| Although renal transplantation ameliorates cardiovascular risk actors by restoring renal function, it introduces new cardiovascular risks including impaired glucose tolerance or diabetes mellitus, hypertension, and dyslipidemia that are derived, in part, from immunosuppressive medications such as calcineurin inhibitors, corticosteroids, or mammalian target of rapamycin inhibitors. New onset diabetes mellitus after transplantation (NODAT) is a serious and common complication following solid organ transplantation. NOD AT has been reported to occur in2%to53%of all solid organ transplants. Kidney transplant recipients who develop NOD AT have variably been reported to be at increased risk of fatal and nonfatal cardiovascular events and other adverse outcomes including infection, reduced patient survival, graft rejection,and accelerated graft loss compared with those who do not develop diabetes. Identification of high-risk patients and implementation of measures to reduce the development of NOD AT may improve long-term patient and graft outcome.Over the years, the precise incidence of new onset diabetes after transplantation (NODAT) has been difficult to determine due to the lack of a standard definition for the condition. Historically, post-transplant diabetes has been variably defined as having random glucose levels greater than200mg/dL or fasting glucose levels greater than140mg/dL, or the need for insulin or oral hypoglycemic agents in the post-transplant period. In2003, the International Expert Panel consisting of experts from both the transplant and diabetes fields set forth the International Consensus Guidelines for the diagnosis and management of NODAT.1,2It was recommended that the definition and diagnosis of NODAT should be based on the definition of diabetes mellitus and impaired glucose tolerance (IGT) described by the World Health Organization(WHO).Risk factors for the development of NODAT are categorized as non-modifiable, modifiable or potentially modifiable, the former category to facilitate the identification of high risk individuals, and the latter two categories to optimize the management of NODAT. Older age has long been observed to be an important risk factor for the development of NODAT. Studys aldemonstrated that transplant recipients older than45years of age were2.2times more likely to develop NODAT than those younger at the time of transplantation (P,0.0001).Similarly, in an analysis of the US Renal Data System(USRDS) consisting of over11,000Medicare beneficiaries who received primary kidney transplants between1996and2000,showed a strong association between older age and NODAT.Similar to the general population, obesity has been shown to be associated with the development of NODAT in most studies.34obesity, defined as a BMI of30kg/m2Analysis of the USRDS database revealed that is one of the strongest risk factors for NODAT (Relative risk (RR) of1.73, P,0.0001). Although some studies failed to demonstrate an association between obesity and the development of NODAT, obesity and its associated peripheral insulin resistance state is a known risk factor for type2diabetes.The now well-established contributory role of corticosteroids on NODAT was first described by Starlz in1964in renal transplant recipients.The diabetogenic effect of corticosteroids has been suggested to be dose-dependent. Single-center studies have demonstrated that oral prednisolone dose reduction to5mg daily significantly improves glucose tolerance during the first year after transplantation while a0.01mg/kg/day increase in prednisolone dose is associated with a5%risk of developing NOD AT. The DIRECT Study was the first multi-center open label, randomized trial to assess glucose abnormalities in de novo kidney transplant patients who were randomized to cyclosporine microemulsion(CSA-ME) or tacrolimus-based immunosuppression.Some early clinical and randomized controlled trial study,whether sirolimus (SRL) alone or combined with CNI drugs had no obvious effect on glucose metabolism after renal transplantation; however, Teutomico A recently study showed that during the treantment from CNI to SLR and combanation CNI and SRL treatment gradually removing the CNI impaired glucose tolerance to increase by30%.A single center study showed that tacrolimus and sirolimus combination therapy was higher than the incidence of tacrolimus NOD AT alone.Cosio et al demonstrated that higher pretransplant glucose is a risk factor for NOD AT at one year.Using patients with pretransplant FPG levels between90and100as the reference group, patients with plasma glucose,90mg/dL have lower risk of NODAT (OR=0.46, P=0.01).In contrast, the risk of NODAT increases as the pretransplant FPG levels increases (FPG=101-109, OR=1.5; and FPG=110-125, OR=7.6, P,0.0001).The development of NODAT has also been shown to be associated with an adverse impact on patient survival and an increased risk of graft rejection and graft loss, as well as an increased incidence of infectious complications. In a study consisting of173renal transplant recipients,1-year patient survival rates in those with, versus those without NODAT were83%versus98%,respectively (P,0.01).54Data from the United Renal Data System consisting of over11,000Medicare beneficiaries who received primary kidney transplants between1996and2000demonstrated that compared to "no diabetes", NODAT was associated with a63%increased risk of graft failure (P,0.0001), a46% increased risk of death-censored graft failure (P,0.0001) and an87%increased risk of mortality(P,0.0001).SRL, a new type of antirejection immunosuppressants, has highly antirejection ability, low renal toxicity, and antitumor effect. SRL is mainly used in the the initial immunization programse;immunization programse based on SRL;CNI Dose reduction by gradually remove from CNI to SRL, conversion from CNI to SRL caused by chronic transplant kidney disease.According to improve the Global prognosis of Kidney Disease (Kidney diseases: Improving Global Outcomes, KDIGO) guide and literature at home and abroad, the traditional oral glucose-lowering treatment strategies often cure NODAT poorly, especially for NODATcaused by for the CNI drugs.Adjustment anti-rejection programs become the first chose, including the CNI dosage reduction,but the CNI dosage reduction can increase the risk ocurance of acute or chronic rejection, and rejection can damage on graft to a great extent, thus reducing/kidney survival rate, clinical doctors mostly is very prudent when weighing the NODAT complications and drug dosage reduction.Our author’s own research center used sirolimus to replace the CNI many years ago and found that blood sugar was declined, diabetes symptoms was improvement in partial patients with NODAT.The hypoglycemic effect even better than stopping using hormone dosage reduction and the CNI hormone reserving therapy, then summarize the diagnosis and treatment of our hospital in recent10years, to evaluate the safety and efficacy of conversion treatmenton on NODAT.Sirolimus, a new macrolide antibiotic, for mammals rapamycin target protein (MammalianTarget of Rapamycin, mTOR) specific blocker, throuh inhibiting mTOR cell signaling pathway, lead to its downstream substrates eukaryotic cell translation inception factor binding protein4e1(e1F4E-binding proteinl,4e-Bp1) and im ribosomal protein kinase (ribosomal protein56kinases, S6Ks) diminished or disappeared, the phosphorylation of regulation and effect cell growth, proliferation and metabolism. According to a recent study,rapamycin plays an important role in glucolipid metabolic disorders and related disease.mTOR is a kind of typical serine/threonine kinase, was related with a variety of human diseases such as cancer, diabetes, obesity, cardiovascular disease and other neurological disorders, such as regulation ofcell cycle and age-related diseases.So targeted inhibiting mTOR pathway could cure various diseases.Recent studies have confirmed that rapamycin islet cells secrete insulin in mice has no obvious inhibition, rapamycin treatment for a long time after the decrease of the insulin release, etc.Insulin receptor substrate1(Insulin receptor substrate, the IRS-1) serine phosphorylation plays an important role in mediating insulin regulation, is the main molecular levels indicater of insulin resistance.Further study found that mTOR S6K/IRS1signaling pathways and other cell signalingr realted protein interactions plays an important role in obesity and IR the pathogenesis.MTOR pathway can negative regulat insulin signal P13K/PKB in adipose tissue and skeletal muscle.At the same time a high-fat diet caused by the IR mTOR and S6K1in rat liver and skeletal muscle protein expression and the expression of phosphorylated proteins were significantly higher than that of normal diet in rats; With insulin can increase the IRS-1after activation of mTOR Ser636/639loci of phosphorylation levels, and the site adjacent to the IRS-1modified protein tyrosine phosphorylation site, the site after phosphorylation reduces its ability to interact with P13K.So activity mTOR pathway can make Ser636/639loci on the IRS-1phosphorylation and inhibited insulin signal transduction, which cause the body to produce IR.Insulin resistance (insulinresistanee, IR) could reduce insulin susceptibility, insulin signaling pathways,was expressed oxidative metabolism of the sugar oxidation reduction in skeletal muscle and fat cells and liver cells can not effectively inhibited glycogen decomposition and sugar dysplasia with increased blood sugar levels;Compensatory secrete insulin increased,islet appear high insulin hematic disease.The molecular mechanisms of insulin resistance is not clear at present,many studies confirmed that the outside world to the signal stimulation mTOR continued high activation, mTOR negative feedback caused by insulin receptor substrate1 (IRS-1).Rapamycin can improve IR state, restore tissue sensitivity to insulin.Tremblay3t3-such as L1in fat cells, confirmed that rapamycin blocking insulin and insulin resistance induced by amino acid, inhibit the excessive phosphorylation of mTOR and S6KI, reverse IR condition the IRS serine phosphorylation, enhance Akt phosphorylation, fat cells increased sugar absorption.TNF alpha is secreted by the various body cells, inflammatory and immune regulation and so on the many kinds of biological function of protein glycosylation, the genes in the chromosome6stretching3, at the same time have antitumor effect.Current research has confirmed the TNF alpha can also effect on insulin signaling pathway, inhibit insulin signal transduction, and leads to insulin resistance, its main mechanism is through the insulin receptor substrate1(IRS1) serine phosphorylation, inhibition of IRS1tyrosine phosphorylation, inhibition of PI3K downstream activity, at the same time reduce the muscle cells, fat cells of the glucose transporter (GLUT-4) receptor gene expression, protein synthesis and transfer to the cell surface, can also inhibit vascular endothelial nitric oxide NO synthase, vasodilator effect caused by the NO reduction, and activate a variety of growth factors, cell adhesion factor, damage cells, endothelial function, and thus the TNF alpha is regarded as one of the important medium of islet cell pathogenic damage. We searth many literatures and found that TNF alpha play an important role in patients with diabetes onset, so this study it to explore therapeutic effect with converion from SRL to CNI on NOD AT and forecast to NOD AT with serum TNF alpha level.Objective1. To evaluate safety and efficacy of sirolimus (SRL) converting to calcineurin inhibitors (CNI) for the treatment of diabetes after kidney transplantation;2. To explore the feasibility of serum TNF-alevel to forecast the incidence of NODAT.MethodsAmong321kidney transplant recipients,34patients developed NODAT (10.59%) and divided into three groups:first14patients (group A)continued with a reduced dose of calcineurin inhibitors (CNI); group B(12patients) were converted to sirolimus; Group C(12patients)were applied with oral hypoglycemic drugs; group A for20%of the standard the CNI dosage reduction scheme, namely tacrolimus concentration of drug at5-7ng/mL, ring spore, maintain drug concentration in the130-150mg/dL;Group B line tacrolimus conversion to sirolimus solution, namely, stop using the CNI drugs into2mg oral sirolimus, sirolimus concentration of drug testing in5days after the transformation, and maintain the sirolimus concentration in7to10ng/mL. To statistics fasting blood sugar and insulin dose in all healthy adults and NOD AT patients before conversion treatment and on one month, three months and six months after the treatment of acute rejection with acute rejection,incidence, infection rate, people/kidney survival rate and complication.Review from March2012to September2013in our huospital,155cases of allograft renal transplantation patients,32patients with postoperative diagnosis NOD AT conversion routine treatment, NOD AT diagnosis standards refer to the WHO standards, and take10healthy adult patients serum in compared group.Line tacrolimus conversion to sirolimus solution, namely, stop using the CNI drugs into2mg oral sirolimus, sirolimus concentration of drug testing in5days after the transformation, and maintain the sirolimus concentration with7to10ng/mL.To statistics fasting blood sugar and serumTNF-a level in all healthy adults and NOD AT patients before conversion treatment and on one month, three months and six months after the treatment of acute rejection with acute rejection,incidence, infection rate, people/kidney survival rate and complication.ResultsAll patients after kindey transplantation needed to monitor blood sugar, and oral hypoglycemic drugs and subcutaneous injection of insulin therapy; patients with diagnosis of NODAT was an average of13.02+1.74mol/L;there was no significant difference between the three groups (P>0.05);In group A fasting plasma glucose levels decreased to8.05±2.45mmol/L in6months, while in groupB, fasting plasma glucose levels decreased to7.45±2.44mmol/L and in group C, fasting plasma glucose levels decreased to9.30±3.89mmol/L; Group A and Group B patients glucose decreased to normal level in12month but the insulin dose need per day in Group A were more than Group B((P<0.05)).Serum creatinine was144.136±61.7mmol/L at the time of conversion and130.5±35.7mmol/L one month after conversion to sirolimus therapy (P<0.05), while in the group of patients remaining with a reduced dose of CNI, serum creatinine was116.6±30.6mmol/L at three month after conversion and119.0±24.6mmol/L at six month after conversion (P>0.05).No benefit of renal function in Group C with the therapy of oral oral hypoglycemic drugs and the creatinine improved. At five-year followup, group A patient and graft survivals were100%and75%, respectively, not significantly different from group B patient (83.4%and68%, respectively, P=0.847). Patient and graft survivals in Group C were less than Group B and Group C.Blood serumTNF-a level was related with fasting plasma glucose levels betwwen healthy adults and patients with NODAT before conversion;After coversion treatment form CNI to sirolimus, the serum level of TNF-α was declined with blood sugar level, the serum level of TNF-α was associated with fasting blood glucose levels on one,six,twelve month after surgery(r>0.5, P<0.05);Conclusion1. This study demonstrated that the therapy of conversion from CNI to SRL in NODAT will ameliorate significantly blood sugar disorder and reduce the dependence on insulin;2. The conversion treatment from CNI to SRL does not increase the incidence of acute or chronic rejection and were safe and feasible for NODAT;3. The conversion treatment from CNI to SRL was even beneficial for part of the CNI nephrotoxicity sensitive patients;4. That the level of serum TNF-α is related to fasting plasma glucose levels in patients with NODAT showed that it can indirectly predict the occurrence of NODAT. |
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