SCREENING OF RECIPIENTS WITH TRANSPLANTATION OF SIGNIFICANT ORGANS
Pre-transplant screening
In evaluating the risks of disease development, one should be guided by medical history and family anamnesis which includes the data on impairments of carbon metabolism [5]. Evaluation of fasting glucose level and oral glucose-tolerance test should be done on regular basis. Patients with fasting glycemia impairment, or with glucose-tolerance impairment, should be oriented, if possible, to changes in their way of lives, which includes weight reduction, diet, physical activities [4].
Post-transplant screening
According to international guidelines 2003 [4], the level of fasting plasma glucose should be defined in all the recipients after the transplantation with the following intervals: at least, once a week during one month after the transplantation; in 3rd, 6th and 12th month after the transplantation; then annually. The level of plasma glucose should be controlled regularly, preferably, while defining the level of immunosuppressor concentration in the blood. It is also necessary to carry out oral glucose-tolerance test, which currently represents golden standard of PTDM diagnostics. Using oral glucose-tolerance test, one can reveal more PTDM patients then by defining fasting plasma glycemia [52].
Transitory hyperglycemia is widely spread after the transplantation (For instance, in recipients with renal graft, it can be observed approximately in 90% cases) [53]. Stress during the operation may lead to hyperglycemia through many mechanisms, such as increase in catecholamines secretion and inflammatory cytokines which have counter-insular effect [54]. Hyperglycemia may also occur in connection with high immunosuppressor dosage during the first weeks after the transplantation [55].
Hence, it is expedient to conduct the PTDM screening-tests in a month after the transplantation, as after this period the patients are quite stable and take relatively stable doses of immunosuppressive therapy. However, it should be taken to account that- though transitory hyperglycemia revealed during the first month after the transplantation, according to international guidelines, can not serve as a criterion for diagnosing PTDM [7], it is an important risk factor for PTDM development during the first year [56].
Glycated hemoglobin may be used for diagnosing PTDM (HbA1c≥6.5%) [6,7]. The level of HbA1c 5.7-6.4% in the early post-transplant period points out the necessity of additional diagnostic tests. Besides, it should be taken to account that anemia of different genesis which often occurs in transplantation, may reduce HbA1c values and thus mask the diagnosis.
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The algorithms of post-transplant PTDM screening are still being discussed.
OBSERVING PTDM PATIENTS
Immunosuppressive mode
Immunosuppressive therapy is the most significant risk factor for PTDM development. Changes in immunosuppressive therapy may improve PTDM course or even contribute to its regression. However, prudence is necessary in modifying immunosuppressive mode. Currently, there is no consensus on this issue.
In accordance with KDIGO guidelines [12], modification of immunosuppressive mode may include:
o Reduction of tacrolimus, cyclosporine A or corticosteroid dosage
o Termination of tacrolimus therapy, or cyclosporine A therapy, or corticosteroid therapy.
o Replacement of tacrolimus with cyclosporine A, mycophenolate mophityl or azathioprine
o Replacement of cyclosporine A with mycophenolate mophityl or azathioprine.
Combined therapy with calcineurin blockers and mTOR inhibitors [57], as well as replacement of tacrolimus by serolimus are not recommended because of insulin resistance intensification [58]. Reduction of tacrolimus dosage [58] and serolimus [57] to the lowest verge of therapeutic dose is not recommended in view of rejection risk, especially in patients with high immunologic risk.
The data on influence of induction therapy on PTDM development are currently also limited. In retrospective monocentre study, in 264 recipients with renal graft induction therapy by basiliximab was associated with higher risk of PTDM development (51,5%) as compared to the patients who got no induction therapy (36,9%), r=0.017 [59] .
Hypoglycemic therapy
International consensus guidelines 2003 suggest applying graduated approach to PTDM treatment. At the first stage it indicates non-drug therapy which includes change in the way of life. The second stage is monotherapy by oral hypoglycemic drugs (OHGD). The third stage is combined OHGD therapy. The 4th stage is combined OHGD-and insulinotherapy. And, finally, monotherapy by insulin [4].
However, phased approach may be unpractical, and in this connection these guidelines were completed with international consensus 2014 [7]. In the first 6 months after the transplantation, PTDM is known to have much more pronounced onset than type 2 diabetes mellitus. Respectively, the treatment should be more aggressive to normalize carbohydrate metabolism, and it shouldn’t be focused only on changes in the way of life. Besides, as it was mentioned above, hyperglycemia in the first month after the transplantation is a risk factor for PTDM development. Thus, fast hyperglycemia correction is necessary to reduce the risk of the disease development. In the randomized study, Hecking et al., in the recipients whose basal insulin was prescribed in glycemia higher than 7,8 mole/l (140 mg/dl), the risk of PTDM development was 73% lower than in the control group where the recipients got hypoglycemic therapy in accordance with the international guideline recommendations 2003 [54].
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Choice of one or another hypoglycemic preparation should be made basing on specific side effects, the graft function, and interaction with immunosuppressive preparations (table 4) [12]. Metformin showed its safety in the study which included 32 recipients during 16 months of therapy [60]. The possible limiting factor for metformin application may be potential aggravation of gastrointestinal side effects which occur in application mecophenolate mophityl or mycophenolic acid. Several studies evidence that application of thiazolidinedione is safe and effective after transplantation, however, side effects of these preparations, such as delay of liquid and increase in mass of the body, aggravation of cardiac insufficiency, urinary bladder cancer, limit the indications for their application.
The preparations which stimulate insulin secretion (secretagogues), e.g., Sulfonylurea preparations and glynides may be used in PTDM treatment, when impairment of insulin secretion is the prevalent mechanism, conditioned by calcineurin inhibitors or mTOR.
Gliquidone does not influence on concentration of immunosuppressors in the blood and, probably, is preferable in prescription for PTDM patients [18].
Currently, there are no reliable studies on safety and efficiency of GLP-1 (Glucagon-like peptide 1). As for DPP-4 inhibitors (dipeptidylpeptidase 4 inhibitors), in recent randomized controlled study Haidinger M. et al. first indicated significant improvement both in postprandial glycemia, and in HbA1c in PTDM treatment by vildagliptin [61]. Besides, as compared to sitagliptin and saxagliptin, vildagliptin is not metabolized by Р450 cytochrome and does not influence on the concentration of immunosuppressors in the blood [12], which, probably, makes it preferable for PTDM treatment.
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Further study of PTDM pathogenesis, as well as more clinical trials are necessary to develop relevant schemes of treatment by oral hypoglycemic drugs.
Table 4. Oral hypoglycemic drugs in PTDM therapy (adapted [12, 18]).
| Class | Preparation | Drug interaction |
| 1G sulfonylurea preparations | All preparations | ↑ CsA concentration |
| 2G sulfonylurea preparations | glipizide, gliclazide, glibenclamide, glimepyride | ↑ CsA concentration |
| Gliquidone | no | |
| glinides | repaglinide | ↑ concentration both of repaglinide, and CsA |
| Nateglinide | ↑ concentration both of nateglinide, and CsA | |
| α-glucosidase inhibitors | Acarbose | No |
| Biguandins | Metformin | No |
| Thiazolidinediones | pioglitazone | No |
| rosiglitazone | No | |
| Agonists of GLP-1 receptors | Exenatid | No |
| DPP-4 inhibitors | Sitagliptin | Metabolized by P450* cytochrome |
| Vildagliptin | No | |
| Saxagliptin | Metabolized by R450* cytochrome |
CsA,Cyclosporine A; GLP-1, Glucagon-like peptide 1; DPP-4, dipeptidyl peptidase 4; * are likely to increase cyclosporine concentration, as well as tacrolimus and mTOR inhibitor
CONCLUSION
PTDM is a frequent complication occurring after transplantation of significant organs. Its development is associated with increase of cardiovascular risk, development of infections and graft rejection. Except for risk factors related to type 2 SD, PTDM development conditions risk factors which are directly related to the transplantation, such as rejection in the anamnesis, incompatibility by HLA-antigens, post-transplant hyperglycemia and the key risk factor– immunosuppressive therapy prescribed after the transplantation. Assessment of risk factors for PTDM development in an individual patient should become an integral part of his/her observation both before, and after the transplantation. Treatment of patients with developed PTDM, or with high risk of disease development, should be based on international guidelines, however, at the same time, apply individual approach. Selection of immunosuppressive protocol and its modification to prevent or soften PTDM clinical course should be conducted considering individual immunologic risk. In general, a great number of issues related to PTDM diagnostics, its pathogenesis, observing patients with high risk or developed disease, are currently not completely solved and require further profound studies. Inclusion of ‘post-transplant diabetes mellitus’ in the diabetes mellitus classification is a separate issue. Currently, there is no such diagnosis, the only wording applicable for this situation is ‘diabetes mellitus induced by preparations or chemicals’. In our opinion, this wording does not completely reflect all the scope of risk factors for the disease development, as well as its pathogenesis, though it indicates to the key mechanism of its development. Probably, further study of this disease will give response to this question.
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COMPETITIVE INTERESTS
The authors declare absence of competitive interests in relation to this copy.
REFERENCES
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