín LM, Suarez G, Bernal C, Serrano J, Muntané J, Padillo FJ, Gómez MA. Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant. World J Transplant 2015; 5:19-25. [PMID: 25815268 PMCID: PMC4371158 DOI: 10.5500/wjt.v5.i1.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/18/2014] [Accepted: 10/29/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors (mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.
METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation (OLT), including all liver recipients with worsening renal function before conversion to mTORi (n = 55 patients) and recipients with normal renal function who converted to mTORi for other reasons (n = 31 patients). We identified patients with diabetes mellitus (n = 28), arterial hypertension (n = 27), proteinuria (n = 27) and all three factors (n = 8) (some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus (DM), hypertension (HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.
RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function (2.14 to 1.77 mg/dL) (P = 0.02). Patients with DM showed no improvement of serum creatinine levels (1.31 mg/dL to 1.37 mg/dL) compared with non DM patients (1.31 mg/dL to 1.15 mg/dL) (P = 0.01), HT patients (1.48 mg/dL to 1.5 mg/dL) with non HT patients (1.21mg/dL to 1.08 mg/dL) and patients with proteinuria (1.44 mg/dL to 1.41 mg/dL) and no proteinuria (1.31 mg/dL to 1.11 mg/dL).
CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to mTORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to mTORi; it also stabilizes renal function. Conversion to mTORi should only be avoided in patients with diabetes, hypertension and proteinuria.
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10
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Tian SY, Feldman BM, Beyene J, Brown PE, Uleryk EM, Silverman ED. Immunosuppressive therapies for the induction treatment of proliferative lupus nephritis: a systematic review and network metaanalysis. J Rheumatol 2014; 41:1998-2007. [PMID: 25225281 DOI: 10.3899/jrheum.140050] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To evaluate and determine the most effective immunosuppressive therapy for the induction treatment of proliferative lupus nephritis (PLN) based on renal remission. METHODS A systematic review of randomized controlled trials was conducted. The outcomes were renal remission at 6 months: (1) normalization of serum creatinine [(sCr), or within 15% of the normal range, i.e., sCr < 132 µmol/l - creatinine remission]; and (2) proteinuric remission (prU < 0.5 g/day/1.73m(2)). A Bayesian network metaanalysis was used. RESULTS The OR (95% credible interval) of inducing an sCr remission at 6 months was 1.70 (0.51, 6.87) for mycophenolate mofetil (MMF) versus cyclophosphamide (CYC); 2.16 (0.38, 13.36) for tacrolimus (Tac) versus CYC; and 1.25 (0.13, 10.51) for Tac versus MMF. For proteinuric remission the OR was 1.46 (0.81, 3.04) for MMF versus CYC; 1.96 (0.80, 5.11) for Tac versus CYC; and 1.34 (0.43, 3.90) for Tac versus MMF. The probability (95% credible interval) of inducing a creatinine remission at 6 months was Tac 56% (19%, 88%); MMF 51% (23%, 79%); and CYC 37% (28%, 47%). The probability of inducing a proteinuric remission was Tac 41% (23%, 63%); MMF 34% (23%, 50%); CYC 26% (20%, 32%); azathioprine 10% (1%, 55%); prednisone 11% (2%, 38%). None of the results were conclusive when examined in a sensitivity analysis. CONCLUSION There is currently insufficient evidence to determine which of these immunosuppressive agents is superior. The probability of renal remission is 50% or lower at 6 months.
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Affiliation(s)
- Simon Yu Tian
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
| | - Brian M Feldman
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
| | - Joseph Beyene
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
| | - Patrick E Brown
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
| | - Elizabeth M Uleryk
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
| | - Earl D Silverman
- From the Institute of Medical Science, Faculty of Medicine, University of Toronto; Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children; Department of Pediatrics, Faculty of Medicine, University of Toronto; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton; Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Toronto; Cancer Care Ontario, Toronto; Hospital Library, The Hospital for Sick Children, Toronto, Ontario, Canada.S.Y. Tian's PhD research is funded in part by the Queen Elizabeth II-Edward Dunlop Foundation Scholarships in Science and Technology, administered at the University of Toronto.S.Y. Tian, MB, MSc, PhD (C), Institute of Medical Science, Faculty of Medicine, University of Toronto, and The Hospital for Sick Children; B.M. Feldman, MD, MSc, FRCPC, Professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and The Hospital for Sick Children; J. Beyene, PhD, Associate Professor, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto; P.E. Brown, PhD, Associate Professor, Cancer Care Ontario, and Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto, Program in Population Genomics, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University; E.M. Uleryk, MLS, Hospital Library, The Hospital for Sick Children; E.D. Silverman, MD, FRCPC, Professor, Division of Rheumatology and Program of Child Health Evaluative Sciences, The Hospital for Sick Children, and Institute of Medical Science, Department of Pediatrics, and Department of Immunology, Univer
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11
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Does the KDIGO CKD risk stratification based on GFR and proteinuria predict kidney graft failure? Int Urol Nephrol 2014; 46:1857-65. [DOI: 10.1007/s11255-014-0761-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/03/2014] [Indexed: 10/25/2022]
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12
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Croze LE, Tetaz R, Roustit M, Malvezzi P, Janbon B, Jouve T, Pinel N, Masson D, Quesada JL, Bayle F, Zaoui P. Conversion to mammalian target of rapamycin inhibitors increases risk ofde novodonor-specific antibodies. Transpl Int 2014; 27:775-83. [DOI: 10.1111/tri.12330] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 11/24/2013] [Accepted: 03/26/2014] [Indexed: 12/01/2022]
Affiliation(s)
| | - Rachel Tetaz
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
| | - Matthieu Roustit
- Centre d'Investigation Clinique; INSERM CIC03; CHU Grenoble; Grenoble France
- INSERM U1042 - HP2; Université Joseph Fourier; Grenoble France
| | - Paolo Malvezzi
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
| | - Bénédicte Janbon
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
| | - Thomas Jouve
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
| | - Nicole Pinel
- Départment d'Anatomo-Pathologie; CHU Grenoble; Grenoble France
| | - Dominique Masson
- Laboratoire d'Immunologie et Histocompatibilité; Etablissement Français du Sang; Grenoble France
| | - Jean-Louis Quesada
- Centre d'Investigation Clinique; INSERM CIC03; CHU Grenoble; Grenoble France
| | - François Bayle
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
| | - Philippe Zaoui
- Clinique Universitaire de Néphrologie; CHU Grenoble; Grenoble France
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13
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Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev (Orlando) 2014; 28:126-33. [PMID: 24685370 DOI: 10.1016/j.trre.2014.03.002] [Citation(s) in RCA: 206] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 03/04/2014] [Accepted: 03/08/2014] [Indexed: 12/29/2022]
Abstract
Mammalian target of rapamycin (mTOR) inhibitors are used as potent immunosuppressive agents in solid-organ transplant recipients (everolimus and sirolimus) and as antineoplastic therapies for various cancers (eg, advanced renal cell carcinoma; everolimus, temsirolimus, ridaforolimus). Relevant literature, obtained from specific PubMed searches, was reviewed to evaluate the incidence and mechanistic features of specific adverse events (AEs) associated with mTOR inhibitor treatment, and to present strategies to effectively manage these events. The AEs examined in this review include stomatitis and other cutaneous AEs, wound-healing complications (eg, lymphocele, incisional hernia), diabetes/hyperglycemia, dyslipidemia, proteinuria, nephrotoxicity, delayed graft function, pneumonitis, anemia, hypertension, gonadal dysfunction, and ovarian toxicity. Strategies for selecting appropriate patients for mTOR inhibitor therapy and minimizing the risks of AEs are discussed, along with best practices for identifying and managing side effects. mTOR inhibitors are promising therapeutic options in immunosuppression and oncology; most AEs can be effectively detected and managed or reversed with careful monitoring and appropriate interventions.
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14
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Xue C, Dai B, Mei C. Long-term treatment with mammalian target of rapamycin inhibitor does not benefit patients with autosomal dominant polycystic kidney disease: a meta-analysis. Nephron Clin Pract 2013; 124:10-6. [PMID: 24022660 DOI: 10.1159/000354398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 06/27/2013] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The role of the mammalian target of rapamycin (mTOR) inhibition in the treatment of autosomal dominant polycystic kidney disease (ADPKD) remains unclear. This meta-analysis included all randomized controlled trials (RCTs) that used mTOR inhibitors (TORIs) to halt the progression of ADPKD. METHODS Databases including MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant trials. RCTs of TORI treatment in patients with ADPKD were included. Effects on the primary outcome [total kidney volume (TKV)] and secondary outcomes [changes in cyst volume (CV) and parenchymal volume (PV), glomerular filtration rate (GFR), proteinuria, and adverse events] were analyzed. RESULTS The results of 5 RCTs, which included 619 patients, were analyzed. TORIs did not significantly reduce TKV [mean difference (WMD) -90.01 ml, 95% CI -235.49 to 55.47, p = 0.23; I(2) = 0%; p for heterogeneity = 0.67]. CV decreased after TORI treatment (WMD -15.08 ml, 95% CI -17.82 to -12.34, p < 0.00001), and PV did not change (WMD -0.55 ml, 95% CI -64.55 to 63.45, p = 0.99). There was no significant difference in GFR between the TORI-treated and control groups (WMD 4.94 ml/min, 95% CI -0.81 to 10.68, p = 0.09). Proteinuria was significantly higher in the TORI-treated group than in the control group (standard mean difference 0.27, 95% CI 0.09-0.44, p = 0.002). CONCLUSION Long-term treatment with TORIs does not benefit patients with ADPKD.
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Affiliation(s)
- Cheng Xue
- Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
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15
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16
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Baas MC, Kers J, Florquin S, de Fijter JW, van der Heide JJH, van den Bergh Weerman MA, ten Berge IJM, Bemelman FJ. Cyclosporine versus everolimus: effects on the glomerulus. Clin Transplant 2013; 27:535-40. [PMID: 23795805 DOI: 10.1111/ctr.12144] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2013] [Indexed: 11/28/2022]
Abstract
Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single-center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above-described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected.
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Affiliation(s)
- Marije C Baas
- Renal Transplant Unit, Division of Internal Medicine, Department of Nephrology, Academic Medical Center, Amsterdam, the Netherlands.
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17
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Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients. Transplantation 2012; 93:1006-12. [PMID: 22357174 DOI: 10.1097/tp.0b013e31824bbd01] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear. METHODS Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion. RESULT After a median (interquartile range) of 3.1 (1.6-4.5) years of follow-up, serum creatinine decreased from 1.9 ± 0.8 to 1.8 ± 0.7 mg/dL (P=0.25) and eGFR increased from 40.8 ± 16.7 to 44.3 ± 20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0-155) to 382 (169-999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥ 1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1-9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6-11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2-2.2, P=0.003). CONCLUSION Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥ 1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.
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18
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Thompson P, Badell IR, Lowe M, Turner A, Cano J, Avila J, Azimzadeh A, Cheng X, Pierson R, Johnson B, Robertson J, Song M, Leopardi F, Strobert E, Korbutt G, Rayat G, Rajotte R, Larsen CP, Kirk AD. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am J Transplant 2012; 12:1765-75. [PMID: 22458586 PMCID: PMC3387302 DOI: 10.1111/j.1600-6143.2012.04031.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ≈ 50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.
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Affiliation(s)
- P Thompson
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - IR Badell
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - M Lowe
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - A Turner
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - J Cano
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - J Avila
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - A Azimzadeh
- Division of Cardiac Surgery, University of Maryland, Baltimore, MD 21201
| | - X Cheng
- Division of Cardiac Surgery, University of Maryland, Baltimore, MD 21201
| | - R Pierson
- Division of Cardiac Surgery, University of Maryland, Baltimore, MD 21201
| | - B Johnson
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - J Robertson
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - M Song
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - F Leopardi
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - E Strobert
- Yerkes National Primate Research Center, Atlanta, GA, USA 30322
| | - G Korbutt
- Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, T6G 2N8, Canada
| | - G Rayat
- Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, T6G 2N8, Canada
| | - R Rajotte
- Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, T6G 2N8, Canada
| | - CP Larsen
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
| | - AD Kirk
- Emory Transplant Center, Emory University, Atlanta, GA, USA 30322
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19
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Oh CK, Ha JW, Kim YH, Kim YL, Kim YS. Safety and Efficacy of the Early Introduction of Everolimus (Certican Ⓡ) with Low Dose of Cyclosporine in de Novo Kidney Recipients after 1 Month of Transplantation (Preliminary Results). KOREAN JOURNAL OF TRANSPLANTATION 2012. [DOI: 10.4285/jkstn.2012.26.2.83] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Affiliation(s)
- Chang-Kwon Oh
- Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Jong Won Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Yeong Hoon Kim
- Department of Nephrology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Yong-Lim Kim
- Department of Nephrology, Kyungpook National University Hospital, Daegu, Korea
| | - Yu Seun Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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20
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Uhlmann D, Weber T, Ludwig S, Ludwig B, Bartels M, Hauss J, Jonas S, Witzigmann H. Long-term outcome of conversion to sirolimus monotherapy after liver transplant. EXP CLIN TRANSPLANT 2012; 10:30-8. [PMID: 22309417 DOI: 10.6002/ect.2011.0086] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES This study sought to assess the long-term efficacy and safety of conversion from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus monotherapy in liver transplant recipients with renal dysfunction. MATERIALS AND METHODS Twenty-five liver transplant recipients with calcineurin inhibitor-based immunosuppression were included in this single-center, prospective study. Indications were renal dysfunction, avoidance of tumor recurrence, combination renal dysfunction and avoidance of tumor recurrence, and calcineurin inhibitor-related adverse effects. RESULTS Mean interval between liver transplant and initiation of sirolimus monotherapy was 51.7 months. The mean follow-up was 75.6 months. The mean ± SD sirolimus whole-blood trough level was 9.0 ± 2.8 ng/mL after 6 months and 6.0 ± 1.8 ng/mL after 18 months. No rejection episodes occurred. There was an improvement of the mean creatinine level: 156.1 ± 54.9 μmol/L before conversion versus 129.1 ± 34.7 μmol/L approximately 3 years after conversion (P < .05). The glomerular filtration rate, measured by technetium Tc-99m-diethylenetriamine penta-acetic aerosol scintigraphy, improved from 27.4 ± 6.8 mL/min/1.73 m(2) before conversion to 43.3 ± 6.3 mL/min/1.73 m(2) at final follow-up. Proteinuria increased after conversion to sirolimus after 6 months (P < .05) and at last follow-up. The systolic blood pressure decreased from 151.5 ± 20.2 to 132.1 ± 19.4 mm Hg, and the diastolic from 89.7 ± 11.2 to 82.1 ± 9.1 mm Hg at last follow-up. Serum cholesterol and serum triglyceride levels were nearly unchanged. However, 50% of the patients were treated with lipid-lowering agents. Four patients had sirolimus-induced adverse effects (thrombocytopenia, gingival hyperplasia, oral ulceration). CONCLUSIONS Conversion from calcineurin inhibitors to sirolimus monotherapy after liver transplant results in stabilization of renal function in 75% to 85% of cases and of blood pressure, without increased risk of rejection. The spectrum of adverse effects is low.
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Affiliation(s)
- Dirk Uhlmann
- Second Department of Surgery, University of Leipzig, Germany
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21
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Diekmann F, Andrés A, Oppenheimer F. mTOR inhibitor-associated proteinuria in kidney transplant recipients. Transplant Rev (Orlando) 2012; 26:27-9. [PMID: 22137729 DOI: 10.1016/j.trre.2011.10.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 10/18/2011] [Indexed: 12/14/2022]
Abstract
The use of mammalian target of rapamycin inhibitor (mTOR-I) after kidney transplantation has been associated with a higher incidence of proteinuria compared with calcineurin inhibitors (CNIs). This review will focus on mTOR-I-associated proteinuria in different settings after kidney transplantation: de novo mTOR-I treatment in combination with CNI, de novo mTOR-I-containing and CNI-free treatment, early conversion from a CNI-based regimen to an mTOR-I-based regimen, and late conversion. Some possible mechanisms of mTOR-I-induced proteinuria will also be reviewed.
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Affiliation(s)
- Fritz Diekmann
- Servicio de Nefrología y Trasplante Renal, Hospital Clínic de Barcelona, Barcelona, Spain.
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22
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Garrouste C, Kamar N, Guilbeau-Frugier C, Guitard J, Esposito L, Lavayssière L, Nogier MB, Cointault O, Ribes D, Rostaing L. Long-term Results of Conversion From Calcineurin Inhibitors to Sirolimus in 150 Maintenance Kidney Transplant Patients. EXP CLIN TRANSPLANT 2012; 10:110-8. [DOI: 10.6002/ect.2011.0116] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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23
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Everolimus with Reduced-dose Cyclosporine Versus Full-dose Cyclosporine and Mycophenolate in De Novo Renal Transplant Patients: A 2-Year Single-Center Experience. Transplant Proc 2012; 44:154-60. [DOI: 10.1016/j.transproceed.2011.11.055] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Kawahara T, Asthana S, Kneteman NM. m-TOR inhibitors: what role in liver transplantation? J Hepatol 2011; 55:1441-51. [PMID: 21781947 DOI: 10.1016/j.jhep.2011.06.015] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 06/28/2011] [Accepted: 06/29/2011] [Indexed: 12/11/2022]
Abstract
The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.
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Affiliation(s)
- Toshiyasu Kawahara
- Division of Transplantation, Department of Surgery, University of Alberta, Canada
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25
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Shamseddin MK, Knoll GA. Posttransplantation proteinuria: an approach to diagnosis and management. Clin J Am Soc Nephrol 2011; 6:1786-93. [PMID: 21734095 DOI: 10.2215/cjn.01310211] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Proteinuria is a common problem encountered in the treatment of renal transplant recipients, occurring in up to 45% of patients. Proteinuria from native kidneys falls rapidly after renal transplantation, and persistent or worsening proteinuria is usually indicative of allograft pathology. Biopsy studies of transplant patients with proteinuria have confirmed that transplant-specific diagnoses (transplant glomerulopathy, interstitial fibrosis and tubular atrophy, and acute rejection) are more commonly found than other proteinuric conditions, such as glomerulonephritis. As in the nontransplant setting, proteinuria is associated with worse clinical outcomes, including an increased risk for death, cardiovascular events, and graft loss. Blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will reduce proteinuria, but the long-term effect of these medications on patient and graft survival remains unknown.
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Affiliation(s)
- M Khaled Shamseddin
- Division of Nephrology, Faculty of Medicine, University of Ottawa Hospital, Ottawa, Ontario, Canada
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26
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Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 2011; 377:837-47. [PMID: 21334736 DOI: 10.1016/s0140-6736(10)62318-5] [Citation(s) in RCA: 274] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-nephrotoxic immunosuppressive strategies that allow reduction of calcineurin-inhibitor exposure without compromising safety or efficacy remain a goal in kidney transplantation. Immunosuppression based on the mammalian-target-of-rapamycin inhibitor everolimus was assessed as a strategy for elimination of calcineurin-inhibitor exposure and optimisation of renal-graft function while maintaining efficacy. METHODS In the ZEUS multicentre, open-label study, 503 patients (aged 18-65 years) who had received de-novo kidney transplants were enrolled. After initial treatment with ciclosporin, based on trough concentrations, and enteric-coated mycophenolate sodium (1440 mg/day, orally), corticosteroids (≥5 mg/day prednisolone or equivalent, orally), and basiliximab induction (20 mg, intravenously, on day 0 [2 h before transplantation], and on day 4), 300 (60%) patients were randomly assigned at 4·5 months in a 1:1 ratio to undergo calcineurin-inhibitor elimination (everolimus-based regimen that was based on trough concentrations [6-10 ng/mL] and enteric-coated mycophenolate sodium [1440 mg/day] with corticosteroids), or continue standard ciclosporin-based treatment. Randomisation was done by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers. The primary objective was to show better renal function (glomerular filtration rate [GFR]; Nankivell formula) with the calcineurin-inhibitor-free everolimus regimen at 12 months after transplantation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00154310. FINDINGS 118 (76%) of 155 everolimus-treated patients and 117 (81%) of 145 ciclosporin-treated patients completed treatment with study drug up to 12 months after transplantation. At this timepoint, the everolimus regimen was associated with a significant improvement in GFR versus the ciclosporin regimen (71·8 mL/min per 1·73 m(2) vs 61·9 mL/min per 1·73 m(2), respectively; mean difference 9·8 mL/min per 1·73 m(2), 95% CI -12·2 to -7·5). Rates of biopsy-proven acute rejection were higher in the everolimus group than in the ciclosporin group after randomisation (15 [10%] of 154 vs five [3%] of 146; p = 0·036), but similar for the full study period (23 [15%] vs 22 [15%]). Compared with the ciclosporin regimen, higher mean lipid concentrations, slightly increased urinary protein excretion, and lower haemoglobin concentrations were noted with the everolimus regimen; thrombocytopenia, aphthous stomatitis, and diarrhoea also occurred more often in the everolimus group. A higher incidence of hyperuricaemia was noted with ciclosporin. INTERPRETATION Early elimination of calcineurin inhibitor by use of everolimus-based immunosuppression improved renal function at 12 months while maintaining efficacy and safety, indicating that this strategy may facilitate improved long-term outcomes in selected patients. FUNDING Novartis Pharma.
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Affiliation(s)
- Klemens Budde
- Department of Nephrology, Charité University, Berlin, Germany.
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Suhail SM, Kee TSY, Woo KT, Tan HK, Yang WS, Chan CM, Foo MWY, Li HH, Siddique MM, Wong KS. Impact of patterns of proteinuria on renal allograft function and survival: a prospective cohort study. Clin Transplant 2011; 25:E297-303. [PMID: 21362048 DOI: 10.1111/j.1399-0012.2011.01415.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Proteinuria is an important complication in renal transplant recipients. The aim of this prospective study was to evaluate the long-term impact of transplant proteinuria patterns on allograft function and survival. METHODS We analyzed urinary protein of a cohort of 83 renal transplants with proteinuria ≥0.5 g/d by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radial immunogel diffusion assay. After initial stratification and analysis, the cohort was followed up for 16 yr. The graft outcome and survival were analyzed using Cox regression model to determine their association with different patterns of initial transplant proteinuria. RESULTS Group with predominantly glomerular (middle- and high-molecular-weight with or without low-molecular-weight) proteinuria (61%) had higher serum creatinine (p < 0.001) than the group with predominantly tubular (low-molecular-weight) proteinuria (39%). The incidences of chronic graft dysfunction and graft loss had increased in the glomerular proteinuria group (p < 0.001, hazard ratio 3.6, 95% confidence interval 1.7-7.5 and p < 0.001, hazard ratio 4.9, 95% confidence interval 1.9-12.1, respectively). Patient death did not differ (p = 0.434, hazard ratio 1.5, 95% confidence interval 0.5-4.5). CONCLUSION Proteinuria in renal transplants can be differentiated into glomerular and tubular types based on molecular weight. Glomerular proteinuria is associated with significant increase in graft dysfunction and graft loss.
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Affiliation(s)
- S M Suhail
- Department of Renal Medicine Department of Clinical Research Duke-NUS Graduate Medical School, Singapore.
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Miles CD, Skorupa JY, Sandoz JP, Rigley TH, Nielsen KJ, Stevens RB. Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus. Clin Transplant 2010; 25:898-904. [DOI: 10.1111/j.1399-0012.2010.01353.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Liefeldt L, Budde K. Risk factors for cardiovascular disease in renal transplant recipients and strategies to minimize risk. Transpl Int 2010; 23:1191-204. [DOI: 10.1111/j.1432-2277.2010.01159.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids. Transplantation 2010; 89:1511-7. [PMID: 20386144 DOI: 10.1097/tp.0b013e3181db09e4] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND To define the role of mammalian target of rapamycin inhibitors in kidney transplantation, we compared efficacy and safety of two immunosuppressive regimens-a calcineurin inhibitor-free regimen with depletive induction versus a calcineurin inhibitor-based regimen. METHODS De novo renal allograft recipients were randomized before transplantation to receive sirolimus (SRL; n=71, group A) or tacrolimus (n=70, group B). All patients received mycophenolate mofetil and corticosteroids. In group A, patients received rabbit antithymocyte globulin induction. In group B, antithymocyte globulin therapy could be given in case of delayed graft function. The estimated glomerular filtration rate (GFR) (Nankivell's formula) at month 12 was the primary endpoint. RESULTS GFR showed no significant difference at month 12, with 56.1 in group A versus 58.4 mL/min/1.73 m in group B. In functioning grafts, renal function was significantly better in the SRL group, with higher GFR values at months 1, 2, 3, 6, and 9 (P<0.05). At month 12, patient survival and incidence of biopsy-proven rejection were not different between groups (95.8% vs. 97.1%, and 16.9% vs. 12.9%, respectively). However, proportion of graft loss was higher with SRL at months 6 and 12 (11.3% vs. 0.0%, P=0.004; 14.1% vs. 4.3%, P=0.044, respectively). Adverse events and premature withdrawals were more frequent with SRL (P<0.001 and P<0.05, respectively), whereas cytomegalovirus infections were more frequent with tacrolimus (P<0.001). CONCLUSION Patients treated with induction plus SRL, mycophenolate mofetil, and corticosteroids may obtain good renal function but have a higher risk of adverse events, drug withdrawal, and graft loss.
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Sirolimus and everolimus reduce albumin endocytosis in proximal tubule cells via an angiotensin II-dependent pathway. Transpl Immunol 2010; 23:125-32. [DOI: 10.1016/j.trim.2010.05.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 02/19/2010] [Accepted: 05/04/2010] [Indexed: 11/23/2022]
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Torres VE, Boletta A, Chapman A, Gattone V, Pei Y, Qian Q, Wallace DP, Weimbs T, Wüthrich RP. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin J Am Soc Nephrol 2010; 5:1312-29. [PMID: 20498248 DOI: 10.2215/cjn.01360210] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.
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Affiliation(s)
- Vicente E Torres
- Division of Nephrology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
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Padiyar A, Bodziak KA, Hricik DE, Augustine JJ. Clinical predictors of proteinuria after conversion to sirolimus in kidney transplant recipients. Am J Transplant 2010; 10:310-4. [PMID: 20055793 DOI: 10.1111/j.1600-6143.2009.02940.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Proteinuria is an increasingly recognized effect of sirolimus (SRL) therapy in kidney transplant recipients. Predictors of proteinuria after conversion to SRL are not well described, and in particular the risk in African-American (AA) kidney recipients is unknown. We sought to analyze risk factors for proteinuria with SRL therapy in a cohort of 39 patients (44% AA) converted from tacrolimus to SRL at a mean time of 4 months posttransplantation. Patients were maintained on therapy with mycophenolate mofetil while most patients underwent early steroid withdrawal. Urinary protein to creatinine ratio (Up/cr) at a mean of 14 months postconversion increased to > or =500 mg/g in 65% of AAs versus 14% of non-AAs (p = 0.001). Mean arterial blood pressure at the time of conversion and pretransplant proteinuric kidney disease were also predictors of proteinuria after SRL conversion. In conclusion, AAs appear to be at high risk for proteinuria and should be monitored closely after conversion to SRL in calcineurin inhibitor sparing protocols.
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Affiliation(s)
- A Padiyar
- Division of Nephrology and Hypertension, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA
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Lee PC, Lee CY, Hu RH, Lo C, Tsai MK, Lee PH. Intrarenal vascular resistance parameters in kidney transplant patients receiving calcineurin inhibitor-based or sirolimus-based regimens. Nephrol Dial Transplant 2009; 25:1675-80. [DOI: 10.1093/ndt/gfp716] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Outcomes With Conversion From Calcineurin Inhibitors to Sirolimus After Renal Transplantation in the Context of Steroid Withdrawal or Steroid Continuation. Transplantation 2009; 88:684-92. [DOI: 10.1097/tp.0b013e3181b27d44] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Pascual J. The use of everolimus in renal-transplant patients. Int J Nephrol Renovasc Dis 2009; 2:9-21. [PMID: 21694916 PMCID: PMC3108759 DOI: 10.2147/ijnrd.s4191] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2009] [Indexed: 11/23/2022] Open
Abstract
Despite advances in immunosuppressive therapy, long-term renal-transplantation outcomes have not significantly improved over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is an important cause of chronic allograft nephropathy (CAN), the major driver of long-term graft loss. Everolimus is a proliferation signal inhibitor with a mechanism of action that is distinct from CNIs. The efficacy and tolerability of everolimus in renal-transplant recipients have been established in a wide range of clinical trials. Importantly, synergism between everolimus and the CNI cyclosporine (CsA) permits CsA dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Currently, everolimus is being investigated in regimens where reduced exposure CNIs are used from the initial post-transplant period to improve renal function and prevent CAN. By inhibiting the proliferation of smooth muscle cells, everolimus may itself delay the progression or development of CAN. Although everolimus is associated with specific side effects, these can generally be managed. By targeting the main causes of short- and long-term graft loss, everolimus has a key role to play in renal transplantation, which is being explored further in a number of ongoing Phase III–IV trials.
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Affiliation(s)
- Julio Pascual
- Servicio de Nefrología, Hospital Ramón y Cajal, 28034 Madrid, Spain
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Stephany BR, Boumitri M, Budev M, Alao B, Poggio ED. Absence of Proteinuria Predicts Improvement in Renal Function After Conversion to Sirolimus-based Immunosuppressive Regimens in Lung Transplant Survivors With Chronic Kidney Disease. J Heart Lung Transplant 2009; 28:564-71. [DOI: 10.1016/j.healun.2009.03.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 03/04/2009] [Accepted: 03/05/2009] [Indexed: 10/20/2022] Open
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Ghiggeri GM, Bruschi M, Musante L, Candiano G, Boccardi C, Citti L, Rastaldi MP, Mangraviti S, Rosso G, Larti A, Rosati A, Urbani A, Gusmano R, Bertoni E, Salvadori M. Post‐transplant proteinuria associated with everolimus: Definition of main features with proteomics. Proteomics Clin Appl 2008; 2:1327-1337. [DOI: 10.1002/prca.200780162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Indexed: 01/11/2025]
Abstract
AbstractLittle is known on both the composition and mechanism(s) of proteinuria associated with the use of mTOR inhibitors, in particular of Everolimus (E). We characterized urinary proteins utilizing an integrated proteomics approach (quantitative essays, 2‐DE, MALDI‐TOF, Western blot) in 48 renal transplant recipients who were alternatively treated with E (n = 31) or with enteric coated mycophenolic acid (EC‐MPA) (n = 17). Twelve E patients (39%) developed high (>3 g/day) or intermediate proteinuria (1–3 g) compared to four (23%) of the EC‐MPA group. Urinary proteins (p<0.001), β2 microglobulin (p<0.001) and α1microglobulin (p<0.025) were higher in E than in EC‐MPA, appeared more rapidly and were inversely correlated with the day of treatment. Proteomics showed a marked increase of all urinary components in E and EC‐MPA patients, major changes involving typical components of glomerular damage (albumin, α1‐Zn glycoprotein, α2HS glycoprotein, leucin‐richα2‐glycoprotein) and specific bio‐markers for E (clusters of α1‐antitrypsin fragments and monoclonal λ chains). Finally, inter‐α‐trypsin‐inhibitor heavy chain H4 precursor was decreased in E and EC‐MPA urine compared to normal urine. In conclusion, E induced massive and generalized proteinuria of mixed glomerular and tubular origin that was correlated with the start of treatment and reached a nephrotic range in few cases. Specific urinary markers reflect renal alterations related to the transplant or specific alterations associated with the drug.
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mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev (Orlando) 2008; 22:125-30. [PMID: 18631865 DOI: 10.1016/j.trre.2007.12.001] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.
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Weintraub L, Li L, Kambham N, Alexander S, Concepcion W, Miller K, Wong C, Salvatierra O, Sarwal M. Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation. Pediatr Transplant 2008; 12:541-9. [PMID: 18564305 DOI: 10.1111/j.1399-3046.2007.00847.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 +/- 22 to 59.38 +/- 28.6 mL/min/1.73 m(2) (p = 0.04) at six months and 57.46 +/- 31.1 mL/min/1.73 m(2) (p = 0.02) at 12 months post-withdrawal. Forty-one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 +/- 1.0 to 1.71 +/- 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI-based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.
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Affiliation(s)
- Lauren Weintraub
- Department of Pediatrics, Stanford University, Stanford, CA, USA.
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41
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Sirolimus (Rapamycin) Induced Proteinuria in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplant. Transplantation 2008; 86:180-1. [DOI: 10.1097/tp.0b013e31817baa80] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hamdy AF, Bakr MA, Ghoneim MA. Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. J Am Soc Nephrol 2008; 19:1225-32. [PMID: 18337483 PMCID: PMC2396928 DOI: 10.1681/asn.2007091001] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Accepted: 12/09/2007] [Indexed: 12/13/2022] Open
Abstract
Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.
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Affiliation(s)
- Ahmed F Hamdy
- Urology and Nephrology Center, Mansoura University, Al-gomhoria Street, Mansoura, Egypt.
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Aliabadi AZ, Pohanka E, Seebacher G, Dunkler D, Kammerstätter D, Wolner E, Grimm M, Zuckermann AO. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant 2008; 8:854-61. [PMID: 18261172 DOI: 10.1111/j.1600-6143.2007.02142.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.
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Affiliation(s)
- A Z Aliabadi
- Department of Cardiothoracic Surgery, Medical University of Vienna, Währinger Gürtel, 18-20, A-1090 Vienna, Austria
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Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 2008; 22:1-15. [PMID: 18217899 DOI: 10.1111/j.1399-0012.2007.00739.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation. MATERIALS AND METHODS A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors' personal files were reviewed. RESULTS Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization. CONCLUSIONS Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.
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Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation 2008; 84:956-64. [PMID: 17989600 DOI: 10.1097/01.tp.0000284808.28353.2c] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND In kidney transplant recipients with alemtuzumab induction maintained on mycophenolate mofetil (MMF) immunosuppression, sirolimus (SRL) promotes significant expansion of circulating CD4+CD25high regulatory T cells (Treg). This might translate into more effective protection against chronic graft injury compared to cyclosporin A (CsA), which, in the same clinical setting, does not affect Treg. METHODS To assess this hypothesis, in the extension of a single-center, prospective, randomized, open, blind endpoint study aimed to assess the effect of low-dose SRL or CsA on circulating Treg, we compared the outcomes of renal transplant recipients on SRL (n=11) or CsA (n=10) by per-protocol biopsies and serial measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and 24-hour proteinuria over 30 months posttransplant. RESULTS Despite 4-fold higher CD4+CD25high Treg counts (22.1+/-12.2% vs. 5.7+/-4.2% of CD3+CD4+ T cells), SRL-treated patients, compared to CsA-treated patients, had a significantly higher tubular C4d staining score (1.1+/-0.6 vs. 0.2+/-0.3, P<0.01), with nonsignificant trends to higher chronic allograft damage index score (5.6+/-2.4 vs. 3.7+/-3.3), faster GFR (-2.92+/-0.33 vs. -0.28+/-0.44 ml/min/1.73 m2 per year), and RPF (-10.80+/-5.45 vs. -1.86+/-3.09 ml/min/1.73 m2 per year) decline, and more clinical proteinuria (n=6 vs. 4). There was no significant correlation between Treg counts and any considered outcome variable in the study group as a whole and within each cohort. CONCLUSIONS These data suggest that, despite enhanced Treg expression, low-dose SRL combined to alemtuzumab induction and MMF-based steroid-free maintenance therapy, does not appreciably protect renal transplant recipients from chronic allograft injury and dysfunction.
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Amer H, Fidler ME, Myslak M, Morales P, Kremers WK, Larson TS, Stegall MD, Cosio FG. Proteinuria after kidney transplantation, relationship to allograft histology and survival. Am J Transplant 2007; 7:2748-56. [PMID: 17941956 DOI: 10.1111/j.1600-6143.2007.02006.x] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria >150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In >84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria >1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p < 0.0001) and higher protein excretion (378 + 997 vs. 955 + 1986 mg/day, p < 0.0001). Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria >500. Thus, proteinuria, usually at low levels (<500 mg/day), is present in 45% of recipients at 1 year. However, and even low levels of proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.
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Affiliation(s)
- H Amer
- Department of Internal Medicine, Division of Nephrology and Hypertension and Transplant Center, Mayo Clinic College of Medicine, Rochester, MN, USA
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Büchler M, Caillard S, Barbier S, Thervet E, Toupance O, Mazouz H, Hurault de Ligny B, Le Meur Y, Thierry A, Villemain F, Heng AE, Moulin B, Morin MP, Noël C, Lebranchu Y. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant 2007; 7:2522-31. [PMID: 17868057 DOI: 10.1111/j.1600-6143.2007.01976.x] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 +/- 27 vs. 57 +/- 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 +/- 19 vs. 60 +/- 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.
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Affiliation(s)
- M Büchler
- Francois Rabelais University, Department of Nephrology and Clinical Immunology, Bretonneau Hospital, CHU Tours, France.
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