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Du Q, Li T, Yi X, Song S, Kang J, Jiang Y. Prevalence of new-onset diabetes mellitus after kidney transplantation: a systematic review and meta-analysis. Acta Diabetol 2024; 61:809-829. [PMID: 38507083 DOI: 10.1007/s00592-024-02253-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/01/2024] [Indexed: 03/22/2024]
Abstract
AIMS Post-transplant diabetes is a prevalent and consequential complication following kidney transplantation, which significantly augments the risk of cardiovascular disease, graft loss, infection, and mortality, thereby profoundly impacting both graft and patient survival. However, the early stages of post-transplant diabetes often go unnoticed or receive inadequate management. Consequently, this study systematically assesses the incidence of new-onset diabetes after kidney transplantation with the aim to enhance medical staff awareness regarding post-transplantation diabetes and provide clinical management guidance. METHODS We conducted a comprehensive search across multiple databases including PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed until September 21, 2023. Data extraction was performed using standardized tables and meta-analysis was conducted using Stata 16.0 software. A random effects model was employed to estimate the combined prevalence along with its corresponding 95% confidence interval. The source of heterogeneity was explored using subgroup analysis and sensitivity analysis, while publication bias was assessed through funnel plot and Egger's test. This study has been registered with PROSPERO under the registration number CRD42023465768. RESULTS This meta-analysis comprised 39 studies with a total sample size of 16,584 patients. The prevalence of new-onset diabetes after transplantation was found to be 20% [95% CI (18.0, 22.0)]. Subgroup analyses were conducted based on age, gender, body mass index, family history of diabetes, type of kidney donor, immunosuppressive regimen, acute rejection episodes, hepatitis C infection status and cytomegalovirus infection. CONCLUSIONS The incidence of post-kidney transplantation diabetes is substantial, necessitating early implementation of preventive and control measures to mitigate its occurrence, enhance prognosis, and optimize patients' quality of life. CLINICAL TRIAL REGISTRATION PROSPERO: CRD42023465768.
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Affiliation(s)
- Qiufeng Du
- College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China
| | - Tao Li
- College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China
| | - Xiaodong Yi
- College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China
| | - Shuang Song
- College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China
| | - Jing Kang
- College of Nursing, Chengdu University of Traditional Chinese Medicine, No.37 Shi-er-qiao Road, Chengdu City, 610075, Sichuan Province, China
| | - Yunlan Jiang
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39 Shi-er-qiao Road, Chengdu City, 610072, Sichuan Province, China.
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Abdelrahman Z, Maxwell AP, McKnight AJ. Genetic and Epigenetic Associations with Post-Transplant Diabetes Mellitus. Genes (Basel) 2024; 15:503. [PMID: 38674437 PMCID: PMC11050138 DOI: 10.3390/genes15040503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance test (OGTT). The task of diagnosing PTDM continues to pose challenges, given the potential for diabetes to manifest at different time points after transplantation, thus demanding constant clinical vigilance and repeated testing. Interpreting HbA1c levels can be challenging after renal transplantation. Pre-transplant risk factors for PTDM include obesity, sedentary lifestyle, family history of diabetes, ethnicity (e.g., African-Caribbean or South Asian ancestry), and genetic risk factors. Risk factors for PTDM include immunosuppressive drugs, weight gain, hepatitis C, and cytomegalovirus infection. There is also emerging evidence that genetic and epigenetic variation in the organ transplant recipient may influence the risk of developing PTDM. This review outlines many known risk factors for PTDM and details some of the pathways, genetic variants, and epigenetic features associated with PTDM. Improved understanding of established and emerging risk factors may help identify people at risk of developing PTDM and may reduce the risk of developing PTDM or improve the management of this complication of organ transplantation.
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Affiliation(s)
- Zeinab Abdelrahman
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, UK
| | - Amy Jayne McKnight
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
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Xu S, Jiang Z, Hu N. Association between Genetic Polymorphisms and Risk of Kidney Posttransplant Diabetes Mellitus: A Systematic Review and Meta-Analysis. Int J Clin Pract 2022; 2022:7140024. [PMID: 35685576 PMCID: PMC9159121 DOI: 10.1155/2022/7140024] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/27/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES The purpose of this study was to clarify the role of genetic factors on posttransplant diabetes mellitus (PTDM) risk. METHODS Relevant publications were systematically retrieved from PubMed, EMBASE, and the Cochrane Library up to December 2020. Data from eligible case-control and cohort studies were extracted for qualitative and quantitative analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association between gene polymorphisms and PTDM in the quantitative meta-analysis. RESULTS A total of 43 eligible articles were identified, and 16 studies on 9 DNA variants from 8 genes were included in the meta-analysis. TCF7L2 rs7903146 was significantly associated with PTDM risk in 5 genetic models (OR (95% CI): allelic: 1.59 (1.17-2.16), P=0.003; dominant recessive: 1.62 (1.14, 2.31), P=0.007; recessive: 1.87 (1.18, 2.94), P=0.007; homozygote: 2.21 (1.23, 3.94), P=0.008; and heterozygote 1.50 (1.08, 2.10), P=0.017). KCNQ1 rs2237892 was significantly correlated with PTDM risk in 3 genetic models (allelic: 0.68 (0.58, 0.81), P < 0.001; dominant: 0.6 (049, 0.74), P < 0.001; and heterozygote: 0.61 (0.48, 0.76), P < 0.001). KCNJ11 rs5219 was significantly linked with PTDM in the recessive genetic model (1.59 (1.01, 2.50), P=0.047). No significant correlations of PTDM with TCF7L2 rs12255372, SLC30A8 rs13266634, PPARγ rs1801282, CDKN2A/B rs10811661, HHEX rs1111875, and IGF2BP2 rs4402960 polymorphisms were found. CONCLUSIONS The gene polymorphisms of TCF7L2 rs7903146, KCNQ1 rs2237892, and KCNJ11 rs5219 may predispose kidney transplant recipients to PTDM. Large sample size studies on diverse ethnic populations were warranted to confirm our findings.
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Affiliation(s)
- Shan Xu
- Department of Pharmacy, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, China
| | - Zhenwei Jiang
- Department of Pharmacy, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou, China
| | - Nan Hu
- Department of Pharmacy, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Changzhou, China
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Quach K, Abdelmasih M, Chen PX, Li Y, Famure O, Nash M, Prasad R, Perkins BA, Yip PM, Kim SJ. Vitamin D Levels and the Risk of Posttransplant Diabetes Mellitus After Kidney Transplantation. Prog Transplant 2021; 31:133-141. [PMID: 33789542 PMCID: PMC8182337 DOI: 10.1177/15269248211002796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Introduction: Given the burden of posttransplant diabetes mellitus and the high prevalence
of low vitamin D levels in kidney transplant recipients, it is reasonable to
consider vitamin D as a novel and potentially modifiable risk factor in this
patient population. Research question: To determine the association between 25- hydroxyvitamin D (25(OH)D) level and
posttransplant diabetes among kidney transplant recipients. Design: In a
multi-center cohort study of 442 patients who received a kidney transplant
between January 1, 2005 and December 31, 2010, serum samples within one-year
before transplant were analyzed for 25(OH)D levels. The association between
25(OH)D and posttransplant diabetes were examined in Cox proportional hazard
models. Results: The median 25(OH)D level was 66 nmol/L. The cumulative probability of
diabetes at 12-months by quartiles of 25(OH)D (< 42, 42 to 64.9, 65 to
94.9, and > 95 nmol/L) were 23.4%, 26.9%, 21.4%, and 15.6%, respectively.
Compared to the highest 25(OH)D quartile, hazard ratios (95% CI) for the
risk were 1.85 (1.03, 3.32), 2.01 (1.12, 3.60), 1.77 (0.96, 3.25) across the
first to third quartiles, respectively. The associations were accentuated in
a model restricted to patients on tacrolimus. When modeled as a continuous
variable, 25(OH)D levels were significantly associated with a higher risk of
diabetes (hazard ratio 1.06, 95% CI: 1.01, 1.13 per 10 nmol/L decrease). Discussion: Serum 25(OH)D was an independent predictor of posttransplant diabetes in
kidney transplant recipients. These results may inform the design of trials
using vitamin D to reduce the risk in kidney transplant recipients.
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Affiliation(s)
- Kevin Quach
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada
| | - Monica Abdelmasih
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada
| | - Pei Xuan Chen
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada
| | - Yanhong Li
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada
| | - Olusegun Famure
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada
| | - Michelle Nash
- Division of Nephrology, St. Michael's Hospital and 7938University of Toronto, Toronto, Ontario, Canada
| | - Ramesh Prasad
- Division of Nephrology, St. Michael's Hospital and 7938University of Toronto, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Division of Endocrinology, Universal Health Network and 7938University of Toronto, Toronto, Ontario, Canada.,Institute of Health Policy, Management and Evaluation, 7938University of Toronto, Toronto, Ontario, Canada
| | - Paul M Yip
- Laboratory Medicine and Pathobiology, University Health Network and 7938University of Toronto, Toronto, Ontario, Canada.,Division of Clinical Biochemistry, 7938University of Toronto, Toronto, Ontario, Canada
| | - S Joseph Kim
- Division of Nephrology and the Kidney Transplant Program, 7989University Health Network, Toronto, Ontario, Canada.,Division of Nephrology, St. Michael's Hospital and 7938University of Toronto, Toronto, Ontario, Canada.,Institute of Health Policy, Management and Evaluation, 7938University of Toronto, Toronto, Ontario, Canada
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Vitamin D Receptor and Vitamin D Binding Protein Gene Polymorphisms Are Associated with Renal Allograft Outcome. Nutrients 2021; 13:nu13041101. [PMID: 33801744 PMCID: PMC8067077 DOI: 10.3390/nu13041101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 11/17/2022] Open
Abstract
Vitamin D deficiency has adverse effects on renal allograft outcomes, and polymorphisms of genes encoding vitamin D-binding protein (VDBP) and vitamin D receptor (VDR) are defined to play a role in these conditions. The goal of the current investigation was to evaluate the connection between those polymorphisms with acute rejection, viral infection history, and recipients’ vitamin D status. In this study, 115 kidney transplant recipients and 100 healthy individuals were included. VDR polymorphisms including FokI (rs2228570), Apal (rs7975232), BsmI (rs1544410), as well as VDBP (rs7040) polymorphisms were studied using high resolution melting (PCR-HRM) analysis among the studied groups. The frequency of G allele in Apal rs7975232 polymorphism in the kidney transplant recipients was 0.63 times lower than healthy individuals (p = 0.026). Further, the G allele frequency in VDBP rs7040 polymorphism was significantly lower in patients with allograft rejection (p = 0.002). Considering the incidence of viral infection, significant differences were identified between the frequencies of VDR FokI (OR = 2.035; 95% CI 1.06–2.89, p = 0.030) and VDBP rs7040 (OR = 0.40; 95% CI 0.24–0.67, p < 0.001) T alleles in the studied groups. Moreover, the VDBP rs7040 GG genotype distribution was low in the recipients with a history of viral infection (p = 0.004). VDR (FokI) and VDBP (rs7040) alleles and their genotype distribution are significantly associated with allograft outcomes including allograft rejection and viral infection in the studied population.
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Zmonarski SC, Banasik M, Golebiowski T, Madziarska K, Mazanowska O, Myszka M, Zmonarska J, Letachowicz K, Dawiskiba T, Krajewska M. Toll-like 4 receptor (TLR4) expression on peripheral blood mononuclear cells in renal transplant recipients with pre-transplant chronic interstitial nephritis indicates patients at risk of graft deterioration. Transpl Immunol 2020; 62:101319. [PMID: 32693120 DOI: 10.1016/j.trim.2020.101319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 07/08/2020] [Accepted: 07/12/2020] [Indexed: 10/23/2022]
Abstract
Data binding the expression of Toll-like 4 receptor (TLR4ex), transplanted kidney function, and the cause of pre-transplant end-stage renal disease are scarcely available. OBJECTIVE To investigate the relationship between pre-transplant chronic interstitial nephritis (CIN), TLR4ex and transplanted kidney function. MATERIALS AND METHODS TLR4ex was measured in peripheral blood mononuclear cells of 43 CIN kidney transplant recipients. We compared TLR4ex among 33 patients with pre-transplant chronic non-infectious interstitial nephritis (NIN) and 10 patients with pre-transplant chronic pyelonephritis (Py). At the beginning (Day-0) TLR4ex, as well as concentrations of cyclosporin A (CyA) and tacrolimus (TAC) were determined. Both CIN and NIN patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Serum creatinine/glomerular filtration rate (sCr/EGFR) was assessed on Day-0 and after the follow-up (F-up). The magnitudes of sCr/EGFR change (ΔsCr/ΔEGFR) were evaluated. The treatment was maintained stable along the F-up period (median 11.9 months). RESULTS Day-0: in CIN with L-TLR4ex TAC was lower but sCr/EGFR were not different from H-TLR4ex; in Py TLR4ex and TAC were lower than in NIN with no difference in sCR/eGFR. After F-up: in CIN with L-TLR4ex sCR/EGFR and ΔsCr/ΔEGFR were worse than in H-TLR4ex; in Py sCR/EGFR and ΔsCr/ΔEGFR were worse than in NIN. The regression analysis points out prospective impact of Py and TLR4ex on sCR/eGFR and ΔsCr/ΔeGFR. CONCLUSION In CIN, both TLR4ex and Tac appear to be a useful positive predictor of the effectiveness of immunosuppression. Chronic pyelonephritis indirectly promotes faster progression of chronic transplanted kidney disease.
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Affiliation(s)
- Sławomir C Zmonarski
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Miroslaw Banasik
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Tomasz Golebiowski
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Katarzyna Madziarska
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Oktawia Mazanowska
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Marta Myszka
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Joanna Zmonarska
- Wroclaw Medical University, Faculty of Medicine, wyb. Ludwika Pasteura 1, 50-367 Wroclaw, Poland.
| | - Krzysztof Letachowicz
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Tomasz Dawiskiba
- Wroclaw Medical University, Department of Vascular, General and Transplant Surgery, Borowska 213 Str., 50-553 Wroclaw, Poland.
| | - Magdalena Krajewska
- Wroclaw Medical University, Department of Nephrology and Transplantation Medicine, Borowska 213 Str., 50-553 Wroclaw, Poland.
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Zmonarski SC, Madziarska K, Golebiowski T, Banasik M, Mazanowska O, Madziarski M, Krajewska M. Can the Toll-like receptors 4 expression in peripheral blood mononuclear cells help assess the effectiveness of immunosuppression and the chance of a future good renal transplant function? Transpl Immunol 2018; 53:43-50. [PMID: 30592973 DOI: 10.1016/j.trim.2018.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 12/24/2018] [Accepted: 12/24/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND A small percentage of peripheral blood mononuclear cells (PBMCs) circulating during the kidney transplantation (KT) period remain in the blood long after transplantation. A part of the PBMCs penetrates the graft. AIM To examine if the choice of immunosuppression may change TLR4ex and how TLR4ex affects the transplant function in the future. MATERIAL The study population-143 transplanted patients (pts) (55 females, 88 males), mean age on recruitment day 50.33 ± 12.8 years old, mean BMI 25.04 ± 4.18. 41 pts. experienced delayed graft function (DGF+). 55 pts. were treated with cyclosporine A (CsA) and 88 with tacrolimus (Tac). All were treated with mofetil mycophenolate (MMF). The PBMCs acquisition and starting point of the follow-up (TLR-day) was at least one month after KT. METHOD We investigated averaged mRNA expression of Toll-like receptors 4 (TLR4ex) in non-stimulated peripheral blood mononuclear cells with the use of real-time polymerase chain reaction. The KT pts. (All, Tac, CsA, DGF+) were divided by the respective median of their TLR4ex (lower: L-TLR4ex, higher: H-TLR4ex). Main clinical parameters and transplant biopsy files (if available) were assessed on TLR-day and post follow-up. RESULTS We found that TLR4ex was reduced for a long time in patients who experienced delayed graft function. L-TLR4ex had a higher proportion of DGF+ patients, and patients treated with CsA but lower of those treated with Tac than in H-TLR4ex. The amplitude of changes in renal function parameters (ΔEGFR%/ΔsCr/ΔsCr%) was clearly less favorable for L-TLR4ex. Tacrolimus expressed a stabilizing effect. Both the positive vasculitis score and chronic graft nephropathy were more frequent in the L-TLR4ex group. On TLR-day an association of renal function and Tac concentration with TLR4ex was clear only in the tacrolimus population. The TLR4ex was lower in patients with a future deterioration of the graft function. CONCLUSION In kidney transplant recipients the occurrence of DGF results in a long-term reduction of the averaged TLR4ex in PBMC. Tacrolimus exerts a clear, stabilizing, positive and dose-dependent effect on TLR4ex. An improvement in renal transplant function may be expected in KT patients with high TLR4ex. Evaluation of the averaged TLR4ex can be used to assess the efficacy of immunosuppression in the treatment with tacrolimus and to estimate the likelihood of deterioration in renal function.
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Affiliation(s)
- Slawomir C Zmonarski
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
| | - Katarzyna Madziarska
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland.
| | - Tomasz Golebiowski
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
| | - Miroslaw Banasik
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
| | - Oktawia Mazanowska
- Faculty of Medicine and Dentistry, Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
| | - Marcin Madziarski
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
| | - Magdalena Krajewska
- Dept. of Nephrology and Transplantation Medicine, Medical University Wroclaw, Poland
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Zhang X, Men T, Liu H, Li X, Wang J, Lv J. Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus. Transpl Immunol 2018; 49:39-42. [PMID: 29665413 DOI: 10.1016/j.trim.2018.04.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 03/31/2018] [Accepted: 04/04/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Post-transplantation diabetes mellitus (PTDM) is a serious metabolic complication after kidney transplantation. The aim of this study was to explore the association of clinical variables and five selected single nucleotide polymorphisms (SNPs) with PTDM in Chinese Han renal allograft recipients taking tacrolimus (TAC). METHODS A total of 129 non-diabetic, primary, Chinese Han renal allograft recipients treated with TAC were enrolled. Five SNPs (CYP3A5 rs776741, rs776746, rs15524, CYP24A1 rs2296241, and PPARG rs1801282) were genotyped and analyzed. RESULTS Among 129 recipients, 17 (13.2%) developed PTDM. Both univariate and multivariate analysis demonstrated that age over 50 years old and CYP24A1 rs2296241 A allele were independently correlated with the development of PTDM, while no significant differences was observed in TAC pharmacokinetics and CYP3A5, PPARG polymorphisms between two groups. CONCLUSIONS Patients with advanced age and CYP24A1 rs2296241 A allele had an increased risk of PTDM after kidney transplantation.
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Affiliation(s)
- Xiaoming Zhang
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan 250014, China
| | - Tongyi Men
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan 250014, China
| | - Haitao Liu
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan 250014, China
| | - Xianduo Li
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan 250014, China
| | - Jianning Wang
- Department of Urology, Qianfoshan Hospital Affiliated to Shandong University, 16766 Jingshi Road, Jinan 250014, China
| | - Jiaju Lv
- Department of Urology, Shandong Provincial Hospital, Shandong University, 324 Jingwuweiqi Road, Jinan 250021, China.
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Benson KA, Chand S, Maxwell AP, Smyth LJ, Kilner J, Borrows R, McKnight AJ. Design and implementation of a custom next generation sequencing panel for selected vitamin D associated genes. BMC Res Notes 2017; 10:348. [PMID: 28754147 PMCID: PMC5534126 DOI: 10.1186/s13104-017-2664-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 07/21/2017] [Indexed: 12/12/2022] Open
Abstract
Background Biologically active vitamin D has an important regulatory role within the genome. It binds the vitamin D receptor (VDR) in order to control the expression of a wide range of genes as well as interacting with the epigenome to modify chromatin and methylation status. Vitamin D deficiency is associated with several human diseases including end-stage renal disease. Methods This article describes the design and testing of a custom, targeted next generation sequencing (NGS) panel for selected vitamin D associated genes. Sequencing runs were used to determine the effectiveness of the panel for variant calling, to compare efficiency and data across different sequencers, and to perform representative, proof of principle association analyses. These analyses were underpowered for significance testing. Amplicons were designed in two pools (163 and 166 fragments respectively) and used to sequence two cohorts of renal transplant recipients on the Ion Personal Genome Machine (PGM)™ and Ion S5™ XL desktop sequencers. Results Coverage was provided for 43.8 kilobases across seven vitamin D associated genes (CYP24A1, CUBN, VDR, GC, NADSYN1, CYP27B1, CYP2R1) as well as 38 prioritised SNPs. Sequencing runs provided sufficient sequencing quality, data output and validated the effective library preparation and panel design. Conclusions This novel, custom-designed, validated panel provides a fast, cost effective, and specific approach for the analysis of vitamin D associated genes in a wide range of patient cohorts. This article does not report results from a controlled health-care intervention. Electronic supplementary material The online version of this article (doi:10.1186/s13104-017-2664-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Katherine Angela Benson
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, BT9 7AB, UK.
| | - Sourabh Chand
- Department of Renal Medicine, Royal Shrewsbury Hospital, Shropshire, UK
| | - Alexander Peter Maxwell
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, BT9 7AB, UK
| | - Laura Jane Smyth
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, BT9 7AB, UK
| | - Jill Kilner
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, BT9 7AB, UK
| | - Richard Borrows
- Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Amy Jayne McKnight
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, BT9 7AB, UK
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10
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Tarnowski M, Słuczanowska-Głabowska S, Pawlik A, Mazurek-Mochol M, Dembowska E. Genetic factors in pathogenesis of diabetes mellitus after kidney transplantation. Ther Clin Risk Manag 2017; 13:439-446. [PMID: 28435278 PMCID: PMC5388273 DOI: 10.2147/tcrm.s129327] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Posttransplant diabetes mellitus (PTDM) is one of the major metabolic complications after transplantation of solid organs including the kidney. This type of diabetes mellitus affects allograft survival, cardiovascular complications and overall patient survival. The modifiable risk factors that contribute to PTDM include obesity, some viral infections (eg, hepatitis C virus, cytomegalovirus) and especially immunosuppressive drugs including corticosteroids, tacrolimus, cyclosporine and sirolimus. Currently, predisposing genetic factors have been considered important in PTDM development. The commonly evaluated genetic determinants include genes encoding transcription factors, cytokines, chemokines, adipokines, ionic channels, glucose transporters, cytochrome P450 enzymes and other enzymes metabolizing drugs, drug transporters. Unfortunately, the results of studies are inconclusive and differ between populations. There is a need for large genome-wide association study to identify the genetic risk factors associated with PTDM development.
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Affiliation(s)
| | | | | | | | - Elżbieta Dembowska
- Department of Periodontology, Pomeranian Medical University, Szczecin, Poland
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11
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Pharmacogenetics of posttransplant diabetes mellitus. THE PHARMACOGENOMICS JOURNAL 2017; 17:209-221. [DOI: 10.1038/tpj.2017.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 12/04/2016] [Accepted: 01/09/2017] [Indexed: 02/08/2023]
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12
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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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Benson KA, Maxwell AP, McKnight AJ. A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation. PLoS One 2016; 11:e0147323. [PMID: 26789123 PMCID: PMC4720424 DOI: 10.1371/journal.pone.0147323] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 12/31/2015] [Indexed: 12/11/2022] Open
Abstract
PURPOSE New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations. METHODS Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes. RESULTS Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals). CONCLUSION Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.
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Affiliation(s)
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
- Regional Nephrology Unit, Belfast City Hospital, Belfast, United Kingdom
| | - Amy Jayne McKnight
- Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
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14
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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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Abstract
PURPOSE OF REVIEW Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. RECENT FINDINGS Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk. SUMMARY Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.
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Zhou TB, Jiang ZP, Huang MF, Su N. Association of vitamin D receptor Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the risk of chronic kidney disease. J Recept Signal Transduct Res 2015; 35:58-62. [PMID: 24898467 DOI: 10.3109/10799893.2014.926928] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of chronic kidney disease (CKD) from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism and the risk of CKD using meta-analysis method. The association studies were identified from PubMed and Cochrane Library on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Five reports were recruited into this meta-analysis for the association of VDR Fok1, TaqI and ApaI gene polymorphism with CKD susceptibility. In this meta-analysis, VDR Fok1, TaqI and ApaI gene polymorphism were not associated with CKD susceptibility for overall populations and in Caucasians. However, the Fok1 f allele, ff genotype and FF genotype were associated with the risk of CKD in Asians. In conclusion, VDR Fok1, TaqI and ApaI gene polymorphism were not associated with CKD risk in overall populations and in Caucasians. But, the Fok1 gene polymorphism was associated with the risk of CKD in Asians. However, more studies should be conducted to confirm it.
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Affiliation(s)
- Tian-Biao Zhou
- Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University , Guangzhou , China
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Veroux M, Tallarita T, Corona D, Sinagra N, Giaquinta A, Zerbo D, Guerrieri C, D'Assoro A, Cimino S, Veroux P. Conversion to sirolimus therapy in kidney transplant recipients with new onset diabetes mellitus after transplantation. Clin Dev Immunol 2013; 2013:496974. [PMID: 23762090 PMCID: PMC3671526 DOI: 10.1155/2013/496974] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 04/22/2013] [Accepted: 04/23/2013] [Indexed: 12/19/2022]
Abstract
New-onset diabetes mellitus after transplantation (NODAT) may complicate 2-50% of kidney transplantation, and it is associated with reduced graft and patient survivals. In this retrospective study, we applied a conversion protocol to sirolimus in a cohort of kidney transplant recipients with NODAT. Among 344 kidney transplant recipients, 29 patients developed a NODAT (6.6%) and continued with a reduced dose of calcineurin inhibitors (CNI) (8 patients, Group A) or were converted to sirolimus (SIR) (21 patients, Group B). NODAT resolved in 37.5% and in 80% patients in Group A and Group B, respectively. In Group A, patient and graft survivals were 100% and 75%, respectively, not significantly different from Group B (83.4% and 68%, resp., P = 0.847). Graft function improved after conversion to sirolimus therapy: serum creatinine was 1.8 ± 0.7 mg/dL at the time of conversion and 1.6 ± 0.4 mg/dL five years after conversion to sirolimus therapy (P < 0.05), while in the group of patients remaining with a reduced dose of CNI, serum creatinine was 1.7 ± 0.6 mg/dL at the time of conversion and 1.65 ± 0.6 mg/dL at five-year followup (P = 0.732). This study demonstrated that the conversion from CNI to SIR in patients could improve significantly the metabolic parameters of patients with NODAT, without increasing the risk of acute graft rejection.
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Affiliation(s)
- Massimiliano Veroux
- Vascular Surgery and Organ Transplant Unit, Department of Surgery Transplantation and Advanced Technologies, University Hospital of Catania, 95123 Catania, Italy.
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