Validation of diagnostic utility of fasting plasma glucose and HbA1c in stable renal transplant recipients one year after transplantation

Ussif et al. BMC Nephrology (2019) 20:12 https://doi.org/10.1186/s12882-018-1171-3 RESEARCH ARTICLE Open Access Validation of diagnostic utility of fasting plasma glucose and HbA1c in stable renal transplant recipients one year after transplantation Amin M. Ussif1*, Anders Åsberg1,2,3, Thea Anine Strøm Halden1, Espen Nordheim1,4, Anders Hartmann1,4 and Trond Jenssen1,5 Abstract Background: The use of HbA1c ≥6.5% for diagnosis of diabetes has been challenged for post-transplantation diabetes mellitus (PTDM) also known as new onset diabetes after transplantation (NODAT) due to a low sensitivity early after renal transplantation. PTDM diagnosed with an oral glucose tolerance test (OGTT) is highly predictable for long-term patient mortality. HbA1c was introduced for diagnosis based on the risk of developing diabetic retinopathy. The utility of HbA1c measures versus glucose criteria has not been widely assessed in stable transplant patients but still HbA1c is widely used in this population. The aim of the present analyses was to validate the utility of fasting plasma glucose (FPG) together with HbA1c in diagnosing PTDM in stable renal transplant recipients (RTRs). Methods: OGTT’s were performed one year after transplantation in 494 consecutive RTRs without diabetes. FPG and HbA1c were obtained the same day, before starting the OGTT. Validation was performed using C-statistics and logistic regression analyses. Results: PTDM was diagnosed in 51 patients (10.3%) by glucose criteria, 38 (74%) patients were diagnosed by FPG ≥7.0 mmol/L [126.1 mg/dl], and 13 (26%) only by 2-h plasma glucose. Six of the latter had HbA1c ≥6.5%. Only seven patients out of the 51 (13.7%) PTDM patients remained undiagnosed when HbA1c ≥6.5% was used together with FPG, and five of these regressed to normal after a median follow-up of 14 months. ROC curves including FPG and HbA1c versus OGTT derived criteria revealed an AUC of 0.858. Conclusions: Combining standard diagnostic FPG and HbA1c criteria captured almost all patients with persistent PTDM in stable RTRs. The combined use of the criteria appears to be an applicable diagnostic strategy for PTDM without the need of an OGTT one year post-transplant. Trial registration: Retrospectively registered. Keywords: Renal transplantation, Post-transplantation diabetes mellitus, Diagnosis, Oral glucose tolerance test, HbA1c * Correspondence: 1 Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, P.O.Box 4950, 0424 Oslo, Nydalen, Norway Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ussif et al. BMC Nephrology (2019) 20:12 Background Post-transplantation diabetes mellitus (PTDM) is a term for diabetes that is diagnosed after solid organ transplantation. The diagnosis has traditionally been based on glucose criteria according to an oral glucose tolerance test (OGTT) [1]. However, with the introduction of HbA1c ≥6.5% as a diagnostic measure for type 2 diabetes [2, 3] questions have been raised regarding the use of this criterion also for PTDM, at least after renal transplantation [4– 6]. While the PTDM diagnosis made by the glucose criterion primarily defines increased mortality risk for the patient [7], the HbA1c criterion in type 2 diabetes is chosen merely according to the risk of developing diabetic retinopathy [8]. Other arguments against the use of HbA1c are particularly relevant to the early phase following renal transplantation with changes in erythropoiesis and introduction of anti-proliferative immunosuppressive drugs amongst other interacting factors on HbA1c [4, 6]. In agreement with these notions a previous study of early PTDM after renal transplantation revealed that the sensitivity of HbA1c ≥6.5% was as low as 50% for the diagnosis of PTDM [9]. When the glucose criteria during OGTT for the diagnosis of PTDM were used, we confirmed previous findings that PTDM had a detrimental effect on long-term cardiovascular outcomes, but HbA1c ≥6.5% per se did not significantly associate with adverse outcomes [7]. Other investigators have argued that a cut-off value for HbA1c ≥6.2% may be reasonable for diagnosis of PTDM in the early phase after transplantation [10]. A combination of the HbA1c criteria and OGTT in high risk patients may be another approach as advocated by an international consensus meeting on PTDM [11]. However, there is probably need for a simplified strategy in daily clinical routine. It is conceivable that HbA1c associates better with glucose long-term than the first months after transplantation. One year after transplantation hemoglobin values are usually normalized and stable in successfully RTRs. During the last few years we have examined almost RTRs at 1 year after transplantation, and included OGTTs for PTDM in patients who did not have a diagnosis of PTDM at this time point. The aims of this study were to examine whether the HbA1c criteria were useful for the diagnosis of PTDM and whether a combination of FPG and HbA1c drawn in a single fasting state could be used for diagnosis without need for an OGTT in a stable phase after renal transplantation. Methods All renal transplantations in Norway are performed at the National Transplant center in Oslo. As part of the routine follow-up most patients return to the transplant center after 1 year for thorough investigations including Page 2 of 6 an OGTT. Only patients without prior diagnosis of diabetes or PTDM undergo the glucose challenge test at that time. In the time period between September 2012 and August 2016 a total of 950 patients over 18 years of age were transplanted and 647 patients were attending 1 year follow-up. Altogether 494 patients without diabetes underwent testing with valid results from the OGTT 1 year after transplantation. The disposition of the patients is shown in Fig. 1. The immunosuppressive protocol consisted of basiliximab (20 mg iv on day 0 and 4) and methylprednisolone (250/500 mg iv on day 0 in standard/high risk patients) induction, followed by tacrolimus, mycophenolate mofetil and prednisolone maintenance. Oral tacrolimus was initiated at the day of transplantation, starting with 0.04 mg/kg twice daily in standard risk patients and Fig. 1 Patient disposition chart Ussif et al. BMC Nephrology (2019) 20:12 Page 3 of 6 0.05 mg/kg twice daily in high risk patients. TDM was applied and doses were (...truncated)