tacrolimus and Magnesium-Deficiency

Post-transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post-transplantation. We conducted a single-center, open-label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Analyses were on intention-to-treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI -1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA-IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Diarrhea; Female; Glucose Tolerance Test; Graft vs Host Disease; Humans; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Magnesium Deficiency; Magnesium Oxide; Male; Middle Aged; Postoperative Complications; Prediabetic State; Receptor, Insulin; Severity of Illness Index; Tacrolimus

We aimed to investigate the frequency of hypomagnesemia and urinary magnesium excretion in pediatric heart transplant recipients.. In this study, 22 pediatric patients who underwent heart transplanted at a single center between March 2014 and April 2015 and who were treated with oral tacrolimus were analyzed prospectively. Serum magnesium, creatinine, and tacrolimus levels and total amount of urinary magnesium excretion were measured. Serum tacrolimus levels were measured 12 hours after the last dose of tacrolimus.. Our patient group included 11 boys (50%) and 11 girls (50%) with a mean age of 16.72 ± 4.78 years. Serum tacrolimus levels were in the therapeutic range, with a mean of 1.48 ± 0.13 ng/mL (range, 1.2-1.69 ng /mL), mean fractional magnesium excretion was 8.59 ± 5.9% (range, 3%-22%), and 24-hour urinary magnesium excretion was 90.2 ± 62.95 mg/d. Hypermagnesuria was assessed in 80% of patients. We found 24-hour urinary magnesium excretion to be higher than normal in 27% of patients. There was no association between serum tacrolimus levels and serum magnesium levels or urinary magnesium excretion.. Serum magnesium levels should be periodically measured in pediatric heart transplant patients treated with tacrolimus.

Topics: Adolescent; Biomarkers; Calcineurin Inhibitors; Child; Child, Preschool; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Magnesium; Magnesium Deficiency; Male; Renal Elimination; Risk Factors; Tacrolimus; Treatment Outcome; Young Adult

New-onset diabetes after transplantation (NODAT) is a significant co-morbidity following kidney transplantation. Lower post-transplant serum magnesium levels have been found to be an independent risk factor for NODAT in adult kidney transplant recipients.. We undertook a retrospective analysis of risk factors for NODAT in pediatric renal transplant recipients at our institution with the aim of determining if hypomagnesemia confers a significant risk of developing NODAT in this patient population.. A total of 173 children with a median age at transplantation of 7.0 (range 1.3-17.5) years were included. Hypomagnesemia was found to be a significant independent risk factor for NODAT (p = 0.01). High trough tacrolimus levels were also independently associated with NODAT (p < 0.001). There was no significant association between NODAT and body mass index at the time of transplantation, monthly cumulative steroid dose or post-transplant cytomegalovirus viremia (p = 0.9, 0.6 and 0.7, respectively).. This study identifies hypomagnesemia as a significant independent risk factor for the development of NODAT in pediatric renal transplant recipients. Given the clear association between hypomagnesemia and NODAT in both adults and children following renal transplantation, further studies are merited to clarify the etiology of this association and to examine the effect of magnesium supplementation on NODAT.

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Cytomegalovirus Infections; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Magnesium Deficiency; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Steroids; Tacrolimus; Transplant Recipients

Tacrolimus (TAC) and cyclosporin (CsA) are commonly responsible for hypomagnesemia that predisposes in turn for hypertension, renal impairment and encephalopathy.. The effects of TAC on Mg(2+)-homeostasis and of pre-existing Mg(2+)-deficiency on TAC immunosuppressive activity were compared to CsA in mice.. Mg(2+) was quantified in plasma, erythrocytes, urine, feces, and femurs from mice treated with TAC 5mg/kg/day. Immunosuppression was assessed in splenocytes by mixed lymphocyte reaction, IL-2 quantification and CN activity determination.. Plasma and urine Mg(2+) levels in TAC-treated mice were significantly lower from day 7 until day 21 (p<0.05 versus control) and returned to control value at day 28. Mg(2+) levels were unchanged in erythrocyte, feces and femur. Inhibition of allogeneic proliferation, IL-2 production and CN activity were 68, 56 and 30% lower (p<0.01) after 7 days of TAC-treatment, and 72, 68 and 51% lower (p<0.01) after 7 days of CsA-treatment with a dose of 50mg/kg/day. Dietary-induced hypomagnesemia resulted in significant inhibition of CN activity (p<0.01) without alteration of IL-2 production or allogeneic proliferation. However, it did not alter the effects observed with CsA- or TAC-treatment on allogeneic proliferation, IL-2 production and CN activity.. By contrast with CsA, long-course TAC-treatment induced an early, but transient, and moderate hypomagnesemia without alteration of bone or erythrocyte stocks, intestinal absorption or renal function. Therefore, in clinical use, TAC should be preferred to CsA in patients with pathological or pharmacological conditions which favor Mg(2+)-deficiency. However, dietary-induced hypomagnesemia did not alter the immunosuppressive effects of TAC and CsA.

Topics: Animals; Calcineurin Inhibitors; Cyclosporine; Dietary Supplements; Erythrocytes; Feces; Female; Femur; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2; Lymphocyte Culture Test, Mixed; Magnesium; Magnesium Deficiency; Mice; Mice, Inbred C57BL; Spleen; Tacrolimus

Since hypomagnesemia occurs frequently in tacrolimus treated patients, we studied the correlation between renal magnesium wasting and tacrolimus blood levels in renal transplant patients.. Serum magnesium, fractional excretion of magnesium (FEMg), and 24-hour urinary excretion of magnesium were measured in 41 transplant patients and 10 healthy volunteers for correlation with tacrolimus level.. Of tacrolimus-treated patients, 43% displayed hypomagnesemia. FEMg (7.42+/-3.59% versus 1.88+/-0.43%) and 24-hour urinary excretion (112.36+/-51.43 mg/dL versus 6.7+/-2.79 mg/dL) were significantly higher among tacrolimus-treated patients than controls. Magnesium replacement did not influence FEMg or 24-hour urinary magnesium excretion. Tacrolimus level was the best predictor of 24-hour urinary magnesium excretion and FEMg. Serum magnesium levels correlated inversely with tacrolimus concentrations and creatinine clearance.. Hypomagnesemia in renal transplant recipients results from renal magnesium wasting. Tacrolimus levels and renal function impact on the excess renal magnesium excretion. Studies of longer duration are warranted to assess the long-term effects of this early posttransplant hypomagnesemia.

Topics: Adult; Cross-Sectional Studies; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnesium; Magnesium Deficiency; Male; Middle Aged; Patient Selection; Tacrolimus

Magnesium deficiency in hairless rats results in a transient erythematous rash within several days, the pathogenetic mechanisms of which are not yet well defined. However, the extremely pruritic rash closely mimics the acute clinical features of atopic dermatitis. Owing to the similarity of clinical signs between hypomagnesaemic rats and patients with atopic dermatitis, this rodent skin condition holds promise as a model for the in vivo evaluation of new treatment modalities against pruritic inflammatory skin conditions. The efficacy of the new ascomycin macrolactam derivative SDZ ASM 981 was tested in hypomagnesaemic rats by systemic or topical administration using prophylactic or therapeutic treatment regimens. Oral treatment of diseased rats with SDZ ASM 981 (12.5 mg kg-1 daily) inhibited the erythematous pruritic rash within 1 day after the start of treatment. This was associated with a clear reduction in histaminaemia, leucocytosis, eosinophilia and serum nitric oxide levels. The same daily oral dose of SDZ ASM 981 administered before the onset of the rash proved to be an efficacious prophylactic treatment regimen to prevent signs. Topical treatment of the ears with 0.4% SDZ ASM 981 locally inhibited and prevented inflammatory changes in a therapeutic and prophylactic treatment regimen, respectively. The histo- and immunopathological skin changes, as well as the numbers of degranulated mast cells in the dermis, were reversed towards normal after oral and topical administration. The pharmacological activity of SDZ ASM 981 reported here corresponds well to its anti-inflammatory and antipruritic activity observed in atopic dermatitis patients, confirming the usefulness of this rat model in drug evaluations.

Topics: Administration, Oral; Administration, Topical; Animals; Dermatitis, Atopic; Dermatologic Agents; Magnesium Deficiency; Male; Rats; Rats, Nude; Tacrolimus

Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (<10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC >500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.

Topics: Actuarial Analysis; Acute Disease; Adolescent; Child; Child, Preschool; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Infections; Liver Failure; Magnesium Deficiency; Male; Methotrexate; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous; Vascular Diseases

Topics: Arrhythmias, Cardiac; Child; Cyclosporine; Drug Therapy, Combination; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Magnesium Deficiency; Tacrolimus

1. FK 506 (Tacrolimus, Prograf) is a novel immunosuppressant which is effective in solid organ transplantation and autoimmune diseases. The lack of a suitable animal model has hindered the study of the nephrotoxicity of the drug which has emerged as a common adverse effect in clinical trials. We report both acute and chronic nephrotoxicity with tacrolimus (FK) in which renal structure and function are worsened by sodium depletion. 2. Pair fed male Sprague-Dawley rats were given FK (3 or 6 mg/kg, p.o.) or vehicle for 7, 21 and 42 days on low salt or normal diet. The FK whole blood trough levels achieved (3-10 ng/mL) were similar to those observed in FK treated transplant patients. 3. In salt depleted animals treated for 7 days, FK (6 mg/kg) decreased renal blood flow and glomerular filtration rate (1.8 +/- 0.1 and 0.2 +/- 0.1 mL/min per 100 g vs 2.9 +/- 0.2 and 1.1 +/- 0.1 mL/min per 100 g in the vehicle group, P < 0.01). 4. After 21 days of treatment of FK on low salt diet but not normal salt, FK induced focal collapse and vacuolization in proximal tubules and discrete or confluent zones of tubulointerstitial oedema and mononuclear cell infiltration. 5. After 42 days in salt depleted rats, there was significant tubulointerstitial scarring that was associated with an increased plasma renin activity (PRA) (64 +/- 10 vs 30 +/- 4 ng AI/mL per h in the vehicle group, P < 0.05). Animals given normal salt diets did not develop significant histological lesions even up to 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Creatinine; Glomerular Filtration Rate; Immunosuppressive Agents; Inulin; Kidney Diseases; Kidney Function Tests; Magnesium Deficiency; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renal Circulation; Renin; Sodium; Tacrolimus; Urodynamics