Hypomagnesemia and the Risk of New-Onset Diabetes Mellitus after Kidney Transplantation J Am Soc Nephrol 27: 1793–1800, 2016 순천향 대학병원 신장내과 강혜란

 New-onset diabetes after transplantation (NODAT)  has become increasingly clear since the late 1990s  In a 10-year cohort study  24% of kidney transplant recipients (KTR) developed NODAT within 3 years of transplantation, many of whom were diagnosed in the early posttransplant period  Compared with nondiabetic KTR, patients with NODAT or pretransplant diabetes  worse long-term allograft function  higher risks of graft failure, post-transplant cardiovascular disease, and mortality Introduction

 New-onset diabetes after transplantation (NODAT)  Various risk factors for the development of NODAT have been identified  Age  Ethnicity  Obesity  Family history of diabetes  Acute rejection  Cytomegalovirus infection  Hepatitis C  Use of corticosteroids  Notably, magnesium(Mg) deficiency Introduction

 Mg  an intracellular cofactor necessary for  glucose transport between membranes  glucose oxidation  insulin-mediated tyrosine kinase pathways  Hypomagnesemia  commonly observed among KTR who are prescribed calcineurin inhibitors (CNI)  It has been suggested that CNI downregulate Mg transport proteins in the renal tubules, leading to increased Mg excretion and wasting Introduction

 Of tacrolimus-treated patients, 43% displayed hypomagnesemia Conclusion : Hypomagnesemia in renal transplant recipients results from renal magnesium wasting Tacrolimus levels and renal function impact on the excess renal magnesium excretion

 hypoMg & Diabetes mellitus  HypoMg is associated with  altered cellular transport of glucose  reduced insulin secretion by b-cells within the pancreas  defective insulin signaling pathways  Several studies in nontransplant populations have shown that  higher consumption of Mg -> lower risk of diabetes mellitus  Other studies have reported a higher incidence of hypoMg among patients with diabetes or prediabetic hyperglycemia compared with nondiabetic controls  Randomized control trials have demonstrated that type II diabetic patients who receive Mg supplement exhibit improved glycemic control

 Among 589 nondiabetic KTR Serum magnesium measurements (mg/dL) on days 7 and 15 as well as at 1, 2, 3, 6, 9, and 12 months after transplantation  Conclusions: No association between hypoMg and NODAT after adjustment for CNI regimen

 Pretransplant magnesium level on development of NODAT within 1 year posttransplant  Mg was measured within the 24 hours preceding kidney transplantation  Among the 154 patients analyzed, 28 (18.2%) developed NODAT at year 1  Conclusion : Low pretransplant Mg level is an independent risk factor of NODAT in kidney transplant recipients

A retrospective analysis of 138 previously nondiabetic renal transplant recipients examine the associations between 1-month post-transplant serum magnesium level and subsequent diagnoses of NODAT/NOPDAT NODAT was diagnosed in 24.6 %, Median time to diagnosis : 20.4 months Conclusions : A lower magnesium level at 1 month after transplantation may be predictive of a subsequent diagnosis of glucose intolerance or diabetes in renal transplant recipients

 To examine the association between serum Mg and risk of NODAT in a large cohort of KTR using comprehensive data from a single-center research database

 Retrospective cohort study  Study population all patients ≥18 years of age received transplants from January 1, 2000–December 31, 2011 (with follow- up until June 30, 2012) at the Toronto General Hospital, University Health Network Exclusion criteria included: (1) prior or simultaneous nonkidney transplant (2) kidney transplants from outside institutions (3) primary nonfunction (4) absence of serum Mg measurements post-transplant (5) history of pretransplant diabetes mellitus (6) NODAT within the first month post-transplant (7) graft failure, death, or loss to follow-up within the first month post-transplant Methods

 Immunosuppression protocol and patient follow-up schedule  Maintenance immunosuppression : calcineurin inhibitor, mycophenolate mofetil, and prednisone  Prior to 2007, the first-line calcineurin inhibitor was cyclosporine  Subsequently, tacrolimus with trough level monitoring became the first- line calcineurin inhibitor  After hospital discharge, routine outpatient blood work (including blood glucose and serum magnesium) was performed  three times per week for 4 weeks  two times per week for 4 weeks  weekly for 8 weeks  biweekly from months 3 to 6  monthly from months 7 to 12  and then every 2 to 3 months beyond 12 months Methods

 Exposure Assessment and Classification HypoMg : serum Mg level <0.74 mmol/L (<1.8 mg/dL) Serum Mg was assessed Time-fixed model : Serum Mg at 1 month posttransplant Conventional time-varying model: updated the level of serum Mg at regular intervals (i.e., every 3 months) over follow-up and related this level to the risk of NODAT over the subsequent 3months Rolling-average time-varying model : mean serum Mg calculated over a 3-month exposure window and attributed this value to the risk of NODAT over the subsequent 3-month risk window Methods

 Outcome Assessment and Classification  NODAT  defined as the occurrence of one or more of the following starting 1month after kidney transplantation: (1) at least two fasting glucose readings ≥7.0 mmol/L (126 mg/dl), (2) at least two nonfasting glucose readings ≥ 11.1mmol/L (200mg/dl), (3) the need for antidiabetic medications (including insulin) persisting beyond the first month after transplantation Censoring events in the survival analysis Graft loss (i.e., return to chronic dialysis or preemptive retransplantation) death with graft function loss to follow-up prior to the development of NODAT Methods

Results

 NODAT  182 events during person-years at risk  Median follow-up : 3.4 years (95% CI : )  Median time to NODAT : 0.6 years (95% CI : )  Incidence rate of NODAT : 6.2/100 person-years

Results

24.3% versus 17.1% at 5 years, P= % versus 17.9% at 5 years, P= % versus 17.5% at 5 years, P< % versus 15.8% at 5 years, P< 0.001

Results

 Our results suggest that lower post-transplant serum magnesium level is an independent risk factor for NODAT in kidney transplant recipients.  Interventions targeting serum magnesium to reduce the risk of NODAT should be evaluated. Conclusions