These authors have contributed equally to this work
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This retrospective study aimed to investigate the effect of diabetes mellitus (DM) on the risks of end-stage kidney disease (ESKD) and post-liver transplantation (post-LT) mortality. Using data from the National Health Insurance Research Database, Taiwan, 3,489 patients who received a LT between 1 January 2005, and 31 December 2015, were enrolled in this study and divided into the pre-existing DM, post-LT DM (PLTDM), and without DM groups. All subjects were followed up from 1 year after LT to the index date for ESKD, and the occurrence of death, or until 31 December 2016. Of the 3,489 patients with LT, 1,016 had pre-existing DM, 215 had PLTDM, and 2,258 had no DM pre- or post-LT. The adjusted HRs of ESKD were 1.77 (95% Confidence Interval [CI], .78–3.99) and 2.61 (95% CI, 1.63–4.18) for PLTDM group and pre-existing DM group compared to without DM group, respectively. For the risk of death, the adjusted HRs were 1.05 (95% CI, .72–1.55) and 1.28 (95% CI, 1.04–1.59) for PLTDM group and pre-existing DM group compared to those without DM group, respectively. The sensitivity analysis for the risk of ESKD and death also revealed the consistent result. Pre-existing DM has significant increase the risk of post-LT ESKD and mortality. The role of PLTDM should be explored to explain postoperative morbidity and mortality.
Liver transplantation (LT) is an effective strategy for treating patients with end-stage liver disease and some types of hepatocellular carcinomas (
Renal dysfunction is common in recipients of liver transplant and is a known risk factor for mortality in patients who have undergone LT (
We conducted a Nationwide population-based retrospective cohort study using data from the NHIRD, Taiwan. Taiwan initiated its National Health Insurance (NHI) program in 1995. The system covered almost 99% of the entire population in 2007. Taiwan’s population in 2015 was approximately 23 million and the more than 99% of the population is covered by the NHI program. De-identified and computerized data were provided by the National Health Insurance Administration, which organizes claims data for NHI and established the NHIRD. The NHIRD contains basic patient information and medical data from medical claims, including clinical diagnostic codes based on the International Classification of Disease, Revision 9, Clinical Modification (ICD-9-CM). According to the guidelines of the NHI program, the diagnosis code for LT would have been entered by a qualified gastroenterologist or transplant surgeon. The study adhered to the ethical standards of the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. No executed prisoners were used as donors.
The recipients were identified from the NHIRD database using the LT surgery code (codes 75020A or 75020B) from 1 January 2005, to 31 December 2015. We excluded patients with missing age and sex data, who were <20 years old at the time of surgery, who had been diagnosed with ESKD before LT, or who had been coding as the Type 1 diabetes after LT. We also excluded patients who had developed ESKD or died within 1 year after LT to reduce the immortal time bias. The recipients were divided into three groups: pre-existing DM, PLTDM, and without DM. DM (ICD-9-CM code: 250) was identified from medical notes recorded either three or more times in the outpatient department or one or more times in the inpatient department within 1 year before the index date of LT. PLTDM group was defined as those diagnosed as having DM after LT within 1 year. After these three groups were defined, all subjects were start followed from 1 year after LT to the index date for ESKD, the occurrence of death, or until 31 December 2016 to evaluate the risk of ESKD. To estimate the risk of death, all subjects were followed from 1 year after LT to the occurrence of death or until 31 December 2016. We showed our detailed main study design for ESKD and death in
The primary outcomes in this study are ESKD and death. Patients who had been diagnosed with ESKD were identified when the use of hemodialysis codes (58001C, 58014C, 58019C, 58020C, 58021C, 58022C, 58023C, 58024C, 58025C, 58027C, 58029C, 58030B, 69006C) was more than 24 times in three consecutive months and peritoneal dialysis codes (58002C, 58009B, 58010A, 58010B, 58011A, 58011AB, 58011B, 58011C, 58012A, 58012B, 58017B, 58017C, 58028C) was more than three consecutive months or renal transplantation surgery (76020A, 76020B) was performed. Mortality data were obtained from the Taiwanese Ministry of Internal Affairs, cause of death database and included information on the date and cause of death.
Comorbidities were identified from medical notes recorded either three or more times in the outpatient department or one or more times in the inpatient department within 1 year before the index date for LT. The following comorbidities were identified among patients in our study cohort with ICD-9-CM codes: hypertension (ICD-9-CM codes: 401–405), hyperlipidemia (ICD-9-CM codes: 272.0–272.4), chronic kidney disease (CKD) (ICD-9-CM codes: 2504, 2741, 28311, 403, 404, 4401, 4421, 4473, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 6421, and 6462), myocardial infarction (ICD-9-CM codes: 410 and 412), and congestive heart failure (ICD-9-CM codes: 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, and 428). Immunosuppressant-use was defined as the use of calcineurin inhibitors, antimetabolic agents (purine antagonist), mammalian target of rapamycin (mTOR) inhibitors, and corticosteroids during hospitalization. The usage of antihypertensive agent for more than 90 days within 1 year before the date for LT was also recorded, including angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), calcium channel blocker (CCB), diuretics,
For baseline covariates, we used the analysis of variance and chi-square test to test continuous variables and category variables among three groups, respectively. To evaluate the risk of ESKD and death, we used the Cox proportional hazard models. In Cox proportional hazard models, we adjusted for potential confounders, such as age, sex, hypertension, hyperlipidemia, CKD, myocardial infarction, congestive heart failure, calcineurin inhibitors, antimetabolic agent (purine antagonist), mTOR inhibitors, corticosteroids, and antihypertensive agents to minimize confounding bias. We also assessed the assumption of proportional hazards for Cox proportional hazard models.
To deal with the immortal time bias, we did sensitivity analyses by using different study design (
A flowchart of the patient selection process is shown in
Flowchart of the selection criteria and process of selecting eligible patients.
Characteristics of liver transplant patients.
Characteristic | DM | PLTDM | Non-DM |
|
---|---|---|---|---|
Number of patients | 1,016 | 215 | 2,258 | |
Age, mean (SD), years | 54.90 ± 7.28 | 53.52 ± 7.99 | 51.53 ± 9.34 | <.0001 |
Age group, years, |
<.0001 | |||
20–39 | 28 (2.8) | 14 (6.5) | 249 (11.0) | |
40–59 | 699 (68.8) | 150 (69.8) | 1,568 (69.4) | |
60–79 | 289 (28.4) | 51 (23.7) | 441 (19.5) | |
Sex, male, |
736 (72.4) | 153 (71.2) | 1,656 (73.3) | .7209 |
Comorbidities before the index date, |
||||
Hypertension | 362 (35.6) | 38 (17.7) | 345 (15.3) | <.0001 |
Hyperlipidemia | 128 (12.6) | 4 (1.9) | 78 (3.5) | <.0001 |
Chronic kidney disease | 179 (17.6) | 20 (9.3) | 190 (8.4) | <.0001 |
Myocardial infarction | 5 (.5) | 0 (.0) | 2 (.1) | .0460 |
Congestive heart failure | 15 (1.5) | 3 (1.4) | 19 (.8) | .2303 |
Treatment with drugs after liver transplant, |
||||
Calcineurin inhibitors | 1,004 (98.8) | 214 (99.5) | 2,229 (98.7) | .5729 |
Antimetabolic agent (Purine antagonist) | 759 (74.7) | 145 (67.4) | 1,614 (71.5) | .0455 |
MTORIs | 204 (20.1) | 19 (8.8) | 393 (17.4) | .0004 |
Corticosteroids | 1,014 (99.8) | 215 (100.0) | 2,253 (99.8) | .7859 |
Treatment with drugs within 1 year prior to liver transplant, |
||||
Antihypertensive agents | 524 (51.6) | 81 (37.7) | 647 (28.7) | <.0001 |
ACEI | 43 (4.2) | 4 (1.9) | 20 (0.1) | <.0001 |
ARB | 132 (13.0) | 8 (3.7) | 83 (3.7) | <.0001 |
CCB | 132 (13.0) | 13 (6.1) | 111 (4.9) | <.0001 |
Diuretic | 582 (57.3) | 135 (62.8) | 1,033 (45.8) | <.0001 |
β-blockers | 379 (37.3) | 64 (29.8) | 513 (22.7) | <.0001 |
α-blockers | 15 (1.5) | 2 (0.9) | 10 (.4) | .0074 |
Hypoglycemic agent | 731 (72.0) | — | — | — |
Type I DM | 74 (7.3) | 0 (0.00) | — | — |
Incidence rate for end-stage renal disease.
No. of event | Person-years | Incidence rate | Crude | Adjusted |
|||
---|---|---|---|---|---|---|---|
Hazard ratio (95% CI) |
|
Hazard ratio (95% CI) |
|
||||
Non-DM | 38 | 8,947 | 4.2 | Ref. | Ref. | ||
PLTDM | 7 | 860 | 8.1 | 1.92 (0.86–4.31) | .1117 | 1.77 (.78–3.99) | .1694 |
DM | 43 | 3,279 | 13.1 | 3.29 (2.12–5.10) | <.0001 | 2.61 (1.63–4.18) | <.0001 |
Adjustment: age, sex, hypertension, hyperlipidemia, chronic kidney disease, myocardial infarction, congestive heart failure, calcineurin inhibitors, antimetabolic agent (Purine antagonist), mTORIs and corticosteroids, antihypertensive agents.
For the risk of death, we show the incidence rate, the crude and the adjusted HRs among three groups during the 12-year follow-up in
Incidence rate for death.
No. of event | Person-years | Incidence rate | Crude | Adjusted |
|||
---|---|---|---|---|---|---|---|
Hazard ratio (95% CI) |
|
Hazard ratio (95% CI) |
|
||||
Non-DM | 285 | 9,032 | 31.6 | Ref. | Ref. | ||
PLTDM | 29 | 878 | 33.0 | 1.05 (.72–1.54) | .7979 | 1.05 (.72–1.55) | .7915 |
DM | 145 | 3,362 | 43.1 | 1.34 (1.10–1.64) | .0045 | 1.28 (1.04–1.59) | .0204 |
Adjustment: age, sex, hypertension, hyperlipidemia, chronic kidney disease, myocardial infarction, congestive heart failure, calcineurin inhibitors, antimetabolic agent (Purine antagonist), mTORIs and corticosteroids, antihypertensive agents.
Otherwise, we also performed the sensitivity analysis for the risk of ESKD and death, which is disclosed in
Sensitivity analysis of risk of end-stage renal disease and death.
No. of event | Person-years | Incidence rate | Crude | Adjusted |
|||
---|---|---|---|---|---|---|---|
Hazard ratio (95% CI) |
|
Hazard ratio (95% CI) |
|
||||
End-stage renal disease | |||||||
Non-DM | 47 | 10,021 | 4.7 | Ref. | Ref. | ||
PLTDM | 14 | 1,740 | 8.0 | 1.74 (0.96–3.16) | .0692 | 1.70 (.93–3.09) | .0847 |
DM | 63 | 4,345 | 14.5 | 3.15 (2.15–4.60) | <.0001 | 2.28 (1.51–3.43) | <.0001 |
Death | |||||||
Non-DM | 456 | 10,146 | 44.9 | Ref. | Ref. | ||
PLTDM | 73 | 1,770 | 41.2 | .90 (.70–1.15) | .4104 | .89 (.69–1.14) | .3383 |
DM | 279 | 4,471 | 62.4 | 1.32 (1.14–1.53) | .0003 | 1.18 (1.01–1.39) | .0373 |
Adjustment: age, sex, hypertension, hyperlipidemia, chronic kidney disease, myocardial infarction, congestive heart failure, calcineurin inhibitors, antimetabolic agent (Purine antagonist), mTORIs and corticosteroids, antihypertensive agents.
The cumulative incidence curves for ESKD and death during the follow-up period are shown in
Cumulative incidence curves for
We performed a Nationwide population-based retrospective cohort study of patients who received an LT between 2005 and 2015 to evaluate the influence of DM on the risk of ESKD and mortality after LT. During the 12-year follow-up period, patients with pre-existing DM had a significantly higher risk of ESKD and mortality after LT. Patients with PLTDM did not increase the risk of ESKD and death after LT compared to those without DM. To our knowledge, this is the first study to examine the risk of ESKD and mortality after LT among patients with pre-existing DM, PLTDM and without DM.
DM is a group of metabolic diseases characterized by hyperglycemia, which is associated with microvascular and macrovascular complications resulting in long-term damage and failure of various organ systems (
In addition to pre-existing DM, PLTDM has emerged as a problem, which is diagnosed according to the 2003 International Consensus Guidelines. LT recipients who had no DM before transplantation but developed symptoms of DM with an elevated random plasma glucose (≥200 mg/dl) or an elevated fasting plasma glucose (≥126 mg/dl) or an elevated 2-h plasma glucose (≥200 mg/dl) during an oral glucose tolerance test were diagnosed to have PLTDM (
LT is associated with a deterioration of renal function in both early and late postoperative periods (
As follow-up is started from date of transplant and PLTDM is defined at any time point during the first post-transplant year, this group will inevitably have survived until diagnosis of PLTDM and as such patients in this group will not be able to experience mortality until their diagnosis of PLTDM. This creates a biased low mortality rate in this group. In order to deal with the immortal time bias in the PLTDM group, we defined PLTDM as those who had been diagnosed of DM within 1-year after LT. We then excluded the patients who had developed ESKD or died within 1 year after LT and started follow-up 1 year after liver transplantation (all groups are defined at this time point as pre-existing DM, PLTDM, or non-DM). Furthermore, we also performed the sensitivity analysis for the risk of ESKD and death, which disclosed the consistent result that patients with pre-existing DM had a significantly higher risk of ESKD and mortality after LT during 12-year follow-up period.
Since the administrative health database have become more accessible, the validity of
A major strength of this retrospective study is the relatively large number of patients with long follow-up periods. We have established the risk of developing ESKD and long-term survival in patients with pre-existing DM and PLTDM and without DM after LT. However, this study has some limitations. First, our results were based on a retrospective cohort study. The NHIRD is a secondary database and information on medical examination data, laboratory data, detailed rejection condition, transient hyperglycemia condition post-LT and the etiology of DM, CKD, death, and LT was not provided by the administrative database. PLTDM can be defined as a degree of hyperglycemia after LT. A reliable diagnosis of PLTDM must be made after the doses of immunosuppressive agents or steroid have been tapered and are stable. In our study, we defined PLTDM as those patients who had been diagnosed of DM within 1-year post-LT and it may create bias of inevitably included post-LT transient hyperglycemia. Second, our cohort study included patients from a 12-year period, and variations in the type of liver donor and the selection criteria for LT may influence long-term outcome. Thirds, ESKD takes times to develop, therefore, if PLTDM affect the outcome of ESKD, it may need longer follow-up period to elucidate the difference. We recommend extending the follow-up period and conducting further prospective studies to clarify long-term outcomes due to the conflicting survival rates reported between patients with PLTDM and without DM. Last, the power of the model for ESKD may not be large enough when we included many covariates in the model. We recommend to included more patients in the LT cohort in the future study.
In conclusion, this study demonstrated that patients with pre-existing DM had a significantly higher risk of developing ESKD and increasing the risk of death
Improvements in early post-liver transplantation (LT) survival rates have increased the importance of understanding the risks factors for late post-LT morbidity and mortality. This retrospective study aimed to investigate the effect of diabetes mellitus (DM) on the risks of end-stage kidney disease (ESKD) and post-LT mortality. This study demonstrated that patients with pre-existing DM had a significantly higher risk of developing ESKD and increasing the risk of death compared to without DM group. We emphasize the need for adequately powered studies to explore the role of Post-LT DM (PLTDM) to explain post-LT morbidity and mortality.
The data underlying this article were provided by National Health Insurance Research Database in Taiwan under license/by permission. The datasets presented in this article are not readily available because it is a restricted database only accessible by formal application to the Health and Welfare Data Science Center of Taiwan. Requests to access the datasets should be directed to the Health and Welfare Data Science Center of Taiwan (
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
C-YL participated in research design, writing, and performance of research. M-YW participated in research design, writing, and performance of research. H-CC participated in research design, writing, and performance of research. T-TC participated in writing and data analysis. L-YH participated in writing and data analysis. M-SW participated in research design, performance of research, and critically revised the manuscript. Y-GC participated in research design, critically revised the manuscript, and performance of research. All authors provided approval for publication of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This work was supported by grants from the National Health Research Institutes (NHRI-EX109-10926HT) and Ministry of Science and Technology (MOST) (MOST109-2314-B-038-106-MY3).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
Main study design for ESKD.
Main study design for death.
Study design in sensitivity analysis for ESKD.
Study design in sensitivity analysis for death.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; ESKD, end-stage kidney disease; HRs, hazard ratios; ICD-9-CM, International Classification of Disease, Revision 9, Clinical Modification; LT, liver transplantation; mTOR, mammalian target of rapamycin; NHI, National Health Insurance; NHIRD, National Health Insurance Research Database; PLTDM, post-liver transplantation diabetes mellitus; Post-LT, post-liver transplantation.