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Skalak HM, Haas K, Laub M, Mulloy LL. New onset diabetic ketoacidosis in a renal transplant recipient. Am J Med Sci 2025; 369:630-633. [PMID: 39214247 DOI: 10.1016/j.amjms.2024.08.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Post-transplant diabetes mellitus (PTDM) is a well-known solid organ transplant complication, which can be related to immunosuppressants, particularly tacrolimus. We report an unusual presentation of PTDM with diabetic ketoacidosis (DKA). This is unique as PTDM typically resembles Type 2 DM, whereas DKA is associated with Type 1 DM and has rarely been reported as a complication of tacrolimus. A 38-year-old African American male on LCP-tacrolimus presented four months post kidney transplant with vomiting, weakness, poor appetite, and polyuria. Labs demonstrated hyperglycemia, ketonuria, and high anion gap metabolic acidosis. He was nonobese and had no personal or family history of Type 2 DM. DKA was suspected to be secondary to tacrolimus-induced pancreatic beta cell damage worsened by supratherapeutic tacrolimus levels. Latent autoimmune diabetes in adults (LADA) was diagnosed when further testing showed insulinopenia, low C-peptide, and anti-glutamic acid decarboxylase (GAD) autoantibodies. He required 120-units of subcutaneous insulin daily. Our literature review revealed only 16 other tacrolimus-induced DKA cases. No cases reported anti-GAD positivity and most showed beta cell toxicity reversibility with tacrolimus tapering or substitution. Our patient was early post-transplant with leukocytopenia, so tacrolimus was not exchanged. This unusual PTDM case may have resulted from both autoimmune and tacrolimus-induced beta cell destruction. Physicians should be aware of new onset LADA post-transplantation and tacrolimus toxicity leading to DKA, even in patients without traditional risk factors. Anti-GAD antibody screening in patients on tacrolimus who develop PTDM may identify patients less likely to recover beta cell function with immunosuppression augmentation which requires careful monitoring.
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Affiliation(s)
| | | | - Melissa Laub
- Clinical Pharmacist, Solid Organ Transplant, Augusta University Medical Center Transplant Program, Augusta, Georgia
| | - Laura L Mulloy
- Professor and Chief Division of Nephrology, Medical College of Georgia at Augusta University, Augusta, Georgia.
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Chastagner D, Arnion H, Danthu C, Touré F, Picard N. Posttransplantation diabetes mellitus (PTDM): pharmacological aspects and genetic predispositions. Pharmacogenomics 2025; 25:707-718. [PMID: 40017426 PMCID: PMC11901360 DOI: 10.1080/14622416.2025.2470613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 02/19/2025] [Indexed: 03/01/2025] Open
Abstract
Posttransplantation diabetes mellitus (PTDM) is a form of diabetes developed after solid organ or stem cell transplantation. This condition shares physiopathological traits with type 2 diabetes, including insulin resistance and β-cells dysfunction and its prevalence varies significantly based on the diagnostic criteria used. Immunosuppressive drugs directly contribute to PTDM risk through intricate impacts on glucose regulation, insulin secretion, and inflammation. In addition, modifiable and non-modifiable environmental risk factors are associated with the onset of this condition. This review aims to provide a comprehensive overview of the multifactorial nature of PTDM in order to highlight candidate genes and variants for pharmacogenetic research. An extensive literature search was conducted to identify studies on pharmacological and genetic factors influencing PTDM development. This review stresses the importance of understanding these interactions for improving PTDM management and underscores the need for further research to refine preventive approaches, ultimately enhancing patient outcomes post-transplantation.
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Affiliation(s)
- Dorian Chastagner
- Inserm, Pharmacology & Transplantation, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
| | - Hélène Arnion
- Inserm, Pharmacology & Transplantation, Limoges, France
- Univ. Limoges, Pharmacology & Transplantation, Faculty of Pharmacy, Limoges, France
| | - Clément Danthu
- Department of Nephrology, Dialysis and Transplantation, CHU Limoges, Limoges, France
| | - Fatouma Touré
- Department of Nephrology, Dialysis and Transplantation, CHU Limoges, Limoges, France
| | - Nicolas Picard
- Inserm, Pharmacology & Transplantation, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France
- Univ. Limoges, Pharmacology & Transplantation, Faculty of Pharmacy, Limoges, France
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Kanbay M, Siriopol D, Guldan M, Ozbek L, Topcu AU, Siriopol I, Tuttle K. Prognostic impact of post-transplant diabetes mellitus in kidney allograft recipients: a meta-analysis. Nephrol Dial Transplant 2025; 40:554-576. [PMID: 39134508 PMCID: PMC11879034 DOI: 10.1093/ndt/gfae185] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Post-transplant diabetes mellitus (PTDM) is a complex condition arising from various factors including immunosuppressive medications, insulin resistance, impaired insulin secretion and inflammatory processes. Its impact on patient and graft survival is a significant concern in kidney transplant recipients. PTDM's impact on kidney transplant recipients, including patient and graft survival and cardiovascular mortality, is a significant concern, given conflicting findings in previous studies. This meta-analysis was imperative not only to incorporate emerging evidence but also to delve into cause-specific mortality considerations. We aimed to comprehensively evaluate the association between PTDM and clinical outcomes, including all-cause and cardiovascular mortality, sepsis-related mortality, malignancy-related mortality and graft loss, in kidney transplant recipients. METHODS PubMed, Ovid/Medline, Web of Science, Scopus and Cochrane Library databases were screened and studies evaluating the effect of PTDM on all-cause mortality, cardiovascular mortality, sepsis-related mortality, malignancy-related mortality and overall graft loss in adult kidney transplant recipients were included. RESULTS Fifty-three studies, encompassing a total of 138 917 patients, evaluating the association between PTDM and clinical outcomes were included. Our analysis revealed a significant increase in all-cause mortality [risk ratio (RR) 1.70, 95% confidence interval (CI) 1.53 to 1.89, P < .001] and cardiovascular mortality (RR 1.86, 95% CI 1.36 to 2.54, P < .001) among individuals with PTDM. Moreover, PTDM was associated with a higher risk of sepsis-related mortality (RR 1.96, 95% CI 1.51 to 2.54, P < .001) but showed no significant association with malignancy-related mortality (RR 1.20, 95% CI 0.76 to 1.88). Additionally, PTDM was linked to an increased risk of overall graft failure (RR 1.33, 95% CI 1.16 to 1.54, P < .001). CONCLUSION These findings underscore the importance of comprehensive management strategies and the need for research targeting PTDM to improve outcomes in kidney transplant recipients.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Dimitrie Siriopol
- Nephrology Department, “Sf. Ioan cel Nou” County Hospital, Suceava, Romania
- “Stefan cel Mare” University, Suceava, Romania
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ahmet U Topcu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ianis Siriopol
- Anaesthesia and Intensive Care Department, “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Katherine Tuttle
- Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, USA
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Kanbay M, Copur S, Topçu AU, Guldan M, Ozbek L, Gaipov A, Ferro C, Cozzolino M, Cherney DZI, Tuttle KR. An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management. Diabetes Obes Metab 2024; 26:2531-2545. [PMID: 38558257 DOI: 10.1111/dom.15575] [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: 01/25/2024] [Revised: 03/09/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - A Umur Topçu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Charles Ferro
- Department of Nephrology, University Hospitals Birmingham and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Katherine R Tuttle
- Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
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Granata S, Mercuri S, Troise D, Gesualdo L, Stallone G, Zaza G. mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation. Front Med (Lausanne) 2023; 10:1168967. [PMID: 37250653 PMCID: PMC10213242 DOI: 10.3389/fmed.2023.1168967] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.
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Affiliation(s)
- Simona Granata
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Sharif A. Interventions Against Posttransplantation Diabetes: A Scientific Rationale for Treatment Hierarchy Based on Literature Review. Transplantation 2022; 106:2301-2313. [PMID: 35696695 DOI: 10.1097/tp.0000000000004198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.
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Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Vranic G, Cooper M. But Why Weight: Understanding the Implications of Obesity in Kidney Transplant. Semin Nephrol 2021; 41:380-391. [PMID: 34715967 DOI: 10.1016/j.semnephrol.2021.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Obesity is increasing in prevalence among candidates for kidney transplant. Understanding the influence of obesity on candidate evaluation, surgical risk, peritransplant management, and post-transplant outcomes is critical to ensuring equitable access to transplant for this growing population.
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Affiliation(s)
- Gayle Vranic
- MedStar Georgetown Transplant Institute, Georgetown University, Washington, DC.
| | - Matthew Cooper
- MedStar Georgetown Transplant Institute, Georgetown University, Washington, DC
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8
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Veroux M, Mattone E, Cavallo M, Gioco R, Corona D, Volpicelli A, Veroux P. Obesity and bariatric surgery in kidney transplantation: A clinical review. World J Diabetes 2021; 12:1563-1575. [PMID: 34630908 PMCID: PMC8472502 DOI: 10.4239/wjd.v12.i9.1563] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/30/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
Obesity is increasing worldwide, and this has major implications in the setting of kidney transplantation. Patients with obesity may have limited access to transplantation and increased posttransplant morbidity and mortality. Most transplant centers incorporate interventions aiming to target obesity in kidney transplant candidates, including dietary education and lifestyle modifications. For those failing nutritional restriction and medical therapy, the use of bariatric surgery may increase the transplant candidacy of patients with obesity and end-stage renal disease (ESRD) and may potentially improve the immediate and late outcomes. Bariatric surgery in ESRD patients is associated with weight loss ranging from 29.8% to 72.8% excess weight loss, with reported mortality and morbidity rates of 2% and 7%, respectively. The most commonly performed bariatric surgical procedures in patients with ESRD and in transplant patients are laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass. However, the correct timing of bariatric surgery and the ideal type of surgery have yet to be determined, although pretransplant LSG seems to be associated with an acceptable risk-benefit profile. We review the impact of obesity on kidney transplant candidates and recipients and in potential living kidney donors, exploring the potential impact of bariatric surgery in addressing obesity in these populations, thereby potentially improving posttransplant outcomes.
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Affiliation(s)
- Massimiliano Veroux
- Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia, University of Catania, Catania 95123, Italy
| | - Edoardo Mattone
- Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania 95123, Italy
| | - Matteo Cavallo
- Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania 95123, Italy
| | - Rossella Gioco
- General Surgery Unit, University Hospital of Catania, Catania 95123, Italy
| | - Daniela Corona
- General Surgery Unit, University Hospital of Catania, Catania 95123, Italy
| | - Alessio Volpicelli
- General Surgery Unit, University Hospital of Catania, Catania 95123, Italy
| | - Pierfrancesco Veroux
- Department of General Surgery and Medical Specialities, University of Catania, Catania 95123, Italy
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Miner M, Elbaum M, Jawiarczyk-Przybyłowska A, Kubicka E. Endocrine complications of new anticancer therapies. POSTEP HIG MED DOSW 2021. [DOI: 10.5604/01.3001.0014.8121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Studying and analyzing of complex molecular mechanisms and immunological processes of
cancer enables oncology to introduce new cancer therapies. In the treatment of cancer, we
successively increase the use of targeted therapies with tyrosine kinase inhibitors and mTOR
inhibitors and immunotherapy using checkpoint inhibitors CTLA-4 (cytotoxic T-cell antigen-4)
and PD-1/PD-L1 (programmed death receptor 1/programmed death ligand 1). New anticancer
drugs gradually replace conventional chemotherapy and have already found application in the
treatment of many cancers, including thyroid cancer, hepatocellular carcinoma, non-small
cell lung cancer, kidney cancer, bladder cancer, melanoma, breast cancer, acute and chronic
myelogenous leukemia. The use of these drugs is less toxic than classical chemotherapy, but
it can cause gastrointestinal, cardiovascular, respiratory, skin and endocrine complications.
Most of the side effects of new cancer therapies are mild and moderate disorders, however
some might be severe and life-threatening. Endocrinopathies are one of the more common
side effects of these treatments. They can affect many endocrine glands (pituitary, thyroid,
parathyroid, adrenal, pancreas) and cause both transient and permanent disorders.
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Affiliation(s)
- Michał Miner
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
| | - Michał Elbaum
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
| | | | - Eliza Kubicka
- Katedra i Klinika Endokrynologii, Diabetologii i Leczenia Izotopami, Uniwersytet Medyczny im. Piastów Śląskich we Wrocławiu
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Kim HD, Chang JY, Chung BH, Kim CD, Lee SH, Kim YH, Yang CW. Effect of Everolimus with Low-Dose Tacrolimus on Development of New-Onset Diabetes After Transplantation and Allograft Function in Kidney Transplantation: A Multicenter, Open-Label, Randomized Trial. Ann Transplant 2021; 26:e927984. [PMID: 33479188 PMCID: PMC7836319 DOI: 10.12659/aot.927984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background This randomized controlled trial aimed to investigate the effect of everolimus (EVL) with low-dose tacrolimus (Tac) on the development of post-transplantation diabetes mellitus (PTDM) in kidney transplantation (KT). Material/Methods Seventy-seven kidney transplant patients from 4 transplant centers were included. Patients were randomized to the “EVL group” (n=38) and the “TAC group” (n=39). The target Tac trough level was 2 to 5 ng/mL in the EVL group and 5 to 10 ng/mL in the TAC group. Results The 1-year cumulative incidence of PTDM in all patients was 7.8%, and no difference was found between the 2 groups (P=0.0819). Insulin resistance measured with the homeostatic model assessment for insulin resistance showed a significant increase only in the TAC group (1.11 to 1.30, P=0.0492). Allograft rejection rate and estimated glomerular filtration rate (eGFR) follow-ups every 3 months were not significantly different between the 2 groups. However, the EVL group showed a significant increase in the mean eGFR at 9 months and 12 months after KT compared to the baseline value (P=0.0242 and 0.0491, respectively). The EVL group showed lower insulin resistance and higher allograft function in comparison to the TAC group. Conclusions EVL-based immunosuppressive therapy with lower Tac exposure could be a safer alternative for maintenance treatment.
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Affiliation(s)
- Hyung Duk Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji-Yeun Chang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Byung Ha Chung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chan-Duck Kim
- Department of Internal Medicine, Kyungpook National University School of Medicine, Deagu, South Korea
| | - Sang-Ho Lee
- Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, South Korea
| | - Yeong Hoon Kim
- Department of Internal Medicine, College of Medicine, Inje University, Pusan, South Korea
| | - Chul Woo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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11
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Hecking M, Sharif A, Eller K, Jenssen T. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics. Transpl Int 2021; 34:27-48. [PMID: 33135259 PMCID: PMC7839745 DOI: 10.1111/tri.13783] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
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Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine IIIClinical Division of Nephrology & DialysisMedical University of ViennaViennaAustria
| | - Adnan Sharif
- Department of Nephrology and TransplantationQueen Elizabeth HospitalBirminghamUK
| | - Kathrin Eller
- Clinical Division of NephrologyMedical University of GrazGrazAustria
| | - Trond Jenssen
- Department of Organ TransplantationOslo University HospitalRikshospitaletOsloNorway
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12
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Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
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Conte C, Maggiore U, Cappelli G, Ietto G, Lai Q, Salis P, Marchetti P, Piemonti L, Secchi A, Capocasale E, Caldara R. Management of metabolic alterations in adult kidney transplant recipients: A joint position statement of the Italian Society of Nephrology (SIN), the Italian Society for Organ Transplantation (SITO) and the Italian Diabetes Society (SID). Nutr Metab Cardiovasc Dis 2020; 30:1427-1441. [PMID: 32605884 DOI: 10.1016/j.numecd.2020.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 12/21/2022]
Abstract
Chronic metabolic alterations such as post-transplant diabetes mellitus (PTDM), dyslipidaemias and overweight/obesity significantly impact on kidney transplant (KT) outcomes. This joint position statement is based on the evidence on the management of metabolic alterations in KT recipients (KTRs) published after the release of the 2009 KDIGO clinical practice guideline for the care of KTRs. Members of the Italian Society of Nephrology (SIN), the Italian Society for Organ Transplantation (SITO) and the Italian Diabetes Society (SID) selected to represent professionals involved in the management of KTRs undertook a systematic review of the published evidence for the management of PTDM, dyslipidaemias and obesity in this setting. The aim of this work is to provide an updated review of the evidence on the prevention, diagnosis and treatment of metabolic alterations in KTRs, in order to support physicians, patients and the Healthcare System in the decision-making process when choosing among the various available options.
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Affiliation(s)
- Caterina Conte
- Università Vita-Salute San Raffaele, Milan, Italy; IRCCS San Raffaele Hospital, Milan, Italy.
| | - Umberto Maggiore
- Dipartimento di Medicina e Chirurgia, University Hospital of Parma, Parma, Italy.
| | - Gianni Cappelli
- University of Modena and Reggio Emilia, Azienda Ospedaliero - Universitaria Policlinico, Modena, Italy.
| | - Giuseppe Ietto
- Ospedale di Circolo e Fondazione Macchi, University of Insubria, Varese, Italy.
| | - Quirino Lai
- Hepato-Biliary Surgery and Organ Transplantation Unit, Sapienza University of Rome, Umberto I Polyclinic of Rome, Rome, Italy.
| | - Paola Salis
- IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy.
| | | | - Lorenzo Piemonti
- Università Vita-Salute San Raffaele, Milan, Italy; IRCCS San Raffaele Hospital, Milan, Italy; Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Antonio Secchi
- Università Vita-Salute San Raffaele, Milan, Italy; IRCCS San Raffaele Hospital, Milan, Italy.
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Risk Factors in and Long-Term Survival of Patients with Post-Transplantation Diabetes Mellitus: A Retrospective Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17124581. [PMID: 32630562 PMCID: PMC7345656 DOI: 10.3390/ijerph17124581] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 12/13/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) is associated with infection, cardiovascular morbidity, and mortality. A retrospective cohort study involving patients who underwent renal transplantation in a transplantation center in Taiwan from January 2000 to December 2018 was conducted to investigate the incidence and risk factors of PTDM and long-term patient and graft survival rates. High age (45-65 vs. <45 years, adjusted odds ratio (aOR) = 2.90, 95% confidence interval (CI) = 1.64-5.13, p < 0.001), high body mass index (>27 vs. <24 kg/m2, aOR = 5.35, 95% CI = 2.75-10.42, p < 0.001), and deceased organ donor (cadaveric vs. living, aOR = 2.01, 95% CI = 1.03-3.93, p = 0.04) were the three most important risk factors for the development of PTDM. The cumulative survival rate of patients and allografts was higher in patients without PTDM than in those with PTDM (p = 0.007 and 0.041, respectively). Concurrent use of calcineurin inhibitors and mammalian target of rapamycin inhibitors (mTORis) decreased the risk of PTDM (tacrolimus vs. tacrolimus with mTORi, aOR = 0.28, 95% CI = 0.14-0.55, p < 0.001). Investigating PTDM risk factors before and modifying immunosuppressant regimens after transplantation may effectively prevent PTDM development.
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15
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Blagosklonny MV. From causes of aging to death from COVID-19. Aging (Albany NY) 2020; 12:10004-10021. [PMID: 32534452 PMCID: PMC7346074 DOI: 10.18632/aging.103493] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/08/2020] [Indexed: 12/19/2022]
Abstract
COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.
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16
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Cohen E, Korah M, Callender G, Belfort de Aguiar R, Haakinson D. Metabolic Disorders with Kidney Transplant. Clin J Am Soc Nephrol 2020; 15:732-742. [PMID: 32284323 PMCID: PMC7269213 DOI: 10.2215/cjn.09310819] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient's ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant. Approximately 60% of nondiabetic patients experience hyperglycemia in the immediate post-transplant phase. Multiple risk factors have been identified related to development of new onset diabetes after transplant, and it is estimated that upward of 7%-30% of patients will develop new onset diabetes within the first year post-transplant. There are a number of medications studied in the kidney transplant population for diabetes management, and recent data and the risks and benefits of each regimen should be optimized. Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in parathyroid hormone levels. Parathyroidectomy and medical management are the options for treatment of secondary hyperparathyroidism, but there is no randomized, controlled trial providing clear recommendations for optimal management, and patient-specific factors should be considered. Obesity is the most common metabolic disorder affecting the transplant population in both the pre- and post-transplant phases of care. Not only does obesity have associations and interactions with comorbid illnesses, such as diabetes, dyslipidemia, and cardiovascular disease, all of which increase morbidity and mortality post-transplant, but it also is intimately inter-related with access to transplantation for patients with kidney failure. We review these metabolic disorders and their management, including data in patients with kidney transplants.
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Affiliation(s)
- Elizabeth Cohen
- Department of Pharmacy, Yale-New Haven Hospital, New Haven, Connecticut
| | - Maria Korah
- Yale University School of Medicine, New Haven, Connecticut
| | - Glenda Callender
- Department of Surgery, Section of Endocrine Surgery, Yale University, New Haven, Connecticut
| | | | - Danielle Haakinson
- Department of Surgery, Section of Transplant, Yale University, New Haven, Connecticut
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17
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Abstract
Solid organ transplantation (SOT) is an established therapeutic option for chronic disease resulting from end-stage organ dysfunction. Long-term use of immunosuppression is associated with post-transplantation diabetes mellitus (PTDM), placing patients at increased risk of infections, cardiovascular disease and mortality. The incidence rates for PTDM have varied from 10 to 40% between different studies. Diagnostic criteria have evolved over the years, as a greater understating of PTDM has been reached. There are differences in pathophysiology and clinical course of type 2 diabetes and PTDM. Hence, managing this condition can be a challenge for a diabetes physician, as there are several factors to consider when tailoring therapy for post-transplant patients to achieve better glycaemic as well as long-term transplant outcomes. This article is a detailed review of PTDM, examining the pathogenesis, diagnostic criteria and management in light of the current evidence. The therapeutic options are discussed in the context of their safety and potential drug-drug interactions with immunosuppressive agents.
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Affiliation(s)
| | - Kathryn Biddle
- St George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Shazli Azmi
- Manchester University NHS Foundation Trust, Manchester, UK
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18
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Yeh H, Lin C, Li YR, Yen CL, Lee CC, Chen JS, Chen KH, Tian YC, Liu PH, Hsiao CC. Temporal trends of incident diabetes mellitus and subsequent outcomes in patients receiving kidney transplantation: a national cohort study in Taiwan. Diabetol Metab Syndr 2020; 12:34. [PMID: 32368254 PMCID: PMC7189729 DOI: 10.1186/s13098-020-00541-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 04/13/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Allograft kidney transplantation has become a treatment of choice for patients with end-stage renal disease (ESRD), and post-transplant diabetes mellitus (PTDM) has been associated with impaired patient and graft survival. Taiwan has the highest incidence and prevalence rates of ESRD with many recipients and candidates of kidney transplantation. However, information about the epidemiologic features of PTDM in Taiwan is incomplete. Therefore, we aimed to investigate the prevalence and incidence of PTDM with subsequent patient and graft outcomes. METHODS Using the Taiwan National Health Insurance Research Database (NHIRD), 3663 kidney recipients between 1997 and 2011 were enrolled. We calculated the cumulative incidences of diabetes mellitus (DM) after transplantation. Cox proportional hazards model with competing risk analysis was used to calculate the hazard ratio (HR) and 95% confidence intervals (CI) between three targeted groups (DM, PTDM, non-DM). The outcomes of primary interest were the occurrence of graft failure excluding death with functioning graft, all-cause mortality, death with functioning graft and major adverse cardiovascular events (MACE) including myocardial infarction (MI), cerebrovascular accident (CVA) and congestive heart failure (CHF). Subgroup analysis for graft failure excluding death with functioning graft, MACE and all-cause mortality was performed, and interaction between PTDM and recipient age was examined. RESULTS Of 3663 kidney transplant recipients, 531 (14%) had pre-existing DM and 631 (17%) developed PTDM. Compared with non-DM group, the PTDM and DM groups exhibited higher risk of graft failure excluding death with functioning graft (PTDM: HR 1.65, 95% CI 1.47-1.85; DM: HR 1.33, 95% CI 1.18-1.50), MACE (PTDM: HR 1.51, 95% CI 1.31-1.74; DM: HR 1.64, 95% CI 1.41-1.9), all-cause mortality (PTDM: HR 1.79, 95% CI 1.59-2.01; DM: HR 2.03, 95% CI 1.81-2.18), and death with functioning graft (PTDM: HR 1.94, 95% CI 1.71-2.20; DM: HR 1.94, 95% CI 1.71-2.21). Both PTDM and DM groups had increased cardiovascular disease-related mortality (PTDM: HR 2.14, 95% CI 1.43-3.20, p < 0.001; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.002), cancer-related mortality (PTDM: HR 1.56, 95% CI 1.18-2.07, p = 0.002; DM: HR 1.89, 95% CI 1.25-2.86, p = 0.027), and infection-related mortality (PTDM: HR 1.47, 95% CI 1.14-1.90, p = 0.003; DM: HR 2.25, 95% CI 1.77-2.84, p < 0.001) compared with non-DM group. The subgroup analyses showed that the add-on risks of MACE and mortality from PTDM were mainly observed in patients who were younger and those without associated comorbidities including atrial fibrillation, cirrhosis, CHF, and MI. Age significantly modified the association between PTDM and MACE (pinteraction < 0.01) with higher risk in recipients with PTDM aged younger than 55 years (adjusted HR 1.64, 95% CI 1.40-1.92, p < 0.001). A trend (pinteraction = 0.06) of age-modifying effect on the association between PTDM and all-cause mortality was also noted with higher risk in recipients with PTDM aged younger than 55 years. CONCLUSIONS In the present population-based study, the incidence of PTDM peaked within the first year after kidney transplantation. PTDM negatively impacted graft and patient outcomes. The magnitude of cardiovascular and survival disadvantages from PTDM were more pronounced in recipients aged less than 55 years. Further trials to improve prediction of PTDM and to prevent PTDM are warranted.
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Affiliation(s)
- Hsuan Yeh
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chihung Lin
- Center for Artificial Intelligence in Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yan-Rong Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chieh-Li Yen
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chia Lee
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jung-Sheng Chen
- Center for Artificial Intelligence in Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Kuan-Hsing Chen
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ya-Chun Tian
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Pi-Hua Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chung Hsiao
- Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Nephrology, New Taipei Municipal TuCheng Hospital, New Taipei, Taiwan
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Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY) 2019; 11:8048-8067. [PMID: 31586989 PMCID: PMC6814615 DOI: 10.18632/aging.102355] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/03/2019] [Indexed: 12/31/2022]
Abstract
From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.
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20
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Fasting and rapamycin: diabetes versus benevolent glucose intolerance. Cell Death Dis 2019; 10:607. [PMID: 31406105 PMCID: PMC6690951 DOI: 10.1038/s41419-019-1822-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 07/17/2019] [Indexed: 02/06/2023]
Abstract
Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.
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Unveiling the Role of DNA Methylation in Kidney Transplantation: Novel Perspectives toward Biomarker Identification. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1602539. [PMID: 30766879 PMCID: PMC6350635 DOI: 10.1155/2019/1602539] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 12/30/2018] [Indexed: 12/13/2022]
Abstract
The burden of chronic kidney disease is dramatically rising, making it a major public health concern worldwide. Kidney transplantation is now the best treatment for patients with end-stage renal disease. Although kidney transplantation may improve survival and quality of life, its long-term results are hampered by immune- and/or non-immune-mediated complications. Thus, the identification of transplanted patients with a higher risk of posttransplant complications has become a big challenge for public health. However, current biomarkers of posttransplant complications have a poor predictive value, rising the need to explore novel approaches for the management of transplant patient. In this review we summarize the emerging literature about DNA methylation in kidney transplant complications, in order to highlight its perspectives toward biomarker identification. In the forthcoming future the monitoring of DNA methylation in kidney transplant patients could become a plausible strategy toward the prevention and/or treatment of kidney transplant complications.
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22
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Conte C, Secchi A. Post-transplantation diabetes in kidney transplant recipients: an update on management and prevention. Acta Diabetol 2018; 55:763-779. [PMID: 29619563 DOI: 10.1007/s00592-018-1137-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 03/26/2018] [Indexed: 12/14/2022]
Abstract
Post-transplantation diabetes mellitus (PTDM) may severely impact both short- and long-term outcomes of kidney transplant recipients in terms of graft and patient survival. However, PTDM often goes undiagnosed is underestimated or poorly managed. A diagnosis of PTDM should be delayed until the patient is on stable maintenance doses of immunosuppressive drugs, with stable kidney graft function and in the absence of acute infections. Risk factors for PTDM should be assessed during the pre-transplant evaluation period, in order to reduce the likelihood of developing diabetes. The oral glucose tolerance test is considered as the gold standard for diagnosing PTDM, whereas HbA1c is not reliable during the first months after transplantation. Glycaemic targets should be individualised, and comorbidities such as dyslipidaemia and hypertension should be treated with drugs that have the least possible impact on glucose metabolism, at doses that do not interact with immunosuppressants. While insulin is the preferred agent for treating inpatient hyperglycaemia in the immediate post-transplantation period, little evidence is available to guide therapeutic choices in the management of PTDM. Metformin and incretins may offer some advantage over other glucose-lowering agents, particularly with respect to risk of hypoglycaemia and weight gain. Tailoring immunosuppressive regimens may be of help, although maintenance of good kidney function should be prioritised over prevention/treatment of PTDM. The aim of this narrative review is to provide an overview of the available evidence on management and prevention of PTDM, with a focus on the available therapeutic options.
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Affiliation(s)
- Caterina Conte
- I.R.C.C.S. Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy.
| | - Antonio Secchi
- I.R.C.C.S. Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Via Olgettina 58, 20132, Milan, Italy
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23
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Song JL, Li M, Yan LN, Yang JY, Yang J, Jiang L. Higher tacrolimus blood concentration is related to increased risk of post-transplantation diabetes mellitus after living donor liver transplantation. Int J Surg 2018; 51:17-23. [PMID: 29360611 DOI: 10.1016/j.ijsu.2017.12.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/03/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS To investigate the association between tacrolimus (TAC) blood concentration and the risk of post-transplantation diabetes mellitus (PTDM) development after living donor liver transplantation (LDLT). METHODS This study reviewed the clinical data of 158 adult LDLT recipients. A cut-off of mean trough concentration of TAC (cTAC) value at the sixth month postoperatively was identified using a receptor operating characteristic curve. Other clinical complications rates were compared between different cTAC groups. RESULTS Thirty-four (21.5%) recipients developed PTDM during follow-up period. Recipients with PTDM suffered lower 1-, 5- and 10-year overall survival rates (85.2%, 64.9%, and 55.6% vs 92.4%, 81.4%, and 79.1%, p < 0.05) and allograft survival rates (87.9%, 76.9%, and 65.9% vs 94.1%, 88.5%, and 86.0%, p < 0.05) than those without PTDM. The best cut-off value of mean cTAC was 5.9 ng/mL. Recipients with higher cTAC (>5.9 ng/mL) were more likely to develop hyperlipidemia (39.6% vs 21.9%, p < 0.05), cardio-cerebral events (7.5% vs1.0%, p < 0.05), and infections (37.7% vs19.0%, p < 0.05) than recipients exposed to low cTAC (≤5.9 ng/mL). However, the two groups showed no difference in the incidence of acute and chronic rejection. CONCLUSION Higher mean cTAC at the sixth month postoperatively is related to increased risk of PTDM in LDLT recipients.
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Affiliation(s)
- Jiu-Lin Song
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ming Li
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lu-Nan Yan
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yin Yang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Yang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li Jiang
- Liver Transplantation Center, Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China.
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24
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Bamgbola O. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab 2016; 7:110-27. [PMID: 27293540 PMCID: PMC4892400 DOI: 10.1177/2042018816641580] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Among other factors, sophistication of immunosuppressive (IS) regimen accounts for the remarkable success attained in the short- and medium-term solid organ transplant (SOT) survival. The use of steroids, mycophenolate mofetil and calcineurin inhibitors (CNI) have led to annual renal graft survival rates exceeding 90% in the last six decades. On the other hand, attrition rates of the allograft beyond the first year have remained unchanged. In addition, there is a persistent high cardiovascular (CV) mortality rate among transplant recipients with functioning grafts. These shortcomings are in part due to the metabolic effects of steroids, CNI and sirolimus (SRL), all of which are implicated in hypertension, new onset diabetes after transplant (NODAT), and dyslipidemia. In a bid to reduce the required amount of harmful maintenance agents, T-cell-depleting antibodies are increasingly used for induction therapy. The downsides to their use are greater incidence of opportunistic viral infections and malignancy. On the other hand, inadequate immunosuppression causes recurrent rejection episodes and therefore early-onset chronic allograft dysfunction. In addition to the adverse metabolic effects of the steroid rescue needed in these settings, the generated proinflammatory milieu may promote accelerated atherosclerotic disorders, thus setting up a vicious cycle. The recent availability of newer agent, belatacept holds a promise in reducing the incidence of metabolic disorders and hopefully its long-term CV consequences. Although therapeutic drug monitoring as applied to CNI may be helpful, pharmacodynamic tools are needed to promote a customized selection of IS agents that offer the most benefit to an individual without jeopardizing the allograft survival.
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Affiliation(s)
- Oluwatoyin Bamgbola
- State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA
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25
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Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients. Transplant Direct 2016; 2:e69. [PMID: 27500260 PMCID: PMC4946511 DOI: 10.1097/txd.0000000000000579] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/14/2016] [Indexed: 01/05/2023] Open
Abstract
Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients.
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26
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Shivaswamy V, Boerner B, Larsen J. Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. Endocr Rev 2016; 37:37-61. [PMID: 26650437 PMCID: PMC4740345 DOI: 10.1210/er.2015-1084] [Citation(s) in RCA: 215] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.
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Affiliation(s)
- Vijay Shivaswamy
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
| | - Brian Boerner
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
| | - Jennifer Larsen
- Division of Diabetes, Endocrinology, and Metabolism (V.S., B.B., J.L.), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198; and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105
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Chand S, McKnight AJ, Shabir S, Chan W, McCaughan JA, Maxwell AP, Harper L, Borrows R. Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation. BBA CLINICAL 2016; 5:41-5. [PMID: 27051588 PMCID: PMC4802392 DOI: 10.1016/j.bbacli.2015.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/07/2015] [Accepted: 12/17/2015] [Indexed: 12/13/2022]
Abstract
Introduction Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development. Methods One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously. Results Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8–63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4–52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08–0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1–45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04–1.0; p = 0.05. Conclusion This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs. General significance
Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases. This alters potential genotype:phenotype association. The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.
Oral glucose tolerance tests reduce time to NODAT diagnosis and missed cases Biochemical testing changes genotype:phenotype association mTOR signalling pathway may be involved in NODAT development
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Key Words
- ATF6, Activated transcription factor
- BMI, Body mass index
- GWAS, Genome-wide association study
- HLA, Human leucocyte antigen
- HNF4, Hepatocyte nuclear factor 4
- NODAT, New-onset diabetes after transplantation
- New-onset diabetes after transplantation
- PI3, Phospho-inositide 3-kinase
- PPARGC1α, Peroxisome proliferator-activated receptor gamma co-activator 1 alpha
- PPARy, Peroxisome proliferator-activated receptor gamma
- PRDM14, PR domain zinc protein 14
- SNP, Single nucleotide polymorphism
- mTOR
- mTOR, Mammalian target of rapamycin
- single nucleotide polymorphisms
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Affiliation(s)
- S Chand
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - A J McKnight
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - S Shabir
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - W Chan
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom
| | - J A McCaughan
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - A P Maxwell
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland
| | - L Harper
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
| | - R Borrows
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom
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Langsford D, Dwyer K. Dysglycemia after renal transplantation: Definition, pathogenesis, outcomes and implications for management. World J Diabetes 2015; 6:1132-51. [PMID: 26322159 PMCID: PMC4549664 DOI: 10.4239/wjd.v6.i10.1132] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 07/06/2015] [Accepted: 08/16/2015] [Indexed: 02/05/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is major complication following renal transplantation. It commonly develops within 3-6 mo post-transplantation. The development of NODAT is associated with significant increase in risk of major cardiovascular events and cardiovascular death. Other dysglycemic states, such as impaired glucose tolerance are also associated with increasing risk of cardiovascular events. The pathogenesis of these dysglycemic states is complex. Older recipient age is a consistent major risk factor and the impact of calcineurin inhibitors and glucocorticoids has been well described. Glucocorticoids likely cause insulin resistance and calcineurin inhibitors likely cause β-cell toxicity. The impact of transplantation in incretin hormones remains to be clarified. The oral glucose tolerance test remains the best diagnostic test but other tests may be validated as screening tests. Possibly, NODAT can be prevented by administering insulin early in patients identified as high risk for NODAT. Once NODAT has been diagnosed altering immunosuppression may be acceptable, but creates the difficulty of balancing immunological with metabolic risk. With regard to hypoglycemic use, metformin may be the best option. Further research is needed to better understand the pathogenesis, identify high risk patients and to improve management options given the significant increased risk of major cardiovascular events and death.
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Palepu S, Prasad GVR. New-onset diabetes mellitus after kidney transplantation: Current status and future directions. World J Diabetes 2015; 6:445-455. [PMID: 25897355 PMCID: PMC4398901 DOI: 10.4239/wjd.v6.i3.445] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 11/14/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
A diagnosis of new-onset diabetes after transplantation (NODAT) carries with it a threat to the renal allograft, as well as the same short- and long-term implications of type 2 diabetes seen in the general population. NODAT usually occurs early after transplantation, and is usually diagnosed according to general population guidelines. Non-modifiable risk factors for NODAT include advancing age, African American, Hispanic, or South Asian ethnicity, genetic background, a positive family history for diabetes mellitus, polycystic kidney disease, and previously diagnosed glucose intolerance. Modifiable risk factors for NODAT include obesity and the metabolic syndrome, hepatitis C virus and cytomegalovirus infection, corticosteroids, calcineurin inhibitor drugs (especially tacrolimus), and sirolimus. NODAT affects graft and patient survival, and increases the incidence of post-transplant cardiovascular disease. The incidence and impact of NODAT can be minimized through pre- and post-transplant screening to identify patients at higher risk, including by oral glucose tolerance tests, as well as multi-disciplinary care, lifestyle modification, and the use of modified immunosuppressive regimens coupled with glucose-lowering therapies including oral hypoglycemic agents and insulin. Since NODAT is a major cause of post-transplant morbidity and mortality, measures to reduce its incidence and impact have the potential to greatly improve overall transplant success.
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Sharif A, Hecking M, de Vries APJ, Porrini E, Hornum M, Rasoul-Rockenschaub S, Krebs G, Berlakovich M, Kautzky-Willer A, Schernthaner G, Marchetti P, Pacini G, Ojo A, Takahara S, Larsen JL, Budde K, Eller K, Pascual J, Jardine A, Bakker SJL, Valderhaug TG, Jenssen TG, Cohney S, Säemann MD. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant 2014; 14:1992-2000. [PMID: 25307034 PMCID: PMC4374739 DOI: 10.1111/ajt.12850] [Citation(s) in RCA: 385] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 05/21/2014] [Accepted: 05/26/2014] [Indexed: 01/25/2023]
Abstract
A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.
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Affiliation(s)
- A. Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Birmingham, UK,Corresponding author: Adnan Sharif,
| | - M. Hecking
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - A. P. J. de Vries
- Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - E. Porrini
- Center for Biomedical Research of the Canary Islands, CIBICAN, University of La Laguna, Tenerife, Spain
| | - M. Hornum
- Department of Nephrology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - G Krebs
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - M. Berlakovich
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - A. Kautzky-Willer
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - G. Schernthaner
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - P. Marchetti
- Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
| | - G. Pacini
- Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy
| | - A. Ojo
- Division of Nephrology, University of Michigan Health System, Ann Arbor, MI
| | - S. Takahara
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - J. L. Larsen
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE
| | - K. Budde
- Department of Nephrology, Charité University, Berlin, Germany
| | - K. Eller
- Clinical Division of Nephrology, Medical University of Graz, Graz, Austria
| | - J. Pascual
- Servicio de Nefrología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - A. Jardine
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - S. J. L. Bakker
- Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands
| | - T. G. Valderhaug
- Department of Endocrinology, Akershus University Hospital, Lorenskog, Norway
| | - T. G. Jenssen
- Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - S. Cohney
- Department of Nephrology, Royal Melbourne and Western Hospitals, Melbourne, Australia
| | - M. D. Säemann
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
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Li ZT, Huang HF, Zeng Z. Pathogenesis and management of FK506- and CsA-induced post-transplant diabetes mellitus: Similarities and differences. Shijie Huaren Xiaohua Zazhi 2014; 22:1093-1100. [DOI: 10.11569/wcjd.v22.i8.1093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tacrolimus (FK506) and cyclosporine (CsA) are clinically commonly used immunosuppressive agents, and both of them belong to calcineurin inhibitors. FK506 is more excellent in anti-rejection therapy. They are similar in pharmacological mechanism, but FK506 is more likely to induce post-transplant diabetes mellitus than CsA. This paper analyzes and compares the similarities and differences in the pathogenesis and management between FK506- and CsA-induced post-transplant diabetes mellitus.
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Welzl K, Kern G, Mayer G, Weinberger B, Säemann MD, Sturm G, Grubeck-Loebenstein B, Koppelstaetter C. Effect of different immunosuppressive drugs on immune cells from young and old healthy persons. Gerontology 2014; 60:229-38. [PMID: 24434865 DOI: 10.1159/000356020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Accepted: 09/16/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Life expectancy, as well as the average age of patients undergoing solid organ transplantation, increases constantly. Consequently, immunosuppressive therapy is no longer limited to young organ recipients. OBJECTIVE Here, we investigate how different types of immunosuppressive therapy, namely the calcineurin inhibitors cyclosporin A and tacrolimus, as well as the mTOR inhibitor rapamycin, affect the function of immune cells in young and elderly persons. METHODS Proliferation, cell viability, cytokine production (IL-2, IFN-γ), H2O2 production and telomere length of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMCs) of young (n = 13; median age 27 years) and old (n = 19; median age 71 years) healthy donors were analyzed. RESULTS The inhibition of proliferation was dampened in PBMCs from elderly donors, especially after incubation with rapamycin. All three immunosuppressive drugs inhibited the production of IL-2 equally well, whereas the production of IFN-γ was less well inhibited by rapamycin. Both calcineurin inhibitors increased H2O2 concentrations after stimulation with PHA and led to a shortening of telomeres in PBMCs from young and old individuals. Rapamycin had only minor effects on H2O2 production and telomere length. CONCLUSION Our results demonstrate that the effects of immunosuppressive drugs on PBMCs differ between young and elderly persons. Calcineurin inhibitors compared to rapamycin have a more pronounced prosenescence effect. These data indicate that specific treatment regimens for the elderly might therefore be considered.
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Affiliation(s)
- Kathrin Welzl
- Immunology Division, Research Institute of Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
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New onset of diabetes after transplantation - an overview of epidemiology, mechanism of development and diagnosis. Transpl Immunol 2013; 30:52-8. [PMID: 24184293 DOI: 10.1016/j.trim.2013.10.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 10/21/2013] [Accepted: 10/21/2013] [Indexed: 12/12/2022]
Abstract
New onset of diabetes after transplantation (NODAT) is a serious and common complication following solid organ transplantation. NODAT has been reported to occur in 2% to 53% of renal transplant recipients. Several risk factors are associated with NODAT, however the mechanisms underlying were unclear. Renal transplant recipients who develop NODAT are reported to be at increased risk of infections, cardiovascular events, graft loss and patient loss. It has been reported that the incidence of NODAT is high in the early transplant period due to the exposure to the high doses of corticosteroids, calcineurin inhibitors and the physical inactivity during that period. In addition to these risk factors the traditional risk factors also play a major role in developing NODAT. Early detection is crucial in the management and control of NODAT which can be achieved through pretransplant screening there by identifying high risk patients and implementing the measures to reduce the development of NODAT. In the present article we reviewed the literature on the epidemiology, risk factors, mechanisms involved and the diagnostic criteria in the development of NODAT. Development of diagnostic tools for the assessment of β-cell function and determination of the role of glycemic control would include future area of research.
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