Research progress in risk factors of post-transplantation diabetes mellitus / 器官移植

Solid organ transplantation has significantly prolonged the survival of patients with end-stage diseases. However, long-term use of immunosuppressants will increase the risk of post-transplantation diabetes mellitus (PTDM) in the recipients, thereby elevating the risk of infection, cardiovascular disease and death. In recent years, with persistent improvement of diagnostic criteria of PTDM, clinicians have deepened the understanding of this disease. Compared with type 2 diabetes mellitus, PTDM significantly differs in pathophysiological characteristics and clinical progression. Hence, different treatment strategies should be adopted. Early identification of risk factors of organ transplant recipients, early diagnosis and intervention are of significance for improving the quality of life of recipients, prolonging the survival of grafts and reducing the fatality of recipients. Therefore, the diagnosis, incidence and risk factors of PTDM were reviewed in this article, aiming to provide reference for clinicians to deliver prompt diagnosis and intervention for PTDM.

Management of immunosuppressive drugs in HIV-positive solid organ transplant recipients / 器官移植

The application of combination antiretroviral therapy (cART) has significantly prolonged the life expectancy of patients infected with human immunodeficiency virus (HIV). However, viral infection and adverse reactions of cART drugs make patients more prone to organ failure. Solid organ transplantation has become a standard treatment for HIV-infected patients with end-stage organ failure. Nevertheless, among HIV-positive soild organ transplant recipients, multiple problems remain to be resolved, such as increased incidence of graft rejection, increased infection risk, drug toxicity and drug interaction between cART therapy and immunosuppressive drugs, etc. It is extremely challenging to deliver appropriate management for HIV-positive soild organ transplant recipients. Therefore, the application of immune induction therapy, calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors and other immunosuppressive drugs in HIV-positive soild organ transplant recipients was reviewed, aiming to provide reference for subsequent management of immunosuppression in HIV-positive soild organ transplant recipients.

The role of mammalian target of rapamycin inhibitor in virus infection of organ transplant recipients / 器官移植

At present, mammalian target of rapamycin (mTOR) inhibitors are commonly-used immunosuppressive drugs after organ transplantation, including sirolimus (rapamycin) and everolimus. mTOR inhibitors not only exert an immunosuppressive effect by inhibiting T cell proliferation, but also possess multiple potential functions, such as antiaging, anti-tumor and anti-virus infection, etc. Virus infection is one of the most common complications after organ transplantation. Current anti-viral treatments are limited and yield poor efficacy. In this article, the role of mTOR pathway in virus infection, the mechanism of common mTOR inhibitors and the role of mTOR inhibitors in different types of virus infections were reviewed, aiming to provide reference for clinical application and subsequent research of mTOR inhibitors in organ transplant recipients.

Risk factors of new-onset hypertriglyceridemia in kidney transplant recipients: a single-center analysis / 器官移植

Objective To identify the risk factors of new-onset hypertriglyceridemia (HTG) in kidney transplant recipients. Methods Clinical data of 149 kidney transplant recipients were retrospectively analyzed. According to serum triglyceride (TG) level after operation, they were divided into the non-HTG group (TG≤1.7 mmol/L, n=60) and new-onset HTG group (TG>1.7 mmol/L, n=89). Baseline data of all recipients were compared between two groups. The risk factors of HTG in kidney transplant recipients were analyzed by generalized estimating equation (GEE), and validated by multiple regression equations. Results No significant differences were observed in baseline data between two groups (all P>0.05). Multivariate analysis showed that the incidence of HTG in the middle and high tacrolimus (Tac) concentration groups was higher than that in the low Tac concentration group [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.22-7.93, P=0.018 in the middle Tac concentration group; OR 5.11, 95%CI 1.31-19.98, P=0.019 in the high Tac concentration group]. Compared with type-A blood recipients, the risk of new-onset HTG was significantly increased in type-O blood counterparts (OR 2.77, 95%CI 1.14-6.71, P=0.024). The risk of new-onset HTG was decreased along with the increase of preoperative globulin level (OR 0.93, 95%CI 0.87-0.99, P=0.043). At postoperative 3 months, Tac blood concentration in the new-onset HTG group was significantly higher compared with that in the non-HTG group, and significant difference was observed (P<0.05). Multiple regression equations confirmed that the risk of new-onset HTG in type-O blood kidney transplant recipients was higher than that in type-A blood counterparts, and the risk of new-onset HTG in the middle and high Tac concentration groups was higher than that in the low Tac concentration group (all P<0.05). Conclusions Type-O blood kidney transplant recipients are more prone to HTG. It is necessary to strengthen postoperative monitoring and control of blood lipids. The blood concentration of Tac probably affects the new-onset HTG in kidney transplant recipients. Maintaining an appropriate blood concentration of Tac may be beneficial to lowering the risk of HTG.

Effects of preoperative mTOR inhibitors on partial nephrectomy for renal angiomyolipoma associated with tuberous sclerosis complex / 中华泌尿外科杂志

Objective:To investigate the effects of preoperative mammalian target of rapamycin(mTOR )inhibitor on partial nephrectomy for renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML).Methods:A retrospective analysis was conducted on clinical data from 13 patients who were diagnosed with TSC-RAML and treated at Peking Union Medical College Hospital between August 2019 and July 2022. This cohort included 4 males and 9 females, with ages ranging from 22 to 66 years. All patients underwent partial nephrectomy, with 2 patients requiring two-stage surgeries due to bilateral RAMLs, resulting in a total of 15 surgeries being performed. Preoperative mTOR inhibitors, specifically everolimus (10 mg/d) or sirolimus (2 mg/d), were administered orally for at least 3 months prior to 7 of the surgeries. The effects of mTOR inhibitors on tumor size, tumor computed tomography attenuation value (CT value), and tumor CT enhancement were evaluated. The comparison of surgery-related clinical parameters was conducted between patients who received preoperative mTOR inhibitors and those who did not to assess the influences of mTOR inhibitors on surgery.Results:Compared to the baseline tumor, there was a significant reduction in tumor diameter after mTOR treatment [(6.4±3.1) cm vs. (8.7±3.9)cm], as well as in the CT value in both the unenhanced phase[(-18.63±48.73)HU vs. (-2.13±51.58)HU] and corticomedullary phase[(13.25±64.01)HU vs. (47.25±66.99)HU]. Additionally, tumor CT enhancement also decreased as compared with that before treatment [(31.88±18.20)HU vs. (49.38±20.63)HU]. Patients who received preoperative mTOR inhibitor showed a trend towards shorter operative time for removing per milliliter of tumor compared to those without preoperative mTOR inhibitor [1.06(0.18, 2.40) min/ml vs. 1.98(0.39, 5.03) min/ml] and so was the renal artery clamping time [0.17(0.03, 0.79) min/ml vs. 0.34(0.10, 1.71) min/ml]. Additionally, the amount of intraoperative bleeding for removing per milliliter of tumor was lower in patients with preoperative mTOR inhibitors compared to those without [0.72(0.19, 0.88) ml/ml vs. 1.69(0.59, 4.54) ml/ml].Conclusions:The administration of mTOR inhibitors before partial nephrectomy in patients with TSC-RAM have the potential to reduce tumor size and blood supply, as well as operative time, renal artery clamping time and intraoperative bleeding, which might contribute to surgery safety and preservation of renal function.

Effect of mammalian target of rapamycin inhibitor on growth in children / 中华实用儿科临床杂志

The mammalian target of rapamycin (mTOR) disorders have a close relationship with autoimmune disease,tuberous sclerosis (TfSC),cancer,obesity and senescence.mTOR inhibitors are wildly used in pediatric renal transplantation and TSC.Growth is an important indicator of children health and safety evaluation of pediatric drugs must include impact on growth.No evidence showed mTOR inhibitors had side effect on growth in children.

Acute Hyperglycemia Associated with Anti-Cancer Medication

Hyperglycemia during chemotherapy occurs in approximately 10% to 30% of patients. Glucocorticoids and L-asparaginase are well known to cause acute hyperglycemia during chemotherapy. Long-term hyperglycemia is also frequently observed, especially in patients with hematologic malignancies treated with L-asparaginase-based regimens and total body irradiation. Glucocorticoid-induced hyperglycemia often develops because of increased insulin resistance, diminished insulin secretion, and exaggerated hepatic glucose output. Screening strategies for this condition include random glucose testing, hemoglobin A1c testing, oral glucose loading, and fasting plasma glucose screens. The management of hyperglycemia starts with insulin or sulfonylurea, depending on the type, dose, and delivery of the glucocorticoid formulation. Mammalian target of rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia, ranging from 13% to 50%. Immunotherapy, such as anti-programmed death 1 (PD-1) antibody treatment, induces hyperglycemia with a prevalence of 0.1%. The proposed mechanism of immunotherapy-induced hyperglycemia is an autoimmune process (insulitis). Withdrawal of the PD-1 inhibitor is the primary treatment for severe hyperglycemia. The efficacy of glucocorticoid therapy is not fully established and the decision to resume PD-1 inhibitor therapy depends on the severity of the hyperglycemia. Diabetic patients should achieve optimized glycemic control before initiating treatment, and glucose levels should be monitored periodically in patients initiating mTOR inhibitor or PD-1 inhibitor therapy. With regard to hyperglycemia caused by anti-cancer therapy, frequent monitoring and proper management are important for promoting the efficacy of anti-cancer therapy and improving patients' quality of life.

Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience.

BACKGROUND: Neuroendocrine tumors (NETs) are rare, heterogeneous, indolent tumors that are relatively insensitive to systemic chemotherapy. Therapeutic strategies for NETs broadly include somatostatin analogs, antiangiogenic therapy, and most recently, mammalian target of rapamycin inhibition. Combination therapy has shown promising antitumor activity and good tolerability in the randomized phase III trials. AIM: The aim was to evaluate the safety and efficacy of Everolimus plus Octreotide long‑acting repeatable (LAR) in patients with advanced NETs in the routine tertiary cancer care setting in India in this postapproval, noninterventional trial. PATIENTS AND METHODS: Patients presenting to selected centers between 2011 and 2013 with histologically confirmed low‑, intermediate‑ or high‑grade advanced NETs who may have had prior exposure to cytotoxic chemotherapy (≤2 lines) were treated with oral Everolimus (10 mg/day) plus intramuscular Octreotide LAR (30 mg once every 28 days) until disease progression or unacceptable toxicity was seen. Patients were evaluated every 3 months for a response to therapy as per Response Evaluation Criteria in Solid Tumors. RESULTS: Everolimus plus Octreotide LAR was associated with a clinical benefit rate of 69% (best evaluable responses: Stable disease [SD] in 10 patients [63%], partial response in 1 patient [6%]). The average duration of therapy was 4.8 cycles, and 3 (17%) patients continued therapy for ≥12 cycles (all achieved SD). The therapy was found to be well‑tolerated in all patients. CONCLUSIONS: Everolimus plus Octreotide LAR appears to be safe and efficacious in patients with advanced NETs who may have had prior exposure to chemotherapy – a finding consistent with recently conducted major trials.

Clinical Application of Mammalian Target of Rapamycin Inhibitor in Kidney Transplantation / 대한이식학회지

Mammalian target of rapamycin inhibitors (mTOR-I)* is a novel immunosuppressive agent that has the variable action mode, such as anti-fibroblastic, anti-tumor and anti-atherosclerotic effect, but doesn't have a nephrotoxicity. Since March 2006, two types of mTOR-I, sirolimus and everolimus, are clinically available in Korea. In this article, we summarize the pharmacologic characteristics of mTOR-I and review the clinical application of mTOR-I as the component of immunosuppressive regimen after kidney transplantation. Sirolimus and everolimus share the same action mode resulting in an arrest of cell cycle (G1 to S phase arrest). Despite the similarities of chemical structure between sirolimus and everolimus, there are remarkable pharmacokinetic differences between the two molecules. In summary, the half-life and time to reach steady state of everolimus is shorter than those of sirolimus. Therefore, there are significant difference in administration interval and mode. Four types of clinical application of mTOR-I were tried in de Novo renal transplant recipients; (1) for replacement of calcineurin inhibitor (CNI), (2) for replacement of antimetabolites, (3) in combination CNI with low dose mTOR-I versus high dose mTOR-I, (4) standard dose CNI plus low dose mTOR-I versus low dose CNI plus high dose mTOR-I. Generally, mTOR-I shows superior results in graft survival rate, acute rejection free rate and graft renal function (eGFR), but shows inferior results in maintenance rate of regimen and occurrence of side effect (such as proteinuria, wound healing problem and dyslipidemia). Conversion from CNI to mTOR-I was tried in recipients with de Novo post- transplant malignancy or chronic allograft dysfunction. These clinical trial data suggest that mTOR-I may be useful in management of selective type of post-transplant malignancy (such as non-melanoma skin cancer, Kaposi's sarcoma and post- transplant lymphoproliferative disease) or chronic allograft dysfunction with CNI nephrotoxicity. Clinical application of mTOR-I makes variable combination of immunosuppressive agent possible. Therefore, it is possible to make the selective or tailored immunosuppressive regimen that yields the best outcome with minimal adverse effect.