Conditionally changeable risk factors
Post-transplant diabetes mellitus: a Review
INTRODUCTION
Post-transplant diabetes mellitus (PTDM) is a frequent complication occurring after transplantation of significant organs. The patients with developed PTDM are at high risk of acute rejection, infections, cardiovascular events, decrease of long-term survivability [1]. In the USA, medical costs on renal graft recipient, with developed PTDM increase by 21 500$ [2].
Before 2003, “diabetes de novo” which developed after transplantation, was called PTDM. The disease was diagnosed if the level of the blood glucose in any moment was ≥ 11,1 mole/l, or the level of fasting blood glucose is ≥ 7,8 mole/l, or if there is a necessity of applying insulin or oral hypoglycemic drugs within more than 1 month after the transplantation [3].
In 2003, the international expert group which included diabetes and transplantation specialists, released the international guidelines. [4,5]. Ever since, PTDM was called “diabetes mellitus first revealed after transplantation” (DMFRT), and its diagnostics should be based on diabetes mellitus diagnosing criteria described by World Health Organization (WHO) and American Diabetes Association (ADA). It comprises fasting plasma glucose ≥ 7,0 mole/l (≥126 mg/dl), random fixation of plasma glucose any time of day regardless of the meal ≥ 11,1 mole/l (≥200 mg/dl), or ≥11,1 mole/l (≥200 mg/dl) within 2 hours after oral glucose-tolerance test (OGTT). In 2010, ADA added glycated hemoglobin (HbA1c) ≥6,5% as a criterion of diagnosing [6]. In 2014, the international expert group released the guidelines [7] where they stated that the term DMFRP can be misleading as it implies exclusion of diabetes mellitus before the transplantation, however, the proper diagnostics is not always done, e.g., diabetes mellitus can also take place before the transplantation. In view of this, they recommended to return to PTDM term which eliminates this disadvantage. The term “pre-DM” should be used for patients with post-transplant hyperglycemia, whose values don’t reach threshold valuations for PTDM diagnosing (disorders of fasting glycemia and/or disorders in glucose tolerance) (table 1).
Table 1. Criteria of diagnostics of carbon metabolism disorders after the transplantation.
| PTDM (diagnosed in 30- 45 days after the transplantation) | Diabetes symptoms plus random definition of glycemia as ≥11.1 mole/l (≥200 mg/dl), or the fasting plasma glucose is ≥7.0 mole/l (≥126 mg/dl), or ≥11.1 mole/l (≥200 mg/dl) in 2 hours after OGTT, or HbA1c is ≥6.5%. |
| o Pre-DM o Disorders in fasting glycemia o Disorders of glucose tolerance o Increased risk of DM development | Fasting plasma glucose 5.6-6.9 mole/l (100-126 mg/dl) Fasting plasma glucose <7.0 mole/l and 7.8-11.1 mole/l in two hours after OGTT HbA1c 5.7-6.4% |
Incidence
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In recipients with renal graft, PTDM amounts to 25%, in recipients with liver graft– 25%, in transplantation of lungs– 30-35%, and in heart transplantation– 40% [8–11].
Registered PTDM rate of morbidity depends on the duration of the observation, presence of risk factors, type of transplantation, as well as the mode of immunosuppressive therapy. The authentic increase in morbidity mainly takes place within the first year after the transplantation. After this period, yearly morbidity of diabetes mellitus is the same as in patients included into the waiting list (about 6% per year) [2]. Thus, in the late period, it is difficult to differ PTDM from true type 2 diabetes mellitus.
RISK FACTORS FOR DEVELOPMENT OF POST-TRANSPLANT DIABETES MELLITUS
PTDM risk factors are usually divided into unchangeable, changeable and conditionally changeable (table2).
Table 2. Risk factors for PTDM development (adapted [12]).
| Unchangeable | Conditionally changeable | Changeable |
| Ethnic origin | HCV-infection | Immunosuppressive therapy: o Calcineurin inhibitors o mTOR inhibitors o Corticosteroids o Induction therapy? |
| Age over 45 | CMV-infection | |
| Male donor | hypomagnesemia | |
| Burdened heredity on diabetes mellitus | Disorders in carbon metabolism before or after the transplantation | |
| HLA A28, A30, B42, etc. |
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| Incompatibility by HLA antigens | Obesity or other components of metabolic syndrome | |
| Presence of rejection in the anamnesis | ||
| Polycystic kidneys? |
Unchangeable risk factors
Age
The age is an important risk factor for PTDM development. Recipients at the age over 45 have 2,2 more odds to develop PTDM than younger recipients at the moment of transplantation (P< 0.0001) [3].
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Besides, when analyzing USRDS (United States Renal Data System) database which comprises more than 11000 people who received renal grafting from 1996 to 2000, Kasiske BL. Et al. showed strong relation between the age and PTDM. As compared to the control group at the age of 18-44, the recipients at the age of 45-59 had a relative risk (RR) of PTDM development 1,9 (P<0.0001), while in recipients older than 60, the relative risk equaled 2,09 (P<0.0001) [13].
Ethnic origin
In monocentre retrospective study which included 122 recipients with renal graft, the risk of PTDM development was twice higher in afroamericans compared to white Caucasians [14]. USRDS data showed that PTDM is more common among afroamericans (the relative risk=1,68, P<0.0001) and Hispanics (the relative risk = 1,35, P<0.0001), compared to Caucasians. [13]
The difference in frequency of PTDM occurrence in patients from different ethnic groups may be partially explained by different pharmacokinetic diabetogenic effect of immunosuppressive preparations. Afroamericans were proven to need a 37% increase of tacrolimus dosage compared to white Caucasians to achieve compared concentrations of the preparation in the blood [15].
Differences in these groups’ way of life may also contribute to the disease development.
Heredity
There is a strong evidence that the recipients with burdened family history of diabetes mellitus have a high risk of PTDM development [16]. The family history is meaningful in transplantation of any significant organ. In multicenter cross study performed in Spain which included 1410 recipients with renal graft, 489 operations on liver transplantation, 207 heart transplantations and 72 lung transplantations, it was proven that in burdened family history, the risk of PTDM development increased by 50% ( odds ratio (OR,) - 1.51) [17].
Earlier, the studies evaluating association of PTDM with single nucleotide polymorphism of different gens were limited by small amount of extracts and the absence of control group which made it impossible to come to any reliable conclusions.
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After 2007, genetic relation between PTDM and type 2 diabetes mellitus was proved by many studies (table 3) [18]. From the moment of the first genome-wide association study (GWAS), over 40 loci associated with development of 2 type diabetes mellitus in general population. Strength of relation between the revealed genetic variants was quite small (the odds ratio from 1,10 to 1,20 for most of them). One of the largest values was 1,55 which was revealed in patients with genetic polymorphism rs7903146 (T allele), of the basic variant of TCF7L2 gen (transcription factor 7-like 2) [19]. This allel is related to disorder in insulin secretion, incretin effect and the speed increase in hepatic glucose production. In the study, Ghisdal L. Et al. Showed the relation between polymorphism of TCF7L2 gen and PTDM development, in sufficiently large group (N=1076) [20].
Table 3.Gens in the studies evaluating genetic predisposition to PTDM (adapted [18]).
| Gen name | Polymorphism | N | Studies | Relation to PTDM | ||
| Apolipoprotein S-III (APOC3) | Sstl | 110 | Rodrigo et al. | No | ||
| Apolipoprotein E (AROE) | ɛ2/ ɛ3/ ɛ4 | 110 | Rodrigo et al. | No | ||
| Interferon-gamma (IFNG) | +874 | 278 | Babel et al. | AA genotype is related to PTDM | ||
| interleukin 10 (IL10) | -1082 | 278 | Babel et al. | No | ||
| Vitamin D receptor (VDR) | TaqI | 70 | Numakura et al. | PTDM is related to TaqI | ||
| ApaI | No | |||||
| BsmI | No | |||||
| G866A | No | |||||
| Cytochrome P450 (CYP3A5) | A6986G | 70 | Numakura et al. | No | ||
| Angiotensin converting enzyme (ACE) | I/D | 70 | Numakura et al. | No | ||
| 42 | Rodríguez-Moreno et al. | No | ||||
| angiotensinogen (AGT) | M235T | 42 | Rodríguez-Moreno et al. | TT genotype is related to PTDM | ||
| Interleukin6 (IL6) | -174 (G>C) | 349 | Bamoulid et al. | CC genotype: Reduction of PTDM risk development | ||
| 335 | Sánchez-Velasco et al. | No | ||||
| 278 | Babel et al. | No | ||||
| Tumor necrosis factor (TNF) | G-238A | 61 | Gençtoy et al. | (AA+GA) genotypes G-238A: High level of fasting insulin and HOMA-IR | ||
| -308 | 278 | Babel et al. | No | |||
| T-specific transcriptional factor 7 (TCF7L2)
| rs7903146 | 589 | Kang et al. | OR of CT genotype: 1.71 | ||
| 1076 | Ghisdal et al. | OR of CT genotype: 1.7; TT genotype: 2.42 | ||||
| 234 | Kurzawski et al. | No | ||||
| 303 | Yang et al. | No | ||||
| Family of solute transporters 30, member 8 (SLC30A8) | rs13266634 | 589 | Kang et al. | OR of CC genotype: 1.96 | ||
| Human hybrid protein (HHEX) | rs1111875 | 589 | Kang et al. | OR of CC genotype: 1.81 | ||
| rs7923837 | OR of GG genotype: 1.84 | |||||
| rs5015480 | OR of CC genotype: 1.97 | |||||
| Regulatory Subunit-1 of cyclin-dependent kinase of type 5 (CDKAL1) | rs10946398 | 589 | Kang et al. | OR of CC genotype: 2.02 | ||
| Inhibitor of cyclin-dependent kinase 2A/2B (CDKN2A/B) | rs10811661 | 589 | Kang et al. | OR of TT genotype: 1.66 | ||
| Potencial-dependent potassium channel 1, KQT family (KCNQ1) | rs2237892 | 589 | Kang et al. | OR of TT genotype: 1.61 | ||
| Calpin 10 (CAPN10) | rs5030952 | 372 | Kurzawski et al. | OR of CT genotype: 2.45 | ||
| Hepatocyte nuclear factor 4a (HNF4A) | rs2144908 | 303 | Yang et al. | OR of AA genotype:1.96 | ||
| rs1884614 | OR of TT genotype: 2.44 | |||||
| Insulin receptor substratum-1 (IRS1) | rs1801278 | 303 | Yang et al. | OR of AA+AG genotypes: 2.71 |
N is the number of patients included into the study; HOMA-IR, homeostasis model assessment of insulin resistance
Higher frequency of PTDM development is connected with HLA-phenotype, as well as one including HLA-A28, A30, V42, etc. Incompatibility by HLA antigens, previous graft rejection, and male donor are also risk factors for the disease development [12].
Polycystic kidneys in the recipient increases the risk of PTDM development by some research data [21], which contradicts to other research data [22].
Conditionally changeable risk factors
HCV-associated PTDM
Connection between hepatitis C and type 2 diabetes mellitus in common population has been known for a long time. Potential mechanisms of diabetogenic effect of HCV-infection include reduction of hepatic glucose absorption, aggravation of gluconeogenesis, direct cytopathic effect of the virus on pancreas beta-cells, development of insulin-resistance (23]. As well as in general population, connection between hepatitis C virus and PTDM development was revealed in recipients of significant organs. Nevertheless, pathogenesis of HCV-associated PTDM has not sufficiently studied yet. Clinical trials of recipients who had an orthotopic liver transplantation, showed that the prevalent factor in the disease development is insulin resistance connected with active HCV-infection. The relation between recurrent hepatitis and increase of viral loading and PTDM development [7, 23]. Besides, in recipients with positive response to antiviral therapy, one could observe improvement of glycemic control [7].
In a small study which included 16 patients on the waiting list for renal transplantation, with stable positive response to treatment of HCV-infection with interferon in pre-transplant period, none of them developed PTDM (observation of the recipients lasted from 2 to 88 months, average 22,5 months) [24]. Probably, efficient treatment of hepatitis C before the transplantation, may potentially reduce the risk of PTDM development.
Cytomegalovirus-associated PTDM
Connection between Cytomegaloviral infection (CMV) and PTDM development was first revealed in 1985 in recipients of renal graft. In the study which comprised 160 recipients with kidney transplantation who were monitored for CMV-infection, within 3 months, it was shown that asymptomatic CMV-infection 4 times increases the risk of PTDM development (RR=4.00, P=0.025) [25]. Patients with active CMV form had depressed insulin secretion as compared to uninfected patients, in which connection one may assume that insulin secretion disorder in beta-cells may be meaningful for CMV-associated PTDM pathogenesis. Probably, CMV-induced emission of pro-inflammatory cytokines may lead to apoptosis and functional disorder of pancreas beta-cells [26].
Hypomagnesemia
Numerous studies show inverse relation between the level of blood magnesium and glycemic control [27].
As well as in general population, hypomagnesemia is an independent predictor of PTDM in recipients with renal and hepatic transplantations. In monocentre retrospective study which comprised 254 recipients with renal transplantation, van Laecke S. et al. showed that hypomagnesemia during the first month after transplantation was connected with PTDM development regardless of applied protocol of immunosuppressive therapy [28].
In the recent study, Augusto J-F. Et al. Showed that hypomagnesemia is the risk factor for PTDM development also in pre-transplant period [29].
CHANGEABLE RISK FACTORS
Metabolic syndrome
Numerous studies show that excess weight and obesity are connected with PTDM development [30]. Analysis of USRDS data indicated that the body mass index over 30 kg/m2 is one of the most significant risk factors for PTDM development (relative risk 1,85, P<0.0001), for recipients with BMI 25 - 29.9 kg/m2, the relative risk equals 1.39, R<0.0001 [31]
In retrospective study which comprised 640 recipients, it was shown that PTDM development in the first year correlates to the number of metabolic syndrome components: 0-0%, 1-24.2%, 2-29.3%, 3-31.0%, 4-34.8% and 5-73.7% (P=0.001). Multifactor analysis which comprised separate metabolic syndrome components, indicated that, of all pre-transplant metabolic syndrome components, only the level of low-density lipoproteins is independently related to risk of PTDM development [32].
In the recent study, Israni AK. Et al. Also indicated that metabolic syndrome is an independent risk factor for PTDM development [33].
Corticosteroid-associated PTDM
The meaning of glucocorticosteroids in PTDM development was first described by Starzl in 1964 in recipients with renal transplantation [3].
Glucocorticoids dose-dependently increase hepatic glucose production (by gluconeogenesis stimulation), increase insulin-resistance, suppress insulin secretion, as well as induce beta-cells apoptosis in high dosage [34].
In monocentre studies conducted in Norway, it was shown that reduction of prednisolone dosage up to 5 mg per day significantly improves glucose tolerance within the first year after the transplantation [35], while the increase of the dosage by 0,01 mg/kg per day increases the risk of PTDM development by 5%. In a small study comprising 57 recipients with renal graft, it was revealed that reduction of prednisolone dosage on average from 16 mg per day (in the rage from 10 mg to 30 mg) up to 9 mg per day (in the range from 5 mg to 12,5 mg) leads to increase of insulin-sensitivity index by 24% [36]. In the retrospective analysis of Organ Procurement Transplant Network/Scientific Registry of Transplant Recipient (OPTN/SRTR) database including over 25000 recipients with renal transplantations carried out from 2004 to 2006, Luan FL. Et al. Indicated that in immunosuppressive therapy which does not include steroids, one could observe significant reduction in probability of PTDM development as compared to immunosuppressive protocols which included steroids. General rate of PTDM morbidity within 3 years after the transplantation, when no steroids were used, accounted for 12,3% versus 17,7% in steroids use (R<0.001) [37]. In retrospective study which included 88 recipients with cardiac transplantation, it was revealed that the patients with developed PTDM had taken higher average dosage of prednisolone as compared to the recipients with no diabetes (0.21 ± 0.03 versus 0.19 ± 0.03 mg/kg /day, P < 0.01) [38].
PTDM associated with calcineurin inhibitors
Calcineurin inhibitors (Cyclosporine A, tocralimus) constitute the basis of modern immunosuppressive therapy. However, their diabetogenic effect is also well-known, tocralimus diabetogenic effect being pronounced stronger than in cyclosporine [39, 40].
Figure 1 gives a scheme of possible ways for diabetogenic effect of tocralimus (I) and cyclosporine A(II).
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