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Post-renal transplant diabetes mellitus in korean subjects: superimposition of transplant-related immunosuppressant factors on genetic and type 2 diabetic risk factors.

ABSTRACT: Postrenal transplantation diabetes mellitus (PTDM), or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, ?-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced ?-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors.

SUBMITTER: Lee HC

PROVIDER: S-EPMC3380123 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Post-renal transplant diabetes mellitus in korean subjects: superimposition of transplant-related immunosuppressant factors on genetic and type 2 diabetic risk factors.

Lee Hyun Chul HC

Diabetes & metabolism journal 20120614 3

Postrenal transplantation diabetes mellitus (PTDM), or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabet ...[more]

PMID: 22737659

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Project description:BACKGROUND:Tacrolimus (FK506)-induced diabetes mellitus is one of the most important factors of post-transplant diabetes mellitus (PTDM). However, the detailed mechanisms underlying PTDM are still unclear. Farnesoid X receptor (FXR) regulates glycolipid metabolism. The objective of this study was to explore whether FXR is involved in the development of tacrolimus-induced diabetes mellitus. METHODS:After C57BL/6J mice were treated with tacrolimus (FK506) for 3 months, the fasting blood glucose levels, body weights, renal morphological alterations, and mRNA expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose transporter 2 (GLUT2) among the control group, the FK506 group and the FK506 + GW4064 (a FXR agonist) group (n = 7) were measured. The intracellular location of peroxisome proliferator activated receptor γ coactivator-1α (PGC1α) and forkhead box O1 (FOXO1) was detected by immunofluorescence. Human renal cortex proximal tubule epithelial cells (HK-2) were treated with 15 μM FK506 or 4 μM FXR agonist (GW4064) for 24, 48 and 72 h, and the expression levels of FXR, gluconeogenesis and glucose uptake, representing the enzymes PEPCK and GLUT2, were detected with real-time PCR and western blot analyses. Finally, the mRNA levels of PEPCK and GLUT2 in HK-2 cells were measured after FXR was upregulated. RESULTS:FK506 significantly inhibited the mRNA and protein levels of FXR at 48 h and 72 h in HK-2 cells (P < 0.05). Meanwhile, FK506 promoted gluconeogenesis and inhibited glucose uptake in HK-2 cells (P < 0.05). However, overexpression of FXR in transfected HK-2 cell lines significantly inhibited gluconeogenesis and promoted glucose uptake (P < 0.05). The FXR agonist GW4064 significantly decreased the fasting blood glucose in mice challenged with FK506 for 3 months (P < 0.05), inhibited gluconeogenesis (P < 0.05) and significantly promoted glucose uptake (P < 0.05). Immunofluorescence staining and western blot analyses further revealed that FXR activation may affect the translocation of PGC1α and FOXO1 from the nucleus to the cytoplasm. CONCLUSIONS:FXR activation may mitigate tacrolimus-induced diabetes mellitus by regulating gluconeogenesis as well as glucose uptake of renal cortex proximal tubule epithelial cells in a PGC1α/FOXO1-dependent manner, which may be a potential therapeutic strategy for the prevention and treatment of PTDM.

Project description:Background: As in younger recipients, post-transplant infection is a frequent and devastating complication after kidney transplantation (KT) in older recipients. However, few studies have analyzed characteristics of post-transplant infection in older kidney recipients. In this study of a nation-wide cohort of older kidney recipients, we investigated the current epidemiology, risk factors, and clinical impacts of early post-transplant infection, which was defined as infectious complications requiring hospitalization within the first 6?months after KT.Methods: Three thousand seven hundred thirty-eight kidney recipients registered in the Korean Organ Transplantation Registry between 2014 and 2017 were enrolled. Recipients were divided into two groups, younger (n?=?3081) and older (n?=?657), with a cutoff age of 60?years. We observed characteristics of early post-transplant infection, and investigated risk factors for the development of infection. We also analyzed the association of early post-transplant infection with clinical outcomes including cardiac events, rejection, graft loss, and all-cause mortality.Results: The incidence of early post-transplant infection was more frequent in older recipients (16.9% in younger group and 22.7% in older group). Bacteria were the most common causative pathogens of early post-transplant infection, and the most frequent site of infection was the urinary tract in both older and younger recipients. Older recipients experienced more mycobacterial infections, co-infections, and multiple site infections compared with younger recipients. In older recipients, female sex (HR 1.398, 95% CI 1.199-1.631), older donor age (HR 1.010, 95% CI 1.004-1.016), longer hospitalization after KT (HR 1.010, 95% CI 1.006-1.014), and experience of acute rejection (HR 2.907, 95% CI 2.471-3.419) were independent risk factors for the development of early post-transplant infection. Experiencing infection significantly increases the incidence of rejection, graft loss, and all-cause mortality.Conclusion: Our results illustrate current trends, risk factors, and clinical impacts of early post-transplant infection after KT in older recipients. Considering the poor outcomes associated with early post-transplant infection, careful screening of recipients at high risk for infection and monitoring of recipients who experience infection are advised. In addition, since older recipients exhibit different clinical characteristics than younger recipients, further studies are needed to establish effective strategies for treating older recipients.

Project description:BackgroundPost-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic nephropathy (DN) occurrence in transplanted kidneys is poorly investigated. Current knowledge describes DN recurrence in graft 5.9 years from kidney transplantation however there is little data about PTDM and DN. Here, we report a clinical case peculiar for an early appearance of advanced glomerular diabetic lesions, after kidney transplantation.Case presentationA 45-year-old Caucasian male affected by autosomal polycystic kidney disease was transplanted with a cadaveric-kidney-donor from 58-year-old male. Induction immunosuppressive therapy included basiliximab and steroids while the maintenance treatment included, tacrolimus, mofetil micophenolate and methylprednisolone. One month after transplantation the patient developed diabetes requiring treatment with repaglinide quickly replaced with insulin to obtain an acceptable glycemic control (HbA1c 52 mmol/mol). Glycosuria was detected persistently during the first six months after transplantation. To achieve further improvement in glycemic control, a shift from tacrolimus to cyclosporine (CyA) was made and steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors toxicity, which was revealed in the 1-year-protocol-biopsy, everolimus was introduced thereby lowering CyA through levels. Moderate hypertension was well controlled with doxazosin. Thirty months after transplantation a second graft biopsy was performed owing to renal function decline and microalbuminuria appearance. Histological analysis surprisingly showed mesangiolysis and microaneurysms; glomerular sclero-hyalinosis and basal membrane thickness and typical nodular glomerulosclerosis. C4d staining was negative and no evidence of immune deposits were detected. Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative. Retrospective analysis on donor history didn't show diabetes or insulin resistance and no diabetic lesions were found in kidney pre-implant biopsy.ConclusionsIn our knowledge, this is the first report describing a very early onset of advanced diabetic glomerular lesions in a graft biopsy after PTDM. We hypothesize that additional factors such as everolimus and hypertension, may have contribute to kidney damage.

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Post-renal transplant diabetes mellitus in korean subjects: superimposition of transplant-related immunosuppressant factors on genetic and type 2 diabetic risk factors.

Publications

Post-renal transplant diabetes mellitus in korean subjects: superimposition of transplant-related immunosuppressant factors on genetic and type 2 diabetic risk factors.

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