Original Clinical ScienceçGeneral
Associations Between Posttransplantation Diabetes Mellitus and Renal Graft Survival Ivar Anders Eide, MD, PhD,1 Thea Anine Strøm Halden, MScPharm,1,2 Anders Hartmann, MD,1,2 Dag Olav Dahle, MD,1 Anders Åsberg, PhD,1,3,4 and Trond Jenssen, MD1,5
Background. Previous reports indicate that posttransplantation diabetes mellitus (PTDM) is associated with overall renal graft loss, but not death-censored graft loss. Methods. In this single-center retrospective cohort study of 2749 adult Norwegian renal transplant recipients, transplanted between 1999 and 2011, we estimated overall and death-censored renal graft loss hazard ratios in patients diagnosed with PTDM, impaired glucose tolerance and diabetes before transplantation, using multivariable Cox proportional hazard regression analysis. Results. A total of 893 renal grafts were lost during the study period, either due to recipient death (n = 540) or death-censored graft loss (n = 353). When the observational time started at time of transplantation, diabetes before transplantation was associated with both overall and death-censored graft loss. Pretransplantation diabetes was also associated with a steeper decline in renal graft function, a higher risk of acute rejections and more renal grafts lost due to acute rejection. In patients with a functional renal graft 1 year after transplantation, PTDM was associated with overall graft loss (hazard ratio, 1.46; 95% confidence interval, 1.13-1.88; P < 0.001), but not death-censored graft loss (hazard ratio, 1.25; 95% confidence interval, 0.80-1.96; P = 0.33). We found no significant associations between PTDM and change in renal function during the first 5 years or acute rejection risk during the first year after renal transplantation. Impaired glucose tolerance was not associated with either overall or death-censored graft loss. Conclusions. The present study confirms previous findings of an increased risk of overall but not death-censored renal graft loss in renal transplant recipients with PTDM. Longstanding diabetes might increase the risk of acute rejections.
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enal transplant recipients (RTRs) are at increased risk of developing diabetes, partly due to side effects of immunosuppressive drugs.1-3 Previous studies have reported a more rapid decline in graft function in RTRs diagnosed with posttransplantation diabetes mellitus (PTDM) and a lower overall graft survival expectancy.4-12 Most cases of renal graft loss are, however, due to recipient death.6,7 Indeed, previous studies report strong positive associations between PTDM and major cardiovascular events13 and mortality.6,14 In surviving patients, studies have failed to detect an association between PTDM and graft failure (death-censored graft
loss; return to dialysis or renal retransplantation),7-12 including an earlier report from our center.7 However, comprehensive data from the US Renal Data System reported a significantly higher risk of death-censored graft loss in patients with PTDM.6 At our center, PTDM is currently diagnosed by either (1) fasting plasma glucose (fPG) ≥ 7.0 mmol/L (≥126 mg/dL) and/or a 2-hour postchallenge plasma glucose (2hPG) of 11.1 mmol/L or greater (≥200 mg/dL) during an oral glucose tolerance test (OGTT) at 10 weeks posttransplant (PTDM by the OGTT criterion) or (2) chronic hyperglycemia during the first 10 weeks after transplantation, defined as repeated elevated measurements of fPG (≥7.0 mmol/L [≥126 mg/dL])
Received 9 October 2015. Revision received 18 March 2016. Accepted 18 March 2016. 1 Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Norway. 2
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Norway.
3
The Norwegian Renal Registry, Oslo University Hospital, Rikshospitalet, Norway.
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Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway. 5
Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway. I.A.E. and T.A.S.H. were supported by public funding grants from the SouthEastern Norway Regional Health Authority. I.A.E. received additional support from other public funding grants: Gidske and Peter Jacob Sørensen Research Fund, The Norwegian National Association for Kidney Patients and Transplant Recipients Research Fund, The Raagholt Foundation, The Freia Corporation Medical Fund, Nathalia and Knut Juul Christensen Research Fund, Signe and Albert Bergsmarken Research Fund and Gertrude and Jack Nelsons Research Fund.
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The authors declare no conflicts of interest. T.J., T.A.S.H., I.A.E., A.H., A.Å., and D.O.D. designed the study. I.A.E. and T.A.S.H. collected data from patient records for patients transplanted at our center between September 30, 1999, and October 14, 2011. I.A.E. and T.A.S.H. analyzed the data. T.A.S.H., I.A.E., A.H., and T.J. edited the article. A.Å. and D.O.D. coedited the article. T.A.S.H., I.A.E., A.H., A.Å., D.O.D., and T.J. all approved the final version of the article. I.A.E. submitted the article. Correspondence: Ivar Anders Eide, Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Postbox 4950 Nydalen, N-0424 Oslo, Norway. (
[email protected]). Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/16/0000-00 DOI: 10.1097/TP.0000000000001259
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Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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and/or random plasma glucose (≥11.1 mmol/L [≥200 mg/ dL]) that fails to normalize (manifest PTDM).15 Beyond the early posttransplantation phase, PTDM is identified by elevated levels of fasting or random plasma glucose and/or elevated glycated hemoglobin (HbA1c) levels. Impaired glucose tolerance (IGT) is defined as normal fPG levels and 2hPG 7.8 to 11.0 mmol/L (140-199 mg/dL) during an OGTT. Diabetes before transplantation is at our center excluded by a compulsory OGTT before entrance on the renal transplant waiting list. The aim of the present study was to estimate associations between PTDM, IGT, and diabetes before transplantation and overall and death-censored renal graft loss in a recent update of our cohort. We also assessed associations between diabetes and the risk of acute rejection episodes and renal graft function. MATERIALS AND METHODS Study Participants
From a total of 2837 consecutive patients who received a renal transplant at our center between September 30, 1999, and October 13, 2011, 2749 patients older than 16 years were eligible for inclusion in the study (Figure 1). Data on glucose and HbA1c measurements at 10 weeks after transplantation were available in 1632 patients, including 75 patients with manifest PTDM and 1557 patients with glucose and HbA1c measurements obtained at 10 weeks posttransplant. Posttransplantation diabetes mellitus by the OGTT criterion was detected in 90 patients and 202 patients had IGT. Between 10 weeks and 1 year posttransplant, PTDM was
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diagnosed in another 66 patients (Figure 1). Informed consent was obtained from all patients. Study Design, Endpoints, Data Collection, and Procedures
Clinical data were extracted from patient records. Endpoint data were provided by The Norwegian Renal Registry. The registry is based on annual reports from all nephrology units and includes all patients on renal replacement therapy in Norway. Overall renal graft loss included both functional grafts lost due to recipient death and death-censored graft loss. Acute rejection episodes were biopsy proven according to the 2007 Banff classification and updates.16 The glucose measurements performed in this study have previously been described in detail.15 Measurements of fPG were performed before glucose administration after a minimum of 8 hours overnight fasting, which included no medical drugs taken in the morning. An OGTT was performed by oral administration of a standard dose of 75-g anhydrous glucose dissolved in 300 mL of water. Postchallenge plasma glucose measurements were obtained 2 hours after glucose administration, after which patients could take their scheduled medication. Patients with ongoing high-dose steroid therapy for acute rejection (n = 14), diabetes before transplantation (n = 499), or patients with manifest PTDM (n = 75) were not scheduled for a routine OGTT. Among 1557 patients who attended a clinical visit 10 weeks after transplantation, OGTT was performed in 1543 patients, and 14 patients had only fPG and HbA1c measurements. Patients diagnosed with PTDM received dietary advice, and most of them were started on insulin or oral glucose-lowering
FIGURE 1. Flowchart for inclusion of patients in the study. Flowchart for inclusion of study participants and detection of PTDM and IGT. Selection of patients subjected to glucose measurements including fPG, 2hPG during an OGTT and HbA1c measurements was based on attendance at a clinical visit 10 weeks posttransplant.
Copyright © 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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therapy. A description of the standard immunosuppressive protocol can be found in the Appendix (SDC, http://links. lww.com/TP/B280). Serum creatinine measurements were performed at 10 weeks posttransplant and thereafter annually. Based on these measurements, we estimated glomerular filtration rates (eGFR) according to the Modification of Diet in Renal Disease equation.17 Change in eGFR was assessed between 10 weeks and 1 year after transplantation and then annually until 5 years posttransplant. Missing data were replaced by the last registered eGFR value for each patient. Change in eGFR during the first 5 years posttransplant was defined as the sum of annual changes in eGFR. Data quality control and handling of missing data have previously been described.18 The study was approved by the Regional Committees for Medical and Health Research Ethics in Norway and was performed in accordance with the Declaration of Helsinki.
Statistical Analysis
Differences in patient characteristics at 10 weeks posttransplant between patients with PTDM, diabetes before transplantation and no diabetes (IGT or normal glucose tolerance) were evaluated by χ2 test, Mann-Whitney U test and independent t test as appropriate (Table 1). Differences between groups in change of eGFR were evaluated with independent t test. The main statistical approach in the present study was Cox proportional hazard regression analysis for estimation of unadjusted and multivariable adjusted hazard ratios for overall renal graft loss (Table 2) and death-censored graft loss (Table 3) for PTDM, IGT, and diabetes before transplantation. We developed 3 Cox regression models, in which the observational time started at either time of transplantation (model A), 10 weeks after transplantation (model B), and 1 year after transplantation (model C). Surviving patients
TABLE 1.
Patient characteristics at 10 weeks after renal transplantation according to diabetes category Diagnostic category
NGT or IGT
No. patients Recipient age, y Donor age, y Sex (male), % Atherosclerotic disease, % First renal transplantation, % Living donor, % No. HLA DR mismatches None, % One, % Two, % Preemptive transplantation, % Dialysis vintage, mo Tacrolimus, % Cyclosporine A, % mTOR inhibitor, % Antihypertensive drugs None or 1, % 2 or 3, % 4 or more, % Smoking status Current smoker, % Former smoker, % Body mass index, kg/m2 Total cholesterol, mg/L Albumin, g/L eGFR, mL/min per 1.73 m2 CMV infection within first 10 weeks, % Acute rejection within first 10 weeks, % Transplant era 1999-2006, % 2007-2011, %
1467 50.6 (15.0) 48.0 (15.6) 66.2 16.3 89.2 42.9
165 59.0 (12.5) 49.1 (16.8) 66.7 25.5 83.6 24.2
42.6 49.5 8.0 25.4 8 (0-18) 20.2 78.8 16.4
44.8 47.3 7.9 24.2 14 (1-25) 19.4 76.4 20.0
54.1 41.8 4.2 14.2 37.4 24.6 (3.7) 246.5 (58.1) 4.02 (0.37) 58.0 (19.3) 1.9 25.4 57.8 42.2
PTDM
Diabetes before transplantation
p1
