EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Hypomagnesemia is considered as an independent risk factor for new-onset diabetes mellitus after kidney transplant. New-onset diabetes mellitus is an important comorbidity associated with allograft failure. In this study, our aim was to investigate the correlation between hypomagnesemia and prevalence of posttransplant diabetes mellitus.

Materials and Methods: We retrospectively evaluated 189 pediatric renal transplant recipients who underwent their first renal transplant. A patient with type 1 diabetes mellitus before transplant was excluded from the analysis. Hypomagnesemia was defined as having serum magnesium levels lower than 1.7 mg/dL. Diabetes was defined according to American Diabetes Association criteria. Serum magnesium and glucose levels at month 1 after transplant were recorded.

Results: We evaluated the records of 188 patients. New-onset diabetes mellitus was diagnosed in 7 patients (3.7%). Hypomagnesemia was shown in 50% of patients (64/120). Mean glucose levels were higher in those with hypomagnesemia than in patients without hypomagnesemia (119.2 vs 91.56 mg/dL, respectively; P = .01) A significant negative correlation was observed between serum magnesium and glucose levels (r = -0.53; P < .05). Mean serum magnesium level in patients with new-onset diabetes mellitus was lower than in patients without diabetes (1.56 ± 0.21 vs 1.75 ± 0.26 mg/dL; P = .052).

Conclusions: Hypomagnesemia is a common problem in pediatric renal transplant. The relationship between serum magnesium and glucose levels suggests that hypomagnesemia plays a role in the development of new-onset diabetes mellitus after transplant. Comprehensive studies are needed to support this association.

Key words : Glucose, Kidney transplantation, Magnesium

New-onset diabetes mellitus after transplant (NODAT) is an important comorbidity associated with allograft failure and increased cardiovascular morbidity and mortality. There are several risk factors associated with NODAT, including age, obesity, immunosuppression, and episodes of rejection.^1-3 Hypomagnesemia induces insulin resistance by acting on cellular glucose transport and insulin secretion⁴ and is considered to be an independent risk factor for new-onset diabetes mellitus after kidney transplant.⁵ Low levels of magnesium or potassium are identified as potentially modifiable risk factors associated with diabetes in the general and adult transplant populations.^6-9 Diuretics, calcineurin inhibitors, and tubular dysfunction may cause electrolyte imbalances in renal transplant recipients.^8,10 The presence of hypomagnesemia early posttransplant is closely related with the use of calcineurin inhibitors (cyclosporine and tacrolimus).^11,12

In this study, our objective was to investigate the correlation between hypomagnesemia and prevalence of posttransplant diabetes mellitus and to draw attention to the importance of monitoring serum magnesium levels.

Materials and Methods

We retrospectively evaluated the medical records of 189 pediatric patients who underwent their first renal transplant. One patient with type 1 diabetes mellitus before transplant was excluded from the analyses. Demographic data, primary diagnoses, donor type, immunosuppressive medications, serum drug levels, and serum magnesium and glucose levels at the end of the first month posttransplant were recorded from patient files. Patients were divided into 2 groups: those with hypomagnesemia and those with normal levels of magnesium. Hypomagnesemia was defined as having serum magnesium levels lower than 1.7 mg/dL. We reviewed whether patients developed NODAT at 6 months posttransplant. Diabetes was defined according to American Diabetes Association criteria.

Statistical analyses
Data of 188 pediatric patients who underwent their first kidney transplant were evaluated with SPSS for Windows (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA). For analysis of study groups, chi-square and Fisher-exact tests were used. We used t test for normally distributed data and Mann-Whitney U test for nonnormally distributed data. Frequencies and percentages were used as descriptive values in categorical data. Arithmetical mean ± standard deviation was used for normally distributed data, and median and interquartile range was used for nonnormally distributed data. Significance was accepted as P ≤ .05.

Of the 188 pediatric patients included in our analyses, 105 (55%) were male and 83 (45%) were female patients. Minimum and maximum ages at transplant were 21 and 259 months, respectively, with mean of 157 ± 55 months. Cause of chronic kidney disease was congenital anomalies of the kidney and urinary tract in 68 patients, glomerulonephritis in 51 patients, cystic kidney disease in 29 patients, genetic diseases in 16 patients, systemic diseases (systemic lupus erythematosus, etc.) in 3 patients, other causes in 11 patients, and unknown cause in 10 patients (Table 1). In 145 patients, the donors were living donors,with the remaining 43 patients having deceased donors. Mean follow-up time was 69.1 ± 38.8 months (range, 6-240 mo). Immunosuppressive medications were tacrolimus in 127 patients, cyclosporine in 57 patients, sirolimus in 2 patients, and everolimus in 2 patients (Table 1).

Seven patients (3.7%) were diagnosed with NODAT; minimum and maximum days of diagnoses after transplant were 1 and 90 days respectively, with a mean of 37 days. Hypomagnesemia was shown in 53% of patients (64/120) after serum magnesium level testing at 1 month posttransplant. Mean serum glucose levels were significantly higher in the hypomagnesemia group than in patients without hypomagnesemia (119.2 vs 91.56 mg/dL, respectively; P = .01). A significant negative correlation was observed between serum magnesium and glucose levels (r = -0.53; P < .05). Mean serum magnesium level of patients with NODAT was lower than in patients without diabetes (1.56 ± 0.21 vs 1.75 ± 0.26 mg/dL; P = .052). Type of immunosuppresion did not affect serum glucose levels (P > .05) (Table 2). Among 120 patients with serum magnesium results, 80 patients were on tacrolimus, 39 patients were on cyclosporine, and 1 patient was on everolimus treatment. With regard to donor type, 24 had deceased donors and 96 had living donors. Among 64 patients who had hypomagnesemia, 45 patients were on tacrolimus, 18 patients were on cyclosporine, and 1 patient was on everolimus treatment. Fifteen of 64 patients with hypomagnesemia had deceased donors, with the remaining 49 having living donors. Relationships between hypomagnesemia and type of immunosuppressive treatment and type of donor were not significant. Mean magnesium level of patients on tacrolimus was 1.7 ± 0.3 mg/dL; in patients on cyclosporine, the level was 1.8 ± 0.4 mg/dL (P = .05). Mean tacrolimus level was 8.79 ± 2.43 ng/mL in the hypomagnesemia group and 9.5 ± 2.67 ng/mL in the group with normal magesium level (not significant; P > .05). Cyclosporine level was 116 ± 49 ng/mL in the hypomagnesemia group and 110.5 ± 53 ng/mL in patients with normal magnesium level (not significant; P > .05) (Table 2).

We found a significant negative correlation between hypomagnesemia and serum glucose levels at 1 month posttransplant among kidney transplant recipients. We also found significantly lower serum magnesium levels in patients with NODAT. Hypomagnesemia is a common problem seen in the general populationwith diabetes^13,14 and is an independent risk factor for diabetes mellitus.¹⁵ Underlying factors associated with hypomagnesemia in patients with diabetes include low dietary magnesium intake, osmotic diuresis due to hyperglycemia, glomerular hyperfiltration, and metabolic acidosis.^4,16,17

Low serum magnesium levels may cause disorders in cellular glucose transport and decrease pancreatic insulin secretion via affecting receptor insulin signaling and insulin-insulin receptor interactions after transplant.^16,18 Supplementation with oral magnesium has a positive impact on insulin sensitivity and glucose metabolism.^19-21

The incidence of diabetes mellitus posttransplant is 10% to 30%.^1,22 Determining the modifiable risk factors of posttransplant diabetes mellitus is essential as it affects patient and graft survival.²³ Known risk factors associated with posttransplant diabetes mellitus are older age, male sex, ethnicity, acute rejection, hepatitis C, higher body mass index, higher pretransplant glucose levels, and higher trough tacrolimus levels.^5,16,24,25 In this study, we found no association between immunsuppressive type and serum glucose levels and NODAT. Calcineurin inhibitors may cause renal magnesium depletion via affecting the magnesium channel transient receptor potential melastatin 6 (TRPM6) in the distal convoluted tubules.^26,27 Calcineurin inhibitors cause direct insult to pancreatic islet cells²⁸ and also inhibit insulin gene transcription.²⁹ Tacrolimus has greater diabetogenic effects than cyclosporine.^26,30,31 In our study, serum glucose levels did not differ between patients on tacrolimus versus cyclosporine. We were not able to show a direct relationship between immunosupressive drug type and hypomagnesemia. However, mean serum magnesium levels were lower in patients on tacrolimus than in those on cyclosporine (P = .05). Trough tacrolimus levels and cyclosporine levels did not differ between hypomagnesemia and normomagnesemia groups. Van Laecke and colleagues⁵ showed that low magnesium levels in the first 4 weeks after kidney transplant are associated with NODAT. Gargand associates²⁶ also demonstrated that, in renal transplant recipients, lower serum magnesium levels at 1 month posttransplant was an important risk factor for development of NODAT and prediabetes. In a study of adult kidney transplant recipients, pretransplant serum magnesium levels in those who developed NODAT were low and pretransplant hypomagnesemia was considered as a risk factor for development of NODAT.³² A recent study in a pediatric cohort determined that hypomagnesemia was a significant independent risk factor for NODAT in renal transplant recipients; moreover, high trough levels of tacrolimus were considered to augment the risk independent of hypomagnesemia.³³ The limitations of our study are its retrospective nature, which affected data availibility. Among 188 pediatric transplant recipients in our study, only 120 patients had measurements of serum magnesium levels at 1 month posttransplant; as a consequence, our study had a smaller sample size. In addition, serum glucose levels could not be sorted as fasting or postprandial, and no data were available on patients who had magnesium supplementation.

We found a negative association between hypomagnesemia and serum glucose levels and NODAT in children after kidney transplant. Hypomagnesemia was a common problem in pediatric renal transplant recipients. The relationship between serum magnesium and glucose levels suggests that hypomagnesemia plays a role in development of NODAT. Further studies are essential to confirm the effects of hypomagnesemia on serum glucose levels and NODAT.

Volume: 18 Issue: 1 January 2020 - Supplement - 1

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