New-Onset Diabetes Mellitus After Kidney Transplantation: The Role of Immunosuppression

Veroux, Massimiliano; Corona, Daniela; Giuffrida, G; Gagliano, M.; Sorbello, Massimiliano; Virgilio, Carla; Tallarita, Tiziano; Zerbo, D.; Giaquinta, Alessia; Fiamingo, Pietro; Macarone, M.; Volti, Giovanni Li; Caglià, Pietro

doi:10.1016/j.transproceed.2008.06.005

Cited by 41 publications

(30 citation statements)

References 16 publications

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“…Valderhang et al have found that the incidence of NODAT was 14% (14). Several authors have shown that the most important risk factors of NODAT are immunosuppressive drugs, but family history, weight, and BMI of the recipient are also essential (3,4,6,15,16). In our study, it was shown that uric acid level was higher in the NODAT group.…”

Section: Discussionsupporting

confidence: 56%

Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation

Borda¹,

Lengyel²,

Várkonyi³

et al. 2014

Acta Physiologica Hungarica

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New-onset diabetes after transplantation (NODAT) is one of the frequent complications following kidney transplantation. Patients were randomized to receive cyclosporine A-or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following three groups based on the results: normal, impaired fasting glucose/impaired glucose tolerance (IFG/IGT), or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (p = 0.0002). Albumin levels were similar, but uric acid level (p = 0.002) and the age of the recipient (p = 0.003) were significantly different comparing the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection (ACR) and interstitial fibrosis/tubular atrophy (IF/TA) were significantly different in the NODAT group. The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

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Section: Discussionsupporting

confidence: 56%

Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation

Borda¹,

Lengyel²,

Várkonyi³

et al. 2014

Acta Physiologica Hungarica

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“…This may be due to the small number of HCV patients in our study. In other studies, acute rejection episode, corticosteroid dose, and the type of immunosuppressant had the strongest impact on PTDM onset [20,21]. Calcineurin inhibitors, both tacrolimus and cyclosporine, have been reported to be associated with an increased risk of PTDM.…”

Section: Discussionmentioning

confidence: 89%

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus

Kim

Kim²,

Park³

et al. 2016

Nephron

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Background: Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after renal transplantation. Activation of the innate immune system via toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance and deficiency. Although links between diabetes, dysregulated innate immune responses, and the TLR signaling pathway have been reported, no study so far has investigated their associations with PTDM. In this study, we ascertained whether single nucleotide polymorphisms (SNPs) in TLRs are associated with PTDM in the Korea population. Methods: A total of 305 patients who received renal transplants without previously diagnosed diabetes were included. We analyzed the association between PTDM development and 6 SNPs within 2 genes of TLR2, 1 gene of TLR4, and 3 genes of TRL6. Results: Of 305 patients, PTDM developed in 51 patients (16.6%). Patients in the PTDM group were older than those in the non-PTDM group (45.56 ± 1.28 vs. 38.28 ± 0.71 years). Patients with PTDM had significantly higher allele frequency compared to those without PTDM for the TLR4 rs1927914*T, TLR6 rs3775073*A, TLR6 rs3821985*C, and TLR6 rs1039559*C alleles. Of the 6 SNPs, rs1927914 in the TLR4 gene and rs1039559 in the TLR6 gene were significantly associated with the development of PTDM after adjustment for age, gender, and tacrolimus usage. Conclusions: Our study demonstrates a significant association between SNPs rs1927914 in TLR4 and rs1039559 in TLR6 and PTDM in the renal transplantation recipient group. These data suggest that the activation of the innate immune system and inflammation via TLR activation might have an essential role in the pathogenesis of PTDM in renal transplantation.

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“…For example, retrospective studies of kidney transplant recipients did not show an association between SIR and increased risk of PTDM [13,14]. However, using data from the United States renal database, SIR was independently associated with increased onset of PTDM in patients with KTX [15].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague–dawley rats

Shivaswamy

McClure

Passer

et al. 2010

Endocr

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Post-transplant diabetes mellitus (PTDM) worsens outcomes after kidney transplantation, and immunosuppression agents contribute to PTDM. We have previously shown that tacrolimus (TAC) and sirolimus (SIR) cause hyperglycemia in normal rats. While there is little data on the mechanism for immunosuppressant-induced hyperglycemia, we hypothesized that the TAC and SIR-induced changes are reversible. To study this possibility, we compared normal rats treated for 2 weeks with either TAC, SIR, or a combination of TAC and SIR prior to evaluating their response to glucose challenge, with parallel groups also treated for 2 weeks after which treatment was stopped for 4 weeks, prior to studying their response to glucose challenge. Mean daily glucose and growth velocity was decreased in SIR, and TAC+SIR-treated animals compared to controls (P < 0.05). TAC, SIR, and TAC+SIR treatment also resulted in increased glucose response to glucose challenge, compared to controls (P < 0.05). SIR-treated animals also had elevated insulin concentrations in response to glucose challenge, compared to controls (P < 0.05). Insulin content was decreased in TAC and TAC+SIR, and islet apoptosis was also increased after TAC+SIR treatment (P < 0.05). Four weeks after treatments were stopped, all differences resolved between groups. In conclusion, TAC, SIR, and the combination of TAC+SIR-induced changes in glucose and insulin responses to glucose challenge that were accompanied by changes in islet apoptosis and insulin content. These changes were no longer present 4 weeks after cessation of therapy suggesting immunosuppressant-induced changes in glucose metabolism are likely reversible.

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New-Onset Diabetes Mellitus After Kidney Transplantation: The Role of Immunosuppression

Cited by 41 publications

References 16 publications

Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation

Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus

Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague–dawley rats

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