Immediately following allogeneic kidney transplantation, the pancreatic beta-cell mass is relentlessly punished by four counterregulatory metabolic factors namely: (1) gluconeogenic surgery-related stress;(2) exogenous glucocortocoid-induced peripheral insulin resistance and hepatic gluconeogenesis;(3) direct beta-cell injury by the calcineurin inhibitor (cyclosporine or tacrolimus) and;(4) increased dietary caloric load secondary to the abrogation of chronic uremia-related anorexia. Consequent to this metabolic engagement, 45-80% of new kidney transplant recipients (KTRs) will manifest persistent reversible hyperglycemia, 30% will maintain chronic impaired glucose intolerance and 15-20% will succumb to new onset diabetes after transplantation (NODAT) by the end of the first post transplant year. NODAT is a form type 2 diabetes mellitus that afflicts up to 30% of kidney transplant recipients who survive through the third post transplant year. NODAT is associated with increased risk for post transplant cardiovascular events, higher health care utilization and dramatically inferior kidney graft and patient survival. The offending determinants of NODAT are largely unavoidable because calcineurin inhibitors are the mainstay immunosuppressive drug for kidney transplantation, 70-80% of KTRs are treated initially high dose corticosteroid followed by low dose maintenance therapy and improved dietary intake is a desired benefit of kidney transplantation. Evidence shows that the state of glucotoxicity induced by persistent hyperglycemia causes continuous decline in pancreatic beta-cell function during the early period of development of type 2 diabetes mellitus. More recently, protection of beta-cells by aggressive lowering of hyperglycemia with early initiation of insulin therapy has shown promise in inducing remission of newly diagnosed type 2 diabetes mellitus in the general population. We posit that early use of insulin therapy in previously non-diabetic KTRs who exhibit abnormal glucose metabolism immediately after kidney transplantation will enable the discontinuation of anti-diabetic therapy during the subsequent follow-up and will result in a reduced incidence of NODAT. We have completed a proof-of-concept clinical trial, using basal insulin during the immediate post-transplant period in 50 KTRs. The prevalence of NODAT at 12 months was reduced by 65%. We now propose to conduct a safety and efficacy open-label, block-randomized clinical trial in a diverse population of KTRs to test the primary hypothesis that an early NPH insulin regimen will reduce the incidence of NODAT from 15% to 10% without a significant difference in the risk of detectable hypoglycemia between the experimental and the control arms of the study. A sample size of 180 KTRs has a 90% power to detect a 30% risk reduction for NODAT at one-year post transplantation after protecting one interim analysis with the O'Brien-Fleming method. The study would be conducted at the University of Michigan Health System (n=90) and the Medical University of Vienna 'General Hospital'(n=90). Participants will be enrolled over a 24 months period with a minimum follow-up of 24 months post randomization.

Public Health Relevance

New onset diabetes after kidney transplantation (NODAT) is a form of type 2 diabetes mellitus cumulatively afflicting 30% of kidney transplant recipients. NODAT is due, in part, to the unavoidable effect of immunosuppressive medications on the pancreatic beta-cells, and we propose a study to use exogenously administered insulin to allow the pancreatic beta-cell mass to rest during its most vulnerable post transplant period. This approach represents a change of paradigm in the management of abnormal glucose metabolism after kidney transplantation with the potential for beneficial long-lasting effects on the clinical and economic outcomes of kidney transplantation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
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Kusek, John W
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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