|
1
|
Budhiraja P, Smith BH, Kukla A, Kline TL, Korfiatis P, Stegall MD, Jadlowiec CC, Cheungpasitporn W, Wadei HM, Kudva YC, Alajous S, Misra SS, Me HM, Rios IP, Chakkera HA. Clinical and Radiological Fusion: A New Frontier in Predicting Post-Transplant Diabetes Mellitus. Transpl Int 2025; 38:14377. [PMID: 40248509 PMCID: PMC12003133 DOI: 10.3389/ti.2025.14377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/24/2025] [Indexed: 04/19/2025]
Abstract
This study developed a predictive model for Post-Transplant Diabetes Mellitus (PTDM) by integrating clinical and radiological data to identify at-risk kidney transplant recipients. In a retrospective analysis across three Mayo Clinic sites, clinical metrics were combined with deep learning analysis of pre-transplant CT images, focusing on body composition parameters like adipose tissue and muscle mass instead of BMI or other biomarkers. Among 2,005 nondiabetic kidney recipients, 335 (16.7%) developed PTDM within the first year. PTDM patients were older, had higher BMIs, elevated triglycerides, and were more likely to be male and non-White. They exhibited lower skeletal muscle area, greater visceral adipose tissue (VAT), more intermuscular fat, and higher subcutaneous fat (all p < 0.001). Multivariable analysis identified age (OR: 1.05, 95% CI: 1.03-1.08, p < 0.0001), family diabetes history (OR: 1.55, CI: 1.14-2.09, p = 0.0061), White race (OR: 0.43, CI: 0.28-0.66, p < 0.0001), and VAT area (OR: 1.37, CI: 1.14-1.64, p = 0.0009) as predictors. The combined model achieved C-statistic of 0.724 (CI: 0.692-0.757), outperforming the clinical-only model (C-statistic 0.68). Patients with PTDM in the first year had higher mortality than those without PTDM. This model improves predictive precision, enabling accurate identification and intervention for at risk patients.
Collapse
Affiliation(s)
- Pooja Budhiraja
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Byron H. Smith
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Aleksandra Kukla
- Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Timothy L. Kline
- Department of Radiology, Mayo Clinic, Rochester, MN, United States
| | | | - Mark D. Stegall
- Department of Surgery, Mayo Clinic, Rochester, MN, United States
| | | | | | - Hani M. Wadei
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Yogish C. Kudva
- Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Salah Alajous
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Suman S. Misra
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Hay Me Me
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Ian P. Rios
- Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, United States
| | | |
Collapse
|
|
2
|
Macakova D, Zadrazil J, Karasek D, Kucerova V, Langova K, Cibickova L. Pulse wave parameters as a predictor of the development of post-transplant diabetes mellitus after kidney transplantation. BMC Nephrol 2025; 26:27. [PMID: 39819315 PMCID: PMC11736939 DOI: 10.1186/s12882-024-03938-8] [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: 09/26/2024] [Accepted: 12/30/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND Kidney transplantation is the preferred treatment for patients with end-stage renal disease, significantly preserving kidney function and patient quality of life. However, post-transplant diabetes mellitus (PTDM) is a common complication, occurring in approximately one-third of renal transplant recipients. This study aims to evaluate the role of pulse wave parameters in predicting PTDM and to identify other pre-transplant risk factors. METHODS This prospective cohort study included 105 patients on the kidney transplant waiting list from 2017 to 2022. Exclusion criteria included any pre-existing diabetes mellitus. Patients underwent physical examinations, laboratory analyses, and pulse wave analysis before transplantation and one year post-transplant. PTDM diagnosis followed International Consensus Guidelines. Data were analyzed using Wilcox test, Bonferroni correction, May-Whitney U-test, and Fisher's exact test, with p < 0.05 considered statistically significant. RESULTS Post-transplant, 21% of patients were diagnosed with PTDM, increasing to 35% 3months post-transplant and 43% at one year post-transplant. Significant findings included: Pre-transplat risk factors for developing PTDM: Proteinuria (p = 0.037, OR = 3.942) and perioperative hyperglycemia (p = 0.003, OR = 4.219 at 3 months; p = 0.001, OR = 4.571 at 1 year). Pulse wave parameters for developing PTDM: Pre-transplant Aortic PP > 45 mmHg (AUC = 0.757) and PWV > 8.5 m/s (AUC = 0.730) were strong predictors of the development of PTDM after 3 months (p < 0.0001). Moreover, we found significant improvements in aortic pulse pressure (Aortic PP) and pulse wave velocity (PWV) post-transplant (p < 0.0001). CONCLUSION Our study confirms that pulse wave parameters, such as Aortic PP and PWV, are significant predictors of PTDM in kidney transplant recipients (KTR). These findings support incorporating pulse wave analysis into routine pre-transplant evaluations to identify high-risk patients. Additionally, monitoring these parameters post-transplant may aid in early intervention and prevention of PTDM, ultimately improving patient outcomes. TRIAL REGISTRATION Ethical approval was obtained from the Ethics Committee of Medical faculty and University Hospital Olomouc (approval no. 94/15).
Collapse
Affiliation(s)
- Dominika Macakova
- 3rd Department of Internal Medicine, University Hospital Olomouc, Olomouc, Czech Republic.
| | - Josef Zadrazil
- 3rd Department of Internal Medicine, University Hospital Olomouc, Olomouc, Czech Republic
| | - David Karasek
- 3rd Department of Internal Medicine, University Hospital Olomouc, Olomouc, Czech Republic
| | - Veronika Kucerova
- Department of Clinical, Biochemistry University Hospital Olomouc, Olomouc, Czech Republic
| | - Katerina Langova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Lubica Cibickova
- 3rd Department of Internal Medicine, University Hospital Olomouc, Olomouc, Czech Republic
| |
Collapse
|
|
3
|
Le Ha K, Nguyen Van D, Do Manh H, Tran Thi D, Nguyen Trung K, Le Viet T, Nguyen Thi Thu H. Elevated Plasma High Sensitive C-Reactive Protein and Triglyceride/High-Density Lipoprotein Cholesterol Ratio are Risks Factors of Diabetes Progression in Prediabetes Patients After Kidney Transplant: A 3-Year Single-Center Study in Vietnam. Int J Gen Med 2024; 17:5095-5103. [PMID: 39526064 PMCID: PMC11550698 DOI: 10.2147/ijgm.s490561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Purpose Determination the rate of developing post-transplant diabetes mellitus (PTDM) in prediabetic patients and the relationship with plasma hs-CRP levels and TG/HDL-C ratio in patients after kidney transplantation from living donors followed for 3 years. Subjects and Methods A total of 206 post-transplant patients diagnosed with prediabetes by oral glucose tolerance test (OGTT) were included in the study. At the time of diagnosis of prediabetes, all patients were clinically examined, paraclinical tests were performed, plasma hs-CRP was quantified, and the TG/HDL-C ratio was determined. Patients are individualized and given a reasonable diet and exercise regimen. Patients had their fasting blood glucose measured monthly or had an OGTT every 3 months. Patients meeting the criteria for diagnosis of PTDM according to the American Diabetes Association (ADA)-2018 were collected during 3 years of follow-up. Results The study group had an average age of 39.46 ± 10.26 years old, including 74.8% males and 25.2% females. The rate of patients who had a development of PTDM from prediabetes was 29.6% (61/206 patients). BMI, plasma TG, HDL-C, hs-CRP, and TG/HDL-C ratio at the time of prediabetes diagnosis were factors related to the progression of PTDM, in which hs-CRP and TG/HDL-C ratio were good predictors (with AUC = 0.85 and 0.874, respectively; p < 0.001). Conclusion After 3 years of follow-up, nearly one-third of prediabetic patients developed PTDM post-living donor kidney transplantation. BMI, plasma TG, HDL-C, hs-CRP, and the TG/HDL-C ratio were linked to DM progression, with hs-CRP and TG/HDL-C being the strongest predictors.
Collapse
Affiliation(s)
- Khoa Le Ha
- Hanoi Medical University, Hanoi, Vietnam
| | - Duc Nguyen Van
- Organ Transplant Center, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Ha Do Manh
- Organ Transplant Center, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Doan Tran Thi
- Department of Metabolic Disorders and Cardiology, National Hospital of Endocrinology, Hanoi, Vietnam
| | - Kien Nguyen Trung
- Hematology and Blood Transfusion Center, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Thang Le Viet
- Organ Transplant Center, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Ha Nguyen Thi Thu
- Organ Transplant Center, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| |
Collapse
|
|
4
|
Diabetic Kidney Disease in Post-Transplant Diabetes Mellitus: Causes, Treatment and Outcomes. Biomedicines 2023; 11:biomedicines11020470. [PMID: 36831005 PMCID: PMC9953284 DOI: 10.3390/biomedicines11020470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/12/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023] Open
Abstract
Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug-drug interactions with immunosuppressive agents.
Collapse
|
|
5
|
Jadlowiec CC, Frasco P, Macdonough E, Wagler J, Das D, Budhiraja P, Mathur AK, Katariya N, Reddy K, Khamash H, Heilman R. Association of DGF and Early Readmissions on Outcomes Following Kidney Transplantation. Transpl Int 2022; 35:10849. [PMID: 36620699 PMCID: PMC9817097 DOI: 10.3389/ti.2022.10849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/15/2022] [Indexed: 12/24/2022]
Abstract
Concerns regarding outcomes and early resource utilization are potential deterrents to broader use of kidneys at risk for delayed graft function (DGF). We assessed outcomes specific to kidneys with DGF that required early readmission following transplant. Three groups were identified: 1) recipients with DGF not requiring readmission, 2) recipients with DGF having an isolated readmission, and 3) recipients with DGF requiring ≥2 readmissions. Most recipients either required a single readmission (26.8%, n = 247) or no readmission (56.1%, n = 517); 17.1% (n = 158), had ≥2 readmissions. Recipients requiring ≥2 readmissions were likely to be diabetic (53.8%, p = 0.04) and have longer dialysis vintage (p = 0.01). Duration of DGF was longer with increasing number of readmissions (p < 0.001). There were no differences in patient survival for those with DGF and 0, 1 and ≥2 readmissions (p = 0.13). Graft survival, however, was lower for those with ≥2 readmissions (p < 0.0001). This remained true when accounting for death-censored graft loss (p = 0.0012). Additional subgroup analysis was performed on mate kidneys with and without DGF and mate kidneys, both with DGF, with and without readmissions. For these subgroups, there were no differences in patient or graft survival. As a whole, patients with DGF have excellent outcomes, however, patients with DGF requiring ≥2 readmissions have lower graft survival. A better understanding of recipient variables contributing to multiple readmissions may allow for improvements in the utilization of DGF at-risk kidneys.
Collapse
Affiliation(s)
- Caroline C. Jadlowiec
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Phoenix, AZ, United States,*Correspondence: Caroline C. Jadlowiec,
| | - Peter Frasco
- Division of Anesthesiology, Mayo Clinic, Phoenix, AZ, United States
| | - Elizabeth Macdonough
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, United States
| | - Josiah Wagler
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Phoenix, AZ, United States
| | - Devika Das
- Division of Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Pooja Budhiraja
- Division of Nephrology, Mayo Clinic, Phoenix, AZ, United States
| | - Amit K. Mathur
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Phoenix, AZ, United States
| | - Nitin Katariya
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Phoenix, AZ, United States
| | - Kunam Reddy
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Phoenix, AZ, United States
| | - Hasan Khamash
- Division of Nephrology, Mayo Clinic, Phoenix, AZ, United States
| | - Raymond Heilman
- Division of Nephrology, Mayo Clinic, Phoenix, AZ, United States
| |
Collapse
|
|
6
|
Clinical outcomes of posttransplantation diabetes mellitus in kidney transplantation recipients: a nationwide population-based cohort study in Korea. Sci Rep 2022; 12:21632. [PMID: 36517524 PMCID: PMC9751267 DOI: 10.1038/s41598-022-25070-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/24/2022] [Indexed: 12/23/2022] Open
Abstract
Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after KT that causes graft failure and cardiovascular complications in kidney transplantation (KT) recipients. Using the national claim data of South Korea, 7612 KT recipients between 2009 and 2017 were analyzed. PTDM was defined as a consecutive 30-day prescription history of antidiabetic medication after KT. Among these patients, 24.7% were diagnosed with PTDM, and 51.9% were diagnosed within 6 months after KT. Compared to patients without PTDM, those with PTDM were older, more likely to be men, more likely to be diagnosed with hypertension and cardio-cerebrovascular disease, and experienced more rejection episodes requiring high-dose steroid treatment after KT. During the follow-up, 607 DCGFs, 230 DWGFs, 244 MACEs, and 260 all-cause mortality events occurred. Patients with PTDM showed a higher risk of DCGF (adjusted hazard ratio [aHR] 1.49; 95% confidence interval [CI] 1.22-1.82; P < 0.001) and MACEs (aHR 1.76; 95% CI 1.33-2.31; P < 0.001) than patients without PTDM. The risks for all clinical outcomes were higher in the insulin group than in the non-use insulin group. PTDM in KT recipients resulted in both worse allograft and patient outcomes represented by DCGF and MACE, especially in patients needing insulin treatment.
Collapse
|
|
7
|
Analysis of risk factors and establishment of a risk prediction model for post-transplant diabetes mellitus after kidney transplantation. Saudi Pharm J 2022; 30:1088-1094. [PMID: 36164572 PMCID: PMC9508626 DOI: 10.1016/j.jsps.2022.05.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/30/2022] [Indexed: 11/22/2022] Open
Abstract
Introduction Post-transplant diabetes mellitus (PTDM) is a known side effect in transplant recipients administered immunosuppressant drugs, such as tacrolimus. This study aimed to investigate the risk factors related to PTDM, and establish a risk prediction model for PTDM. In addition, we explored the effect of PTDM on the graft survival rate of kidney transplantation recipients. Methods Patients with pre-diabetes mellitus before kidney transplant were excluded, and 495 kidney transplant recipients were included in our study, who were assigned to the non-PTDM and PTDM groups. The cumulative incidence was calculated at 3 months, 6 months, 1 year, 2 years, and 3 years post-transplantation. Laboratory tests were performed and the tacrolimus concentration, clinical prognosis, and adverse reactions were analyzed. Furthermore, binary logistic regression analysis was used to identify the independent risk factors of PTDM. Results Age ≥ 45 years (adjusted odds ratio [aOR] 2.25, 95% confidence interval [CI] 1.14–3.92; P = 0.015), body mass index (BMI) > 25 kg/m2 (aOR 3.12, 95% CI 2.29–5.43, P < 0.001), tacrolimus concentration > 10 ng/mL during the first 3 months post-transplantation (aOR 2.46, 95%CI 1.41–7.38; P < 0.001), transient hyperglycemia (aOR 4.53, 95% CI 1.86–8.03; P < 0.001), delayed graft function (DGF) (aOR 1.31, 95% CI 1.05–2.39; P = 0.019) and acute rejection (aOR 2.16, 95% CI 1.79–4.69; P = 0.005) were identified as independent risk factors of PTDM. The PTDM risk prediction model was developed by including the above six risk factors, and the area under the receiver operating characteristic curve was 0.916 (95% CI 0.862–0.954, P < 0.001). Furthermore, the cumulative graft survival rate was significantly higher in the non- PTDM group than in the PTDM group. Conclusions Risk factors related to PTDM were age ≥ 45 years, BMI > 25 kg/m2, tacrolimus concentration > 10 ng/mL during the first 3 months post-transplantation, transient hyperglycemia, DGF and acute rejection.
Collapse
|
|
8
|
Singer J, Aouad LJ, Wyburn K, Gracey DM, Ying T, Chadban SJ. The Utility of Pre- and Post-Transplant Oral Glucose Tolerance Tests: Identifying Kidney Transplant Recipients With or at Risk of New Onset Diabetes After Transplant. Transpl Int 2022; 35:10078. [PMID: 35368638 PMCID: PMC8967957 DOI: 10.3389/ti.2022.10078] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/24/2022] [Indexed: 11/13/2022]
Abstract
Background: New onset diabetes after transplant (NODAT) is common in kidney transplant recipients (KTRs). Identifying patients at risk prior to transplant may enable strategies to mitigate NODAT, with a pre-transplant oral glucose tolerance test (OGTT) suggested by the KDIGO 2020 Guidelines for this purpose. Methods: We investigated the utility of pre- and post-transplant OGTTs to stratify risk and diagnose NODAT in a retrospective, single-centre cohort study of all non-diabetic KTRs transplanted between 2003 and 2018. Results: We identified 597 KTRs who performed a pre-transplant OGTT, of which 441 had their post-transplant glycaemic status determined by a clinical diagnosis of NODAT or OGTT. Pre-transplant dysglycaemia was identified in 28% of KTRs and was associated with increasing age (p < 0.001), BMI (p = 0.03), and peritoneal dialysis (p < 0.001). Post-transplant dysglycaemia was common with NODAT and impaired glucose tolerance (IGT) occurring in 143 (32%) and 121 (27%) patients, respectively. Pre-transplant IGT was strongly associated with NODAT development (OR 3.8, p < 0.001). Conclusion: A pre-transplant OGTT identified candidates at increased risk of post-transplant dysglycaemia and NODAT, as diagnosed by an OGTT. Robust prospective trials are needed to determine whether various interventions can reduce post-transplant risk for candidates with an abnormal pre-transplant OGTT.
Collapse
Affiliation(s)
- Julian Singer
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Leyla J Aouad
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Kate Wyburn
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - David M Gracey
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Tracey Ying
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Steven J Chadban
- Department of Renal Medicine, Kidney Centre, Level 2 Professor Marie Bashir Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
9
|
Kotha S, Lawendy B, Asim S, Gomes C, Yu J, Orchanian-Cheff A, Tomlinson G, Bhat M. Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients: Systematic review and meta-analysis. World J Transplant 2021; 11:432-442. [PMID: 34722172 PMCID: PMC8529944 DOI: 10.5500/wjt.v11.i10.432] [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: 06/20/2021] [Revised: 08/27/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease. Post-transplant diabetes mellitus (PTDM) is a common complication in solid organ transplant recipients, and significantly compromises long-term survival beyond a year.
AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.
METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus, 51242 on Cyclosporine and 3020 on Sirolimus. Random effects meta-analyses was used to calculate incidence.
RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus (OR = 1.4 95%CI: 1.0–2.0) and sirolimus (OR = 1.8; 95%CI: 1.5–2.2) than with Cyclosporine. The overall incidence of PTDM at years 2-3 was 17% for kidney, 19% for liver and 22% for heart. The risk factors for PTDM most frequently identified in the primary studies were age, body mass index, hepatitis C, and African American descent.
CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term (2-3 years post-transplant), whereas sirolimus exhibits higher diabetogenicity in the long-term (5-10 years post-transplant). This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.
Collapse
Affiliation(s)
- Sreelakshmi Kotha
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 7JD, United Kingdom
| | - Bishoy Lawendy
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Saira Asim
- Multi Organ Transplant Program, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Charlene Gomes
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Jeffrey Yu
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - Ani Orchanian-Cheff
- Department of Multi-Organ Transplantation, Toronto General Hospital, Toronto M5G 2C4, Canada
| | - George Tomlinson
- Dalla Lana School of Public Health, Department of Medicine, University Health Network - Toronto General Hospital, University of Toronto, Toronto M5G 2C4, Canada
| | - Mamatha Bhat
- Multi-organ Transplant, Toronto General Hospital, Toronto M5G 2C4, Canada
| |
Collapse
|
|
10
|
Malik RF, Jia Y, Mansour SG, Reese PP, Hall IE, Alasfar S, Doshi MD, Akalin E, Bromberg JS, Harhay MN, Mohan S, Muthukumar T, Schröppel B, Singh P, Weng FL, Thiessen Philbrook HR, Parikh CR. Post-transplant Diabetes Mellitus in Kidney Transplant Recipients: A Multicenter Study. KIDNEY360 2021; 2:1296-1307. [PMID: 35369651 PMCID: PMC8676388 DOI: 10.34067/kid.0000862021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023]
Abstract
Background De novo post-transplant diabetes mellitus (PTDM) is a common complication after kidney transplant (KT). Most recent studies are single center with various approaches to outcome ascertainment. Methods In a multicenter longitudinal cohort of 632 nondiabetic adult kidney recipients transplanted in 2010-2013, we ascertained outcomes through detailed chart review at 13 centers. We hypothesized that donor characteristics, such as sex, HCV infection, and kidney donor profile index (KDPI), and recipient characteristics, such as age, race, BMI, and increased HLA mismatches, would affect the development of PTDM among KT recipients. We defined PTDM as hemoglobin A1c ≥6.5%, pharmacological treatment for diabetes, or documentation of diabetes in electronic medical records. We assessed PTDM risk factors and evaluated for an independent time-updated association between PTDM and graft failure using regression. Results Mean recipient age was 52±14 years, 59% were male, 49% were Black. Cumulative PTDM incidence 5 years post-KT was 29% (186). Independent baseline PTDM risk factors included older recipient age (P<0.001) and higher BMI (P=0.006). PTDM was not associated with all-cause graft failure (adjusted hazard ratio (aHR), 1.10; 95% CI, 0.78 to 1.55), death-censored graft failure (aHR, 0.85; 95% CI, 0.53 to 1.37), or death (aHR, 1.31; 95% CI, 0.84 to 2.05) at median follow-up of 6 (interquartile range, 4.0-6.9) years post-KT. Induction and maintenance immunosuppression were not different between patients who did and did not develop PTDM. Conclusions PTDM occurred commonly, and higher baseline BMI was associated with PTDM. PTDM was not associated with graft failure or mortality during the 6-year follow-up, perhaps due to the short follow-up time.
Collapse
Affiliation(s)
- Rubab F. Malik
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yaqi Jia
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sherry G. Mansour
- Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut,Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Peter P. Reese
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania,Department of Biostatistics, Epidemiology & Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania,Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Isaac E. Hall
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Sami Alasfar
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mona D. Doshi
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Enver Akalin
- Kidney Transplant Program, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
| | - Jonathan S. Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland,Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Meera N. Harhay
- Department of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania,Department of Epidemiology and Biostatistics, Drexel University Dornsife School of Public Health, Philadelphia, Pennsylvania,Tower Health Transplant Institute, Tower Health System, West Reading, Pennsylvania
| | - Sumit Mohan
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York,Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, New York
| | - Thangamani Muthukumar
- Department of Medicine, Division of Nephrology and Hypertension, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York,Department of Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York
| | | | - Pooja Singh
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - Francis L. Weng
- Saint Barnabas Medical Center, RWJBarnabas Health, Livingston, New Jersey
| | | | - Chirag R. Parikh
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
11
|
Ahmed SH, Chowdhury TA, Hussain S, Syed A, Karamat A, Helmy A, Waqar S, Ali S, Dabhad A, Seal ST, Hodgkinson A, Azmi S, Ghouri N. Ramadan and Diabetes: A Narrative Review and Practice Update. Diabetes Ther 2020; 11:2477-2520. [PMID: 32909192 PMCID: PMC7480213 DOI: 10.1007/s13300-020-00886-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Indexed: 02/06/2023] Open
Abstract
Fasting in the Islamic month of Ramadan is obligatory for all sane, healthy adult Muslims. The length of the day varies significantly in temperate regions-typically lasting ≥ 18 h during peak summer in the UK. The synodic nature of the Islamic calendar means that Ramadan migrates across all four seasons over an approximately 33-year cycle. Despite valid exemptions, there is an intense desire to fast during this month, even among those who are considered to be at high risk, including many individuals with diabetes mellitus. In this review we explore the current scientific and clinical evidence on fasting in patients with diabetes mellitus, focussing on type 2 diabetes mellitus and type 1 diabetes mellitus, with brief reviews on pregnancy, pancreatic diabetes, bariatric surgery, the elderly population and current practice guidelines. We also make recommendations on the management of diabetes patients during the month of Ramadan. Many patients admit to a do-it-yourself approach to diabetes mellitus management during Ramadan, largely due to an under-appreciation of the risks and implications of the rigors of fasting on their health. Part of the issue may also lie with a healthcare professional's perceived inability to grasp the religious sensitivities of Muslims in relation to disease management. Thus, the pre-Ramadan assessment is crucial to ensure a safe Ramadan experience. Diabetes patients can be risk-stratified from low, medium to high or very high risk during the pre-Ramadan assessment and counselled accordingly. Those who are assessed to be at high to very high risk are advised not to fast. The current COVID-19 pandemic upgrades those in the high-risk category to very high risk; hence a significant number of diabetes patients may fall under the penumbra of the 'not to fast' advisory. We recognize that fasting is a personal choice and if a person chooses to fast despite advice to the contrary, he/she should be adequately supported and monitored closely during Ramadan and for a brief period thereafter. Current advancements in insulin delivery and glucose monitoring technologies are useful adjuncts to strategies for supporting type 1 diabetes patients considered to be high risk as well as 'high-risk' type 2 patients manage their diabetes during Ramadan. Although there is a lack of formal trial data, there is sufficient evidence across the different classes of therapeutic hypoglycaemic agents in terms of safety and efficacy to enable informed decision-making and provide a breadth of therapeutic options for the patient and the healthcare professional, even if the professional advice is to abstain. Thus, Ramadan provides an excellent opportunity for patient engagement to discuss important aspects of management, to improve control in the short term during Ramadan and to help the observants understand that the metabolic gains achieved during Ramadan are also sustainable in the other months of the year by maintaining a dietary and behavioural discipline. The application of this understanding can potentially prevent long-term complications.
Collapse
Affiliation(s)
- Syed H Ahmed
- Department of Endocrinology and Metabolic Medicine, Countess of Chester Hospital NHS Foundation Trust, Chester, UK.
- School of Medicine, University of Liverpool, Liverpool, UK.
| | | | - Sufyan Hussain
- Department of Diabetes and Endocrinology, Guy's & St Thomas' NHS Foundation Trust, London, UK
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
- Institute of Diabetes, Endocrinology and Obesity, King's Health Partners, London, UK
| | - Ateeq Syed
- Department of Diabetes and Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ali Karamat
- Department of Diabetes and Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ahmed Helmy
- Department of Diabetes and Endocrinology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Salman Waqar
- Nuffield Department of Primary Care Health Sciences, University Oxford, Oxford, UK
| | - Samina Ali
- NHS Greater Glasgow and Clyde, Glasgow, UK
| | | | - Susan T Seal
- Department of Endocrinology and Metabolic Medicine, Countess of Chester Hospital NHS Foundation Trust, Chester, UK
| | - Anna Hodgkinson
- Department of Diabetes and Endocrinology, Guy's & St Thomas' NHS Foundation Trust, London, UK
- NHS South East London Clinical Commissioning Group, London, UK
| | - Shazli Azmi
- Institute of Cardiovascular Science, University of Manchester, Manchester, UK
- Manchester Diabetes Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Nazim Ghouri
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
- Department of Diabetes and Endocrinology, Queen Elizabeth University Hospital, Glasgow, UK
| |
Collapse
|
|
12
|
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.
Collapse
Affiliation(s)
| | - Kathryn Biddle
- St George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Shazli Azmi
- Manchester University NHS Foundation Trust, Manchester, UK
| |
Collapse
|
|
13
|
Gomes-Neto AW, Osté MC, Sotomayor CG, van den Berg E, Geleijnse JM, Berger SP, Gans RO, Bakker SJ, Navis GJ. Mediterranean Style Diet and Kidney Function Loss in Kidney Transplant Recipients. Clin J Am Soc Nephrol 2020; 15:238-246. [PMID: 31896540 PMCID: PMC7015079 DOI: 10.2215/cjn.06710619] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 11/22/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Despite improvement of short-term graft survival over recent years, long-term graft survival after kidney transplantation has not improved. Studies in the general population suggest the Mediterranean diet benefits kidney function preservation. We investigated whether adherence to the Mediterranean diet is associated with kidney outcomes in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We included 632 adult kidney transplant recipients with a functioning graft for ≥1 year. Dietary intake was inquired using a 177-item validated food frequency questionnaire. Adherence to the Mediterranean diet was assessed using a nine-point Mediterranean Diet Score. Primary end point of the study was graft failure and secondary end points included kidney function decline (doubling of serum creatinine or graft failure) and graft loss (graft failure or death with a functioning graft). Cox regression analyses were used to prospectively study the associations of the Mediterranean Diet Score with study end points. RESULTS During median follow-up of 5.4 (interquartile range, 4.9-6.0) years, 76 participants developed graft failure, 119 developed kidney function decline, and 181 developed graft loss. The Mediterranean Diet Score was inversely associated with all study end points (graft failure: hazard ratio [HR], 0.68; 95% confidence interval [95% CI], 0.50 to 0.91; kidney function decline: HR, 0.68; 95% CI, 0.55 to 0.85; and graft loss: HR, 0.74; 95% CI, 0.63 to 0.88 per two-point increase in Mediterranean Diet Score) independent of potential confounders. We identified 24-hour urinary protein excretion and time since transplantation to be an effect modifier, with stronger inverse associations between the Mediterranean Diet Score and kidney outcomes observed in participants with higher urinary protein excretion and participants transplanted more recently. CONCLUSIONS Adherence to the Mediterranean diet is associated with better kidney function outcomes in kidney transplant recipients.
Collapse
Affiliation(s)
- António W. Gomes-Neto
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Maryse C.J. Osté
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Camilo G. Sotomayor
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Else van den Berg
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | | | - Stefan P. Berger
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Reinold O.B. Gans
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Stephan J.L. Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| | - Gerjan J. Navis
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and
| |
Collapse
|
|
14
|
Cai R, Wu M, Lin M, Guo X, Xing Y. Pretransplant Homeostasis Model Assessment of Insulin Resistance and Fasting Plasma Glucose Predict New-Onset Diabetes After Renal Transplant in Chinese Patients. Transplant Proc 2019; 51:768-773. [PMID: 30979462 DOI: 10.1016/j.transproceed.2019.01.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/25/2018] [Accepted: 01/17/2019] [Indexed: 10/27/2022]
Abstract
BACKGROUND AND AIM The present study aims to determine if homeostasis model assessment of insulin resistance (HOMA-IR) index, fasting plasma glucose (FPG), and plasma insulin (Ins) are able to predict development of new onset diabetes after transplant (NODAT) for kidney recipients. METHODS We performed a single-center retrospective study of 123 nondiabetic patients receiving a first renal transplant. The NODAT was diagnosed between 1 month and 1 year post transplant. Both univariate and multivariable analyses, including logistic regression analysis and Cox proportional hazards model, were applied to dissect potential pretransplant risk factors of NODAT. RESULTS A total of 26.8% (33/123) of recipients developed NODAT in the first year post transplant. The NODAT patients showed higher HOMA-IR index and increased levels of FPG and Ins than non-NODAT. Interestingly, we consistently revealed that both FPG (logistic: odds ratio [OR], 3.17 [1.41-6.45]; P = .01; Cox: OR, 2.75 [1.26-4.56]; P = .02) and HOMA-IR index (logistic: OR, 1.73 [1.21-2.87]; P = .02; Cox: OR, 1.72 [1.21-2.46]; P = .002) robustly predicted the development of NODAT. However, these analyses showed that neither plasma Ins nor hemoglobin A1c was associated with NODAT. CONCLUSION Our findings suggest that pretransplant HOMA-IR and FPG are independent predictors for the development of NODAT in Chinese nondiabetic patients receiving a first renal transplant.
Collapse
Affiliation(s)
- R Cai
- Department of Organ Transplantation, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - M Wu
- Department of Nephrology, Longyan First Hospital, Longyan, Fujian, China
| | - M Lin
- Department of Organ Transplantation, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - X Guo
- Department of Organ Transplantation, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Y Xing
- Department of Nephrology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
15
|
Cai R, Wu M, Xing Y. Pretransplant metabolic syndrome and its components predict post-transplantation diabetes mellitus in Chinese patients receiving a first renal transplant. Ther Clin Risk Manag 2019; 15:497-503. [PMID: 30936711 PMCID: PMC6422405 DOI: 10.2147/tcrm.s190185] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Post-transplantation diabetes mellitus (PTDM) remains a major clinical challenge following renal transplant. Identification of pretransplant modifiable risk factors may allow timely interventions to prevent PTDM. This study aims to determine whether pretransplant metabolic syndrome and its components are able to predict PTDM in Chinese patients receiving their first renal transplant. Patients and methods We conducted a single-center retrospective study of 633 non-diabetic patients receiving a first kidney transplant. PTDM was diagnosed between 1 month and 1 year post-transplant. Multivariable logistic regression and Cox proportional hazards model were applied to detect potential pretransplant risk factors for PTDM. Results One year post-transplant, 26.2% of recipients had developed PTDM. PTDM patients had significantly higher fasting plasma glucose (FPG) (P=0.026) and body mass index (BMI) (P=0.006) than non-PRDM patients, and lower levels of high-density lipoprotein cholesterol (P=0.015). The presence of metabolic syndrome was an independent risk factor for PTDM, as assessed by multivariable logistic regression analysis (OR 1.28, 95% CI 1.04–1.51, P=0.038) and Cox proportional hazards model (OR 2.75, 95% CI 1.45–6.05, P=0.021). Moreover, both FPG >5.6 mmol/L and BMI >28 kg/m2 (obesity) were able to predict PTDM. Conclusion Our results suggest that the presence of metabolic syndrome and its components, impaired fasting glycemia and obesity, are independent risk factors for PTDM in Chinese non-diabetic patients receiving a first renal transplant. Interventions aimed at improving pretransplant metabolic syndrome may reduce the incidence of PTDM.
Collapse
Affiliation(s)
- Ruiming Cai
- Department of Organ Transplantation, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China
| | - Meng Wu
- Department of Nephrology, Longyan First Hospital, Longyan 364000, Fujian, China
| | - Yanfang Xing
- Department of Nephrology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, Guangdong, China,
| |
Collapse
|
|
16
|
Dubois-Laforgue D. [Post-transplantation diabetes mellitus in kidney recipients]. Nephrol Ther 2017; 13 Suppl 1:S137-S146. [PMID: 28577736 DOI: 10.1016/j.nephro.2017.01.011] [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: 12/22/2016] [Revised: 01/15/2017] [Accepted: 01/17/2017] [Indexed: 10/19/2022]
Abstract
Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post-transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different.
Collapse
Affiliation(s)
- Danièle Dubois-Laforgue
- Service de diabétologie, hôpital Cochin-Port Royal, 123, boulevard Port-Royal, 75014 Paris, France; Inserm U1016, institut Cochin, 22, rue Méchain, 75014 Paris, France.
| |
Collapse
|
|
17
|
Xie L, Tang W, Wang X, Wang L, Lu Y, Lin T. Pretransplantation Risk Factors Associated With New-onset Diabetes After Living-donor Kidney Transplantation. Transplant Proc 2017; 48:3299-3302. [PMID: 27931572 DOI: 10.1016/j.transproceed.2016.10.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/28/2016] [Accepted: 10/27/2016] [Indexed: 02/05/2023]
Abstract
Mid-term date of kidney recipients with new-onset diabetes mellitus after transplantation (NODAT) was poor. We made a retrospective study of 397 patients who had living-donor kidney transplantation between January 2007 and May 2010 in our center. Pretransplantation risk factors for NODAT were identified by univariate and multivariate analyses. The mean follow-up was 53.5 ± 10.4 months. The prevalence of NODAT was 9.3%. Univariate analyses found the mean recipient age ≥40 years, body mass index (BMI) ≥24 kg/m2, family history of diabetes, fasting blood glucose (FBG) ≥5.6 mmol/L, 2-hour plasma glucose ≥7.8 mmol/L, and tacrolimus were risk factors for NODAT. In logistic regression, BMI ≥24 kg/m2 (odds ratio [OR]: 4.14, confidence interval [CI]: 2.02 ∼ 8.49, P < .001), family history of diabetes (OR: 2.62, CI: 1.09 ∼ 6.34, P = .032), and FBG ≥5.6 mmol/L (OR: 3.21, CI: 1.52 ∼ 6.79, P = .002) were independent risk factors. In conclusion, the mid-term prevalence of NODAT in Chinese renal recipients was low (9.3%). Pretransplantation independent risk factors were BMI ≥24 kg/m2, family history of diabetes, and FBG ≥5.6 mmol/L; thus identifying which factors might help to prevent NODAT.
Collapse
Affiliation(s)
- L Xie
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| | - W Tang
- National Office for Maternal and Child Health Surveillance, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - X Wang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - L Wang
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Y Lu
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - T Lin
- Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
18
|
Nakamura A, Iwami D, Miyoshi H, Morita K, Taguri M, Terauchi Y, Shinohara N, Atsumi T. Impact of renal transplantation on glucose tolerance in Japanese recipients with impaired glucose tolerance. Diabet Med 2017; 34:569-576. [PMID: 27505857 DOI: 10.1111/dme.13199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/08/2016] [Indexed: 12/30/2022]
Abstract
AIMS To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. METHODS We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). RESULTS Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. CONCLUSIONS More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients.
Collapse
Affiliation(s)
- A Nakamura
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo
| | - D Iwami
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo
| | - H Miyoshi
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo
| | - K Morita
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo
| | - M Taguri
- Department of Biostatistics, Yokohama City University, Yokohama
| | - Y Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - N Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo
| | - T Atsumi
- Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo
| |
Collapse
|
|
19
|
Tillmann FP, Radtke A, Rump LC, Quack I. Effect of Prediabetes on Allograft Survival and Evolution of New-Onset Diabetes After Transplant in Deceased-Donor Kidney Transplant Recipients During Long-Term Follow-Up. EXP CLIN TRANSPLANT 2017; 15:620-626. [PMID: 28332958 DOI: 10.6002/ect.2016.0196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES This study investigated the effect of prediabetes in long-term deceased-donor renal transplant recipients regarding graft survival, graft function, and evolution of new-onset diabetes after transplant compared with a control group of graft recipients with normal glucose tolerance test results. MATERIALS AND METHODS This was a follow-up trial of 187 deceased-donor renal transplant recipients. Based on oral glucose tolerance test results, the cohort was divided into groups A and B, comprising individuals with normal glucose metabolism (n = 130, 69.9%) and individuals with prediabetes (n = 56, 30.1%). Data are shown as means ± standard errors. RESULTS Both groups showed similar total transplant survival (116.8 ± 5.4 vs 114.5 ± 7.4 mo; P = .742) and transplant survival measured since oral glucose tolerance test (58.5 ± 1.4 vs 59.5 ± 1.9 mo; P = .990, Mantel-Cox P = .943). Univariate and multivariate Cox regression analyses showed no association of prediabetes with graft loss. Transplant function changes were similar between cohorts (-3 ± 1 vs -5 ± 2 mL/min/1.73 m2 body surface area, using the Chronic Kidney Disease Epidemiology Collaboration formula; P = .538). At 5-year follow-up, recipients with prediabetes had higher hemoglobin A1c than controls (5.99% ± 0.10% vs 5.67% ± 0.04%; P = .002). Prediabetes was associated with a 4.5-fold increased hazard of new-onset diabetes after transplant (P = .021). CONCLUSIONS Prediabetes was associated with a 4.5-fold higher hazard ratio for new-onset diabetes after transplant but not with reduced graft function or survival.
Collapse
Affiliation(s)
- Frank Peter Tillmann
- Klinik für Nephrologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
| | | | | | | |
Collapse
|
|
20
|
Vanhove T, Remijsen Q, Kuypers D, Gillard P. Drug-drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus. Transplant Rev (Orlando) 2016; 31:69-77. [PMID: 27665059 DOI: 10.1016/j.trre.2016.09.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/01/2016] [Accepted: 09/09/2016] [Indexed: 02/06/2023]
Abstract
Post-transplant diabetes mellitus is a frequent complication of solid organ transplantation that generally requires treatment with lifestyle interventions and antidiabetic medication. A number of demonstrated and potential pharmacokinetic drug-drug interactions (DDIs) exist between commonly used immunosuppressants and antidiabetic drugs, which are comprehensively summarized in this review. Cyclosporine (CsA) itself inhibits the cytochrome P450 (CYP) 3A4 enzyme and a variety of drug transporters. As a result, it increases exposure to repaglinide and sitagliptin, will likely increase the exposure to nateglinide, glyburide, saxagliptin, vildagliptin and alogliptin, and could theoretically increase the exposure to gliquidone and several sodium-glucose transporter (SGLT)-2 inhibitors. Currently available data, although limited, suggest that these increases are modest and, particularly with regard to gliptins and SGLT-2 inhibitors, unlikely to result in hypoglycemia. The interaction with repaglinide is more pronounced but does not preclude concomitant use if repaglinide dose is gradually titrated. Mycophenolate mofetil and azathioprine do not engage in DDIs with any antidiabetic drug. Although calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORi) are intrinsically prone to DDIs, their disposition is not influenced by metformin, pioglitazone, sulfonylureas (except possibly glyburide) or insulin. An effect of gliptins on the disposition of CNIs and mTORi is unlikely, but has not been definitively ruled out. Based on their disposition profiles, glyburide and canagliflozin could affect CNI and mTORi disposition although this requires further study. Finally, delayed gastric emptying as a result of glucagon-like peptide-1 agonists seems to have a limited, but not necessarily negligible effect on CNI disposition.
Collapse
Affiliation(s)
- Thomas Vanhove
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
| | - Quinten Remijsen
- Department of Medical Affairs, AstraZeneca BeLux, Uccle, Belgium
| | - Dirk Kuypers
- Department of Microbiology and Immunology, KU Leuven - University of Leuven, and Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Pieter Gillard
- Laboratory and Clinic of Experimental Medicine and Endocrinology, KU Leuven - University of Leuven, and Department of Endocrinology, University Hospital Leuven, Leuven, Belgium
| |
Collapse
|
|
21
|
Lv C, Zhang Y, Chen X, Huang X, Xue M, Sun Q, Wang T, Liang J, He S, Gao J, Zhou J, Yu M, Fan J, Gao X. New-onset diabetes after liver transplantation and its impact on complications and patient survival. J Diabetes 2015; 7:881-90. [PMID: 25676209 DOI: 10.1111/1753-0407.12275] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/13/2015] [Accepted: 01/27/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of the present study was to investigate the incidence and risk factors of new-onset diabetes after transplantation (NODAT) in liver transplant recipients and the influence of NODAT on complications and long-term patient survival. METHODS We examined 438 patients who underwent liver transplantation between April 2001 and December 2008 and were not diabetic before transplantation. RESULTS The mean (± SD) follow-up duration was 2.46 ± 1.62 years. The incidence of NODAT 3, 6, 9, 12, 36, and 60 months after transplantation was 44.24%, 25.59%, 23.08%, 25.17%, 17.86%, and 18.18%, respectively. Multifactor analysis indicated that preoperative fasting plasma glucose (FPG) levels and donor liver steatosis were independent risk factors for NODAT, whereas administration of an interleukin-2 receptor (IL-2R) antagonist reduced the risk of NODAT. Compared with the no NODAT group (N-NODAT), the NODAT group had a higher rate of sepsis and chronic renal insufficiency. Mean survival was significantly longer in the N-NODAT than NODAT group. Cox regression analysis showed that pre- and/or postoperative FPG levels, tumor recurrence or metastasis, and renal insufficiency after liver transplantation were independent risk factors of mortality. Pulmonary infection or multisystem failure were specific causes of death in the NODAT group, whereas patients in both groups died primarily from tumor relapse or metastasis. CONCLUSIONS Preoperative FPG levels and donor liver steatosis were independent risk factors for NODAT, whereas administration of an IL-2R antagonist reduced the risk of NODAT. Patients with NODAT had reduced survival and an increased incidence of sepsis and chronic renal insufficiency. Significant causes of death in the NODAT group were pulmonary infection and multisystem failure.
Collapse
Affiliation(s)
- Chaoyang Lv
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Yao Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Xianying Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
- Department of Endocrinology and Metabolism, Hainan Provincial Nong Ken Hospital, Hainan, China
| | - Xiaowu Huang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Mengjuan Xue
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Qiman Sun
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Ting Wang
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Jing Liang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Shunmei He
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jian Gao
- Center of Clinical Epidemiology and Evidence-based Medicine, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Mingxiang Yu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Zhongshan Hospital, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Shanghai, China
| |
Collapse
|
|
22
|
Gaynor JJ, Ciancio G, Guerra G, Sageshima J, Hanson L, Roth D, Goldstein MJ, Chen L, Kupin W, Mattiazzi A, Tueros L, Flores S, Barba LJ, Lopez A, Rivas J, Ruiz P, Vianna R, Burke GW. Single-centre study of 628 adult, primary kidney transplant recipients showing no unfavourable effect of new-onset diabetes after transplant. Diabetologia 2015; 58:334-45. [PMID: 25361829 DOI: 10.1007/s00125-014-3428-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/01/2014] [Indexed: 01/28/2023]
Abstract
AIMS/HYPOTHESIS To better understand the implications of new-onset diabetes after transplant (NODAT), we used our prospectively followed cohort of 628 adult primary kidney transplant recipients to determine the prognostic impact of pretransplant diabetes and NODAT. METHODS The study cohort consisted of all participants in four randomised immunosuppression trials performed at our centre since May 2000. For each cause-specific hazard analysed, Cox stepwise regression was used to determine a multivariable model of significant baseline predictors; the multivariable influence of having pretransplant diabetes and NODAT (t) (the latter defined as a zero-one, time-dependent covariate) was subsequently tested. Similar analyses of estimated glomerular filtration rate (eGFR) at 36 and 60 months post transplant were performed using stepwise linear regression. Finally, a repeated measures analysis of mean HbA1c as a function of diabetes category (pretransplant diabetes vs NODAT) and randomised trial (first to fourth) was performed. RESULTS Median follow-up was 56 months post transplant. Patients with pretransplant diabetes comprised 23.4% (147/628), and 22.5% (108/481) of the remaining patients developed NODAT. Pretransplant diabetes had no prognostic influence on first biopsy-proven acute rejection and death-censored graft failure hazard rates, nor on eGFR, but was associated with significantly higher rates of death with a functioning graft (DWFG) (p = 0.003), DWFG due to a cardiovascular event (p = 0.005) and infection that required hospitalisation (p = 0.03). NODAT (t) had no unfavourable impact on any of these hazard rates nor on eGFR, with actuarial freedom from DWFG remaining at over 90% among patients in pre- and post-NODAT states at 72 months post transplant/NODAT. Mean HbA1c for patients in the first to fourth randomised trials, averaged across diabetes category, decreased by trial (7.28%, 6.92%, 6.87% and 6.64% [56.1, 52.1, 51.6 and 49.1 mmol/mol], respectively; p = 0.02). CONCLUSIONS/INTERPRETATION Less-than-expected post-NODAT risk for graft loss and death may exist in the current climate of tighter glucose monitoring post transplant.
Collapse
Affiliation(s)
- Jeffrey J Gaynor
- Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Highland Professional Building, 1801 NW 9th Avenue, Miami, FL, 33136, USA,
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Tufton N, Ahmad S, Rolfe C, Rajkariar R, Byrne C, Chowdhury TA. New-onset diabetes after renal transplantation. Diabet Med 2014; 31:1284-92. [PMID: 24975051 DOI: 10.1111/dme.12534] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/08/2014] [Accepted: 06/24/2014] [Indexed: 12/12/2022]
Abstract
Renal transplantation has important benefits in people with end-stage renal disease, with improvements in mortality, morbidity and quality of life. Whilst significant advances in transplantation techniques and immunosuppressive regimens have led to improvements in short-term outcomes, longer-term outcomes have not improved dramatically. New-onset diabetes after transplantation appears to be a major factor in morbidity and cardiovascular mortality in renal transplant recipients. The diagnosis of new-onset diabetes after renal transplantation has been hampered by a lack of clarity over diagnostic tests in early studies, although the use of the WHO criteria is now generally accepted. HbA1c may be useful diagnostically, but should probably be avoided in the first 3 months after transplantation. The pathogenesis of new-onset diabetes after renal transplantation is likely to be related to standard pathogenic factors in Type 2 diabetes (e.g. insulin resistance, β-cell failure, inflammation and genetic factors) as well as other factors, such as hepatitis C infection, and could be exacerbated by the use of immunosuppression (glucocorticoids and calcineurin inhibitors). Pre-transplant risk scores may help identify those people at risk of new-onset diabetes after renal transplantation. There are no randomized trials of treatment of new-onset diabetes after renal transplantation to determine whether intensive glucose control has an impact on cardiovascular or renal morbidity, therefore, treatment is guided by guidelines used in non-transplant diabetes. Many areas of uncertainty in the pathogenesis, diagnosis and management of new-onset diabetes after renal transplantation require further research.
Collapse
Affiliation(s)
- N Tufton
- Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry, London, UK
| | | | | | | | | | | |
Collapse
|
|
24
|
Kohok DD, Shah S, Kumar R, Venuto L, Gudleski G, Venuto R. Interventions to reduce clinical inertia in cardiac risk factor management in renal transplant recipients. J Clin Hypertens (Greenwich) 2014; 16:127-32. [PMID: 24433451 PMCID: PMC8031565 DOI: 10.1111/jch.12249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 11/13/2013] [Accepted: 11/19/2013] [Indexed: 11/29/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTRs). Clinical inertia (CI) is defined as "recognition of the problem, but failure to act." The effect of educational interventions in minimizing CI in CVD risk factor management was assessed. Educational sessions were conducted among 201 RTRs to inform them about their goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C) and glycated hemoglobin (HbA1c). Physicians were reminded about treatment goals using checklists. Pre-intervention and post-intervention CI was measured as "no action" or "appropriate action" by the physicians. Post-intervention percentage of RTRs with "no clinical action" for BP, LDL-C, and HbA1c control decreased from 10.8% to 3.8% (P=.02), 28.2% to 11.1% (P=.008), and 10.3% to 4.5% (P=.05), respectively, while those with "appropriate action" increased from 66.2% to 83.3% (P<.001), 68.7% to 79.4% (P=.008), and 85.1% to 93.2% (P=.03), respectively. Educational interventions and patient participation were shown to reduce CI.
Collapse
Affiliation(s)
| | - Silvi Shah
- Department of Internal MedicineBuffaloNY
| | | | - Lisa Venuto
- Nephrology DivisionUniversity at BuffaloSchool of Medicine and Biomedical SciencesBuffaloNY
| | | | - Rocco Venuto
- Department of Internal MedicineBuffaloNY
- Nephrology DivisionUniversity at BuffaloSchool of Medicine and Biomedical SciencesBuffaloNY
| |
Collapse
|
|
25
|
Boerner BP, Miles CD, Shivaswamy V. Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation. Int J Endocrinol 2014; 2014:617638. [PMID: 24817885 PMCID: PMC4003765 DOI: 10.1155/2014/617638] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 02/21/2014] [Accepted: 03/07/2014] [Indexed: 02/06/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is a common comorbidity after renal transplantation. Though metformin is the first-line agent for the treatment of type 2 diabetes, in renal transplant recipients, metformin is frequently avoided due to concerns about renal dysfunction and risk for lactic acidosis. Therefore, alternative first-line agents for the treatment of NODAT in renal transplant recipients are needed. Sitagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, has a low incidence of hypoglycemia, is weight neutral, and, in a small study, did not affect immunosuppressant levels. However, long-term sitagliptin use for the treatment of NODAT in kidney transplant recipients has not been studied. We retrospectively analyzed renal transplant recipients diagnosed with NODAT and treated with sitagliptin to assess safety and efficacy. Twenty-two patients were started on sitagliptin alone. After 12 months of followup, 19/22 patients remained on sitagliptin alone with a significant improvement in hemoglobin A1c. Renal function and immunosuppressant levels remained stable. Analysis of long-term followup (32.5 ± 17.8 months) revealed that 17/22 patients remained on sitagliptin (mean hemoglobin A1c < 7%) with 9/17 patients remaining on sitagliptin alone. Transplant-specific adverse events were rare. Sitagliptin appears safe and efficacious for the treatment of NODAT in kidney transplant recipients.
Collapse
Affiliation(s)
- Brian P. Boerner
- Department of Internal Medicine, University of Nebraska Medical Center, 984130 Nebraska Medical Center, Omaha, NE 68198, USA
| | - Clifford D. Miles
- Department of Internal Medicine, University of Nebraska Medical Center, 984130 Nebraska Medical Center, Omaha, NE 68198, USA
| | - Vijay Shivaswamy
- Department of Internal Medicine, University of Nebraska Medical Center, 984130 Nebraska Medical Center, Omaha, NE 68198, USA
- VA Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105, USA
- *Vijay Shivaswamy:
| |
Collapse
|
|
26
|
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.
Collapse
|
|
27
|
Cotovio P, Neves M, Rodrigues L, Alves R, Bastos M, Baptista C, Macário F, Mota A. New-onset diabetes after transplantation: assessment of risk factors and clinical outcomes. Transplant Proc 2013; 45:1079-83. [PMID: 23622631 DOI: 10.1016/j.transproceed.2013.03.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND New-onset diabetes after transplantation (NODAT) is a serious complicatin of kidney transplantation (KT) with adverse impacts on graft and patient survivals. This study aims assess potential risk factors for development of NODAT and compare clinical outcomes of KT recipients with versus without NODAT. METHODS We retrospectively evaluated 648 patients who underwent KT between 2005 and 2009. From the 83 (12.8%) subjects who developed NODAT, we selected 47 for comparison with controls free of diabetes. RESULTS The diagnosis of NODAT was made at 4.3 ± 8.5 months after transplantation in 47 patients, including 76.6% males, with an overall mean age of 54.5 ± 10.8 years. Patients with NODAT presented higher pretransplantation fasting plasma glucose levels (P < .001) as well as cyclosporine and tacrolimus trough levels (P = .003 and P < .001, respectively). On multivariate analysis, higher pretransplantation fasting plasma glucose and higher tacrolimus, but not cyclosporine concentrations were independent predictors of NODAT. No differences were found for other potential risk factors. Upon follow-up at 6, 12, 24, 36, 48, and 60 months, renal function (estimated Glomerular Filtration Rate using Modification of Diet in Renal Disease), 24 hour proteinuria and proportions of patients with hypertension were similar between groups. Patients with NODAT showed comparable numbers of hospitalizations and infections, as well as acute rejection episodes and acute cardiovascular events as their counterparts. Event-free survival (loss of graft function/death with functioning graft) was similar between the groups (P = .418; K-M). DISCUSSION In our population, higher pretransplantation fasting plasma glucose levels and higher tacrolimus concentrations were independent predictors of NODAT. During a mean follow-up of 3 years, NODAT was not associated with worse clinical outcomes.
Collapse
Affiliation(s)
- P Cotovio
- Department of Nephrology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Watanabe M, Yamashita K, Suzuki T, Kamachi H, Kuraya D, Koshizuka Y, Ogura M, Yoshida T, Aoyagi T, Fukumori D, Shimamura T, Okimura K, Maeta K, Miura T, Sakai F, Todo S. ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates. Am J Transplant 2013; 13:1976-88. [PMID: 23841873 DOI: 10.1111/ajt.12330] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 05/08/2013] [Accepted: 05/10/2013] [Indexed: 01/25/2023]
Abstract
A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti-CD154 monoclonal antibodies (mAbs). Previously, we demonstrated that ASKP1240, which is a fully human anti-CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201-12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post-PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti-donor cellular responses and development of anti-donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.
Collapse
Affiliation(s)
- M Watanabe
- First Department of Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
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.
Collapse
Affiliation(s)
- Massimiliano Veroux
- Vascular Surgery and Organ Transplant Unit, Department of Surgery Transplantation and Advanced Technologies, University Hospital of Catania, 95123 Catania, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Hecking M, Werzowa J, Haidinger M, Hörl WH, Pascual J, Budde K, Luan FL, Ojo A, de Vries APJ, Porrini E, Pacini G, Port FK, Sharif A, Säemann MD. Novel views on new-onset diabetes after transplantation: development, prevention and treatment. Nephrol Dial Transplant 2013; 28:550-66. [PMID: 23328712 DOI: 10.1093/ndt/gfs583] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.
Collapse
Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Early posttransplantation hyperglycemia in kidney transplant recipients is associated with overall long-term graft losses. Transplantation 2012; 94:714-20. [PMID: 22965263 DOI: 10.1097/tp.0b013e31825f4434] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The association of early-onset posttransplantation hyperglycemia with long-term renal allograft survival is unknown. METHODS Seventy-one (SD 9) days after transplantation, 1410 first-time kidney transplant recipients without diabetes underwent an oral glucose tolerance test and were observed until primary outcome (graft loss) or December 31, 2008 (median [range], 6.0 years [0.3-13.8 years]). We used multivariable Cox regression analysis adjusted for age, gender, body mass index, creatinine level, donor age, preemptive transplantation, deceased donor, early rejection, and early cytomegalovirus infection to estimate hazard ratios for overall and death-censored allograft survival. RESULTS A total of 392 (28%) recipients experienced graft failure, and 235 (60%) were induced by death. Each 1 mmol/L increase in 2-hr plasma glucose (2hPG) was associated with 7% and 3% increased risk of unadjusted and adjusted overall graft failure (hazard ratio [95% confidence interval], 1.07 [1.04-1.10] and 1.03 [1.00-1.07]). Fasting plasma glucose was associated with unadjusted but not adjusted overall graft failure (1.09 [1.01-1.18] and 1.07 [0.98-1.17]). Neither 2hPG nor fasting plasma glucose was associated with death-censored graft loss (P=0.578 and P=0.896). Compared with recipients with normal glucose tolerance, recipients with posttransplantation diabetes mellitus showed a tendency toward increased overall multiadjusted graft failure (1.30 [0.98-1.73]). This was not observed in patients with impaired fasting glucose or impaired glucose tolerance. CONCLUSIONS In this study, 2hPG was associated with overall graft failure but not death-censored graft failure. The link between 2hPG and graft failure may be explained by the association with mortality.
Collapse
|
|
32
|
Lowe M, Badell IR, Thompson P, Martin B, Leopardi F, Strobert E, Price AA, Abdulkerim HS, Wang R, Iwakoshi NN, Adams AB, Kirk AD, Larsen CP, Reimann KA. A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am J Transplant 2012; 12:2079-87. [PMID: 22845909 PMCID: PMC3410651 DOI: 10.1111/j.1600-6143.2012.04054.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.
Collapse
Affiliation(s)
- M Lowe
- Emory Transplant Center, Department of Surgery, Emory University, Atlanta, GA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Ruderman I, Masterson R, Yates C, Gorelik A, Cohney SJ, Walker RG. New onset diabetes after kidney transplantation in autosomal dominant polycystic kidney disease: a retrospective cohort study. Nephrology (Carlton) 2012; 17:89-96. [PMID: 21854501 DOI: 10.1111/j.1440-1797.2011.01507.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND New onset diabetes after transplantation (NODAT) is a common adverse outcome of organ transplantation that increases the risk of cardiovascular disease, infection and graft rejection. In kidney transplantation, apart from traditional risk factors, autosomal dominant polycystic kidney disease (ADPKD) has also been reported by several authors as a predisposing factor to the development of NODAT, but any rationale for an association between ADPKD and NODAT is unclear. We examined the cumulative incidence of NODAT in or own transplant population comparing ADPKD patients with non-ADPKD controls. METHODS A retrospective cohort study to determine the cumulative incidence of patients developing NODAT (defined by World Health Organization-based criteria and/or use of hypoglycaemic medication) was conducted in 79 patients with ADPKD (79 transplants) and 423 non-ADPKD controls (426 transplants) selected from 613 sequential transplant recipients over 8 years. Patients with pre-existing diabetes as a primary disease or comorbidity and/or with minimal follow up or early graft loss/death were excluded. RESULTS Of the 502 patients (505 transplants) studied, 86 (17.0%) developed NODAT. There was no significant difference in the cumulative incidence of NODAT in the ADPKD (16.5%; CI 13.6-20.7%) compared with the non-ADPKD (17.1%; CI 8.3-24.6%) control group. Of the 13 patients in the ADPKD group with NODAT, three required treatment with insulin with or without oral hypoglycaemic agents. Among the 73 NODAT patients in the non-ADPKD group, eight received insulin with or without oral hypoglycaemics. Furthermore, of the patients that did develop NODAT, there was no difference in the time to its development in patients with and without ADPKD. CONCLUSION There was no evidence of an increased incidence of NODAT in ADPKD kidney transplant recipients.
Collapse
Affiliation(s)
- Irene Ruderman
- Department of Nephrology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | | | | | | | | | | |
Collapse
|
|
34
|
Stevens KK, Patel RK, Jardine AG. HOW TO IDENTIFY AND MANAGE DIABETES MELLITUS AFTER RENAL TRANSPLANTATION. J Ren Care 2012; 38 Suppl 1:125-37. [DOI: 10.1111/j.1755-6686.2012.00282.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
35
|
Prokai A, Fekete A, Pasti K, Rusai K, Banki NF, Reusz G, Szabo AJ. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012; 13:81-91. [PMID: 21595806 DOI: 10.1111/j.1399-5448.2011.00782.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration ≥ 11.1 mmol/L or fasting plasma glucose (FPG) ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM.
Collapse
Affiliation(s)
- A Prokai
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol 2011; 8:34-42. [PMID: 22083141 DOI: 10.1038/nrneph.2011.174] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
New-onset diabetes mellitus after kidney transplantation (NODAT) is widely acknowledged to be associated with increased morbidity and mortality, as well as poor quality of life. Clear evidence links the occurrence of NODAT to accelerated progression of some macrovascular and/or microvascular complications. However, the evidence that some complications commonly attributed to diabetes mellitus occur in the context of transplantation lacks robustness. Certain complications are transplantation-specific and prevalent, but others are not frequently observed or documented. For this reason, it is essential that clinicians are aware of the array of potential complications associated with NODAT in kidney allograft recipients. Rather than simply translating evidence from the general population to the high-risk transplant recipient, this Review aims to provide specific guidance on diabetes-related complications in the context of a complex transplantation environment.
Collapse
Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Renal Institute of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.
| | | |
Collapse
|
|
37
|
Jenssen T, Hartmann A. Prevention and management of transplant-associated diabetes. Expert Opin Pharmacother 2011; 12:2641-55. [PMID: 22047007 DOI: 10.1517/14656566.2011.628936] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION New-onset diabetes after transplantation (NODAT) is considered to be a major cause of cardiovascular disease and death among patients with a functioning allograft. A major challenge is to reduce the incidence of NODAT and to treat it optimally once it has occurred. AREAS COVERED This review presents current data on how to prevent NODAT in patients at risk, with a focus on modifications in the immunosuppressive regimen. Current suggestions for detection and treatment of NODAT are also presented. EXPERT OPINION Prevention of NODAT is possible by assessing the patient's glycemic risk prior to transplantation and tailoring the treatment (e.g., choice and dosage of immunosuppressive agents) after transplantation. An oral glucose tolerance test is still the gold standard to detect NODAT in patients at risk (prediabetes) but algorithms can be used to select those who should be tested. The treatment of NODAT involves a broad approach on risk factors for cardiovascular events and graft loss. Future studies on the use of oral hypoglycemic agents in NODAT are still needed.
Collapse
Affiliation(s)
- Trond Jenssen
- Oslo University Hospital Rikshospitalet, Section of Nephrology, Department of Organ Transplantation, Oslo, Norway.
| | | |
Collapse
|
|
38
|
New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation 2011; 91:334-41. [PMID: 21242885 DOI: 10.1097/tp.0b013e318203c25f] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND New-onset diabetes after transplant (NODAT) is a serious complication after kidney transplantation. We studied the relationship between steroid-free maintenance regimens and NODAT in a national cohort of adult kidney transplant patients. METHODS A total of 25,837 previously nondiabetic kidney transplant patients, engrafted between January 1, 2004, and December 31, 2006, were included in the study. Logistic regression analysis was used to compare the risk of developing NODAT within 3 years after transplant for patients discharged with and without steroid-containing maintenance immunosuppression regimens. The effect of transplant program-level practice regarding steroid-free regimens on the risk of NODAT was studied as well. RESULTS The cumulative incidence of NODAT within 3 years of transplant was 16.2% overall; 17.7% with maintenance steroids and 12.3% without (P<0.001). Patients discharged with steroids had 42% greater odds of developing NODAT compared with those without steroids (adjusted odds ratio [AOR]=1.42, 95% confidence interval [CI]=1.27-1.58, P<0.001). The maintenance regimen of tacrolimus and mycophenolate mofetil or mycophenolate sodium was associated with 25% greater odds of developing NODAT (AOR=1.25, 95% CI=1.08-1.45, P=0.003) than the regimen of cyclosporine and mycophenolate mofetil or mycophenolate sodium. Several induction therapies also were associated with lower odds of NODAT compared with no induction. Patients from programs that used steroid-free regimens for a majority of their patients had reduced odds of NODAT compared with patients from programs discharging almost all of their patients on steroid-containing regimens. CONCLUSION The adoption of steroid-free maintenance immunosuppression at discharge from kidney transplantation in selected patients was associated with reduced odds of developing NODAT within 3 years.
Collapse
|
|
39
|
Räkel A, Karelis AD. New-onset diabetes after transplantation: risk factors and clinical impact. DIABETES & METABOLISM 2011; 37:1-14. [PMID: 21295510 DOI: 10.1016/j.diabet.2010.09.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Revised: 09/17/2010] [Accepted: 09/21/2010] [Indexed: 02/06/2023]
Abstract
With improvements in patient and graft survival, increasing attention has been placed on complications that contribute to long-term patient morbidity and mortality. New-onset diabetes after transplantation (NODAT) is a common complication of solid-organ transplantation, and is a strong predictor of graft failure and cardiovascular mortality in the transplant population. Risk factors for NODAT in transplant recipients are similar to those in non-transplant patients, but transplant-specific risk factors such as hepatitis C (HCV) infection, corticosteroids and calcineurin inhibitors play a dominant role in NODAT pathogenesis. Management of NODAT is similar to type 2 diabetes management in the general population. However, adjusting the immunosuppressant regimen to improve glucose tolerance must be weighed against the risk of allograft rejection. Lifestyle modification is currently the strategy with the least risk and the most benefit.
Collapse
Affiliation(s)
- A Räkel
- Department of Medicine, hôpital Saint-Luc, centre de recherche, centre hospitalier, University of Montreal, René-Lévesque-Est, Québec, Canada.
| | | |
Collapse
|
|
40
|
Klein CL, Brennan DC. The Tradeoff Between the Risks of Acute Rejection and New-Onset Diabetes After Kidney Transplant. Am J Kidney Dis 2010; 56:1026-8. [DOI: 10.1053/j.ajkd.2010.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 09/15/2010] [Indexed: 11/11/2022]
|
|
41
|
Kuo HT, Sampaio MS, Vincenti F, Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database. Am J Kidney Dis 2010; 56:1127-39. [PMID: 20934793 DOI: 10.1053/j.ajkd.2010.06.027] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 06/29/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes and acute rejection are major contributors to morbidity and mortality in kidney transplant recipients. Immunosuppressive medications decrease acute rejection, but increase the frequency of new-onset diabetes after transplant. Our objective was to investigate the joint associations of diabetes (pretransplant diabetes and new-onset diabetes after transplant) and acute rejection with transplant outcomes in a recent transplant cohort. STUDY DESIGN Historical cohort study. SETTING & PARTICIPANTS 37,448 recipients (age ≥ 18 years; 2004-2007) surviving with a functioning transplant for longer than 1 year were identified in the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database as of May 22, 2009. PREDICTORS Recipients were stratified into 6 mutually exclusive groups according to status of diabetes and acute rejection at 1 year: group 1, neither (reference; n = 20,964); group 2, new-onset diabetes alone (n = 2,140); group 3, pretransplant diabetes alone (n = 10,730); group 4, acute rejection alone (n = 2,282); group 5, new-onset diabetes and acute rejection (n = 361); and group 6, pretransplant diabetes and acute rejection (n = 1,061). Analyses were adjusted for other recipient, donor, and transplant characteristics. OUTCOMES MEASUREMENTS: Multivariate Cox regression analysis of time to transplant failure (overall and death censored) and mortality (all-cause and cardiovascular). RESULTS Median follow-up after 1 year was 548 days (25th-75th percentiles, 334-752 days). During this time, there were 3,047 outcomes of overall transplant failure. New-onset diabetes alone (group 2) was not associated significantly with any study outcomes. Groups 3-6 were associated with higher overall transplant failure risk. However, only groups 4-6 were associated with higher death-censored transplant failure risk. Group 3, 4, and 6 were associated with higher all-cause mortality risk, whereas only groups 3 and 6 were associated with higher cardiovascular mortality risk. LIMITATIONS Potential information bias with exposure, covariable, or outcome misclassification; relatively short follow-up. CONCLUSIONS Pretransplant diabetes is the major predictor of all-cause and cardiovascular mortality, and acute rejection during the first year is the major predictor of death-censored transplant failure in kidney recipients surviving with a functioning transplant for at least 1 year. The influence of new-onset diabetes on long-term outcomes needs further observation.
Collapse
Affiliation(s)
- Hung-Tien Kuo
- Nephrology, UCLA Medical Center, Los Angeles, CA, USA
| | | | | | | |
Collapse
|
|
42
|
Luan FL, Samaniego M. Transplantation in diabetic kidney failure patients: modalities, outcomes, and clinical management. Semin Dial 2010; 23:198-205. [PMID: 20374550 DOI: 10.1111/j.1525-139x.2010.00708.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre-emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre-existent DM or NODAT involves a multi-pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re-transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.
Collapse
Affiliation(s)
- Fu L Luan
- Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
| | | |
Collapse
|
|
43
|
Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, Massari P, Mondragon-Ramirez GA, Agarwal M, Di Russo G, Lin CS, Garg P, Larsen CP. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10:535-46. [PMID: 20415897 DOI: 10.1111/j.1600-6143.2009.03005.x] [Citation(s) in RCA: 715] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Belatacept, a costimulation blocker, may preserve renal function and improve long-term outcomes versus calcineurin inhibitors in kidney transplantation. This Phase III study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) assessed a more intensive (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. The co-primary endpoints at 12 months were patient/graft survival, a composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m(2) at Month 12 or a decrease in mGFR > or =10 mL/min/1.73 m(2) Month 3-Month 12) and the incidence of acute rejection. At Month 12, both belatacept regimens had similar patient/graft survival versus cyclosporine (MI: 95%, LI: 97% and cyclosporine: 93%), and were associated with superior renal function as measured by the composite renal impairment endpoint (MI: 55%; LI: 54% and cyclosporine: 78%; p < or = 0.001 MI or LI versus cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p < or = 0.001 MI or LI versus cyclosporine). Belatacept patients experienced a higher incidence (MI: 22%, LI: 17% and cyclosporine: 7%) and grade of acute rejection episodes. Safety was generally similar between groups, but posttransplant lymphoproliferative disorder was more common in the belatacept groups. Belatacept was associated with superior renal function and similar patient/graft survival versus cyclosporine at 1 year posttransplant, despite a higher rate of early acute rejection.
Collapse
Affiliation(s)
- F Vincenti
- Kidney Transplant Service, University of California-San Francisco, San Francisco, CA, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Kalantar-Zadeh K, Derose SF, Nicholas S, Benner D, Sharma K, Kovesdy CP. Burnt-out diabetes: impact of chronic kidney disease progression on the natural course of diabetes mellitus. J Ren Nutr 2009; 19:33-7. [PMID: 19121768 PMCID: PMC2652655 DOI: 10.1053/j.jrn.2008.11.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2008] [Indexed: 11/11/2022] Open
Abstract
Many individuals with diabetic nephropathy, the leading cause of chronic kidney disease (CKD) in the United States, progress to stage 5 of CKD and undergo maintenance dialysis treatment. Recent data indicate that in up to one third of diabetic dialysis patients with a presumptive diagnosis of diabetic nephropathy, glycemic control improves spontaneously with the progression of CKD, loss of residual renal function, and the initiation of dialysis therapy, leading to normal-to-low hemoglobin A1c (<6%) and glucose levels, requiring cessation of insulin or other anti-diabetic medications. Potential contributors to this so-called "burnt-out diabetes" include decreased renal and hepatic insulin clearance, a decline in renal gluconeogenesis, deficient catecholamine release, diminished food intake (because of anorexia or diabetic gastroparesis), protein-energy wasting (with resultant loss of weight and body fat), and the hypoglycemic effects of dialysis treatment. Although the concept of "burnt-out diabetes" appears in sharp contradistinction to the natural history of diabetes mellitus, studying this condition and its potential causes and consequences, including the role of genetic factors, may lead to a better understanding of the pathophysiology of metabolic syndrome and diabetes mellitus in the CKD population and in many other individuals with chronic disease states associated with wasting syndrome that can confound the natural history of diabetes.
Collapse
Affiliation(s)
- Kamyar Kalantar-Zadeh
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
- Division of Nephrology, UCLA Center for Health Sciences, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Stephen F. Derose
- Dept. of Research, Kaiser Permanente of Southern California, Pasadena, CA
| | - Susan Nicholas
- Division of Nephrology, UCLA Center for Health Sciences, UCLA David Geffen School of Medicine, Los Angeles, CA
| | | | - Kumar Sharma
- Translational Research in Kidney Disease, University of California San Diego, Division of Nephrology, La Jolla, CA
| | - Csaba P Kovesdy
- Division of Nephrology, CA; Salem VA Medical Center, Division of Nephrology, Salem, VA
- University of Virginia, Charlottesville, VA
| |
Collapse
|
|
45
|
Abstract
SUMMARY This article reviews the clinical aspects and epidemiological links between diabetes mellitus and renal transplantation, and emphasizes areas that warrant further clarification. In particular, we summarize the data for various immunosuppression medications on the risk of new-onset diabetes after transplantation (NODAT). An increased mechanistic understanding of new-onset diabetes might provide new insights into the pathophysiology of this complication after solid organ transplantation. Claims that selecting immunosuppression regimen to minimize the risk of NODAT, nevertheless, are currently not supported by the scientific published work. Intuitively, strategies that aim to change the underlying biology of the disease process of NODAT are desirable; among them, lifestyle modification is currently the most promising in terms of real benefit with the least risk.
Collapse
Affiliation(s)
- Kai Ming Chow
- Department of Medicine and Therapeutics, Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China
| | | |
Collapse
|
|
46
|
Abstract
New-onset diabetes mellitus is a common complication of solid organ transplantation and is likely to become even more common with the current epidemic of obesity in some countries. It has become clear that both new-onset diabetes and prediabetic states (impaired fasting glucose and impaired glucose tolerance) negatively influence graft and patient survival after transplantation. This observation forms the basis for recommending meticulous screening for glucose intolerance before and after transplantation. Although a number of clinical factors including age, weight, ethnicity, family history, and infection with hepatitis C are closely associated with the new-onset diabetes mellitus, immunosuppression with corticosteroids, calcineurin inhibitors and possibly sirolimus plays a dominant role in its pathogenesis. Management of new-onset diabetes after transplantation generally conforms to the guidelines for treatment of type 2 diabetes mellitus in the general population. However, further studies are needed to determine the optimal immunosuppressive regimens for patients with this disorder.
Collapse
Affiliation(s)
- Kenneth A Bodziak
- Department of Medicine, Division of Nephrology and Hypertension, Case Western Reserve University and the Transplantation Service, University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | | |
Collapse
|