Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.

Correlation Between Serum Parathormone Levels With Urinary Magnesium Excretion In Patients With Non-Dialytic Chronic Kidney Disease

Background: Disorders of mineral metabolism occur in most patients with chronic kidney disease (CKD). The aim of this work was to correlate serum parathyroid hormone (PTH) levels with urinary magnesium excretion in patients with non-dialysis CKD.Methods: Cross-sectional study with patients with CKD undergoing non-dialysis treatment in stages 3A, 3B and 4. Concentrations of creatinine, magnesium, calcium, phosphorus, parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D] and alkaline phosphatase (ALP) were determined in blood samples. The assessment of urinary magnesium levels was performed by means of total daily excretion and by the excretion fraction (FEMg). Results: The study evaluated 163 patients with a mean age of 60.7 ± 11.7 years and 51.0% were male. In the highest quartile of PTH (> 89.5pg / ml), the mean levels of FEMg and ALP were higher (p <0.05), as well as the levels of serum calcium and eGFR were lower (p <0.05). In the unadjusted regression analysis, the following variables were related to serum PTH levels: FEMg (odds ratio (OR) = 1.12; 95% confidence intervals (CI): 1.02–1.23), Calcium (OR = 0.45; 95% CI: 0.22-0.90), ALP (OR = 1.02; 95% CI: 1.00-1.03) and eTFG (OR = 0.92; 95% CI: 1.00-1.03). After an adjusted analysis, only one FEMg and ALP will remain correlated with PTH. Conclusion: In patients with non-dialysis CKD, with higher levels of PTH, higher mean columns of ALP and FEMg, and lower levels of serum calcium and eGFR. FEMg and ALP were some variables that remained associated with PTH.

Correlation Between Serum Parathormone Levels With Urinary Magnesium Excretion in Patients With Non-Dialytic Chronic Kidney Disease

Background: Disorders of mineral metabolism occur in most patients with chronic kidney disease (CKD). The aim of this work was to correlate serum parathyroid hormone (PTH) levels with urinary magnesium excretion in patients with non-dialysis CKD. Methods: Cross-sectional study with patients with CKD undergoing non-dialysis treatment in stages 3A, 3B and 4. Concentrations of creatinine, magnesium, calcium, phosphorus, parathyroid hormone, vitamin D and alkaline phosphatase were determined in blood samples. The assessment of urinary magnesium levels was performed by means of total daily excretion and by the excretion fraction (FEMg). Results: The study evaluated 163 patients with mean age of 60.7 ± 11.7 and 51.0% were male. A positive correlation was observed between PTH and alkaline phosphatase (r = 0.26; p = 0.006) and FEMg (r = 0.17; p = 0.020). Calcium (r = -0.23; p = 0.002), magnesium in 24-hour urine (r = -0.18; p = 0.020) and estimated glomerular filtration rate (r = -0.47; p = 0.001) demonstrated negative correlation with PTH. Conclusion: Elevated levels of PTH correlated positively with FEMg, regardless of the presence of serum magnesium alterations, and FEMg can be used as another indicator for the treatment of hyperparathyroidism.

Disorders of tubular electrolyte handling

Glycosuria—glucose reabsorption in the proximal tubule is carried out by two different pairs of apical Na+-dependent (SGLT1 and -2) and basolateral Na+-independent (GLUT1 and -2) glucose transporters. Abnormalities in renal glucose transport can be seen in association with other defects of proximal tubular transport. Familial renal glycosuria is a rare autosomal recessive condition caused by mutations in the SGLT2-encoding gene, SLC5A2. Phosphate-handling disorders—the plasma concentration of inorganic phosphate depends on the balance between intestinal absorption, renal excretion, and the internal contribution from bone. Changes of serum phosphate levels can be caused by numerous inherited and acquired conditions. Disorders associated with increased urinary phosphate excretion and low serum phosphate levels produce symptoms that mainly affect the bones: rickets in children and osteomalacia in adults. Magnesium-handling disorders—normal plasma magnesium concentration is achieved by variation of urinary magnesium excretion in response to altered uptake by the intestine. The main site of magnesium absorption is the small bowel, via paracellular simple diffusion at high intraluminal concentrations, and via active transcellular uptake through the magnesium channel TRPM6 at low concentrations. Regulation and fine-tuning of serum magnesium concentration occurs primarily in the kidney. Genetic disorders of magnesium handling include Gitelman’s syndrome. Aminoaciduria and renal Fanconi’s syndrome—most amino acids (except for tryptophan, which is protein bound) are freely filtered by the glomerulus, after which 95 to 99.9% are reabsorbed in the proximal tubules by apical Na+-dependent cotransporters and Na+-independent cotransporters. Aminoaciduria is defined as urinary excretion of more than 5% of the filtered load of an amino acid. Renal Fanconi’s syndrome is characterized by a generalized defect of both Na+-coupled and receptor-mediated proximal tubular transport.

Proton-Pump Inhibitors and Hypomagnesaemia in Kidney Transplant Recipients

Proton-pump inhibitors (PPIs) are commonly used after kidney transplantation and there is rarely an incentive to discontinue treatment. In the general population, PPI use has been associated with hypomagnesaemia. We aimed to investigate whether PPI use is associated with plasma magnesium, 24-h urinary magnesium excretion and hypomagnesaemia, in kidney transplant recipients (KTR). Plasma magnesium and 24-h urinary magnesium excretion were measured in 686 stable outpatient KTR with a functioning allograft for ≥1 year from the TransplantLines Food and Nutrition Biobank and Cohort-Study (NCT02811835). PPIs were used by 389 KTR (56.6%). In multivariable linear regression analyses, PPI use was associated with lower plasma magnesium (β: −0.02, P = 0.02) and lower 24-h urinary magnesium excretion (β: −0.82, P < 0.001). Moreover, PPI users had a higher risk of hypomagnesaemia (plasma magnesium <0.70 mmol/L), compared with non-users (Odds Ratio (OR): 2.12; 95% confidence interval (CI) 1.43–3.15, P < 0.001). This risk tended to be highest among KTR taking high PPI dosages (>20 mg omeprazole Eq/day) and was independent of adjustment for potential confounders (OR: 2.46; 95% CI 1.32–4.57, P < 0.005). No interaction was observed between PPI use and the use of loop diuretics, thiazide diuretics, tacrolimus, or diabetes (Pinteraction > 0.05). These results demonstrate that PPI use is independently associated with lower magnesium status and hypomagnesaemia in KTR. The concomitant decrease in urinary magnesium excretion indicates that this likely is the consequence of reduced intestinal magnesium absorption. Based on these results, it might be of benefit to monitor magnesium status periodically in KTR on chronic PPI therapy.

Educational level and risk of chronic kidney disease: longitudinal data from the PREVEND study

Background The longitudinal association between low education and chronic kidney disease (CKD) and its underlying mechanisms is poorly characterized. We therefore examined the association of low education with incident CKD and change in kidney function, and explored potential mediators of this association. Methods We analysed data on 6078 participants from the community-based Prevention of Renal and Vascular End-stage Disease study. Educational level was categorized into low, medium and high (&lt; secondary, secondary/equivalent, &gt; secondary schooling, respectively). Kidney function was assessed by estimating glomerular filtration rate (eGFR) by serum creatinine and cystatin C at five examinations during ∼11 years of follow-up. Incident CKD was defined as new-onset eGFR &lt;60 mL/min/1.73 m2 and/or urinary albumin ≥30 mg/24 h in those free of CKD at baseline. We estimated main effects with Cox regression and linear mixed models. In exploratory causal mediation analyses, we examined mediation by several potential risk factors. Results Incident CKD was observed in 861 (17%) participants. Lower education was associated with higher rates of incident CKD [low versus high education; hazard ratio (HR) (95% CI) 1.25 (1.05–1.48), Ptrend = 0.009] and accelerated eGFR decline [B (95% CI) −0.15 (−0.21 to −0.09) mL/min/1.73 m2/year, Ptrend &lt; 0.001]. The association between education and incident CKD was mediated by smoking, potassium excretion, body mass index (BMI), waist-to-hip ratio (WHR) and hypertension. Analysis on annual eGFR change in addition suggested mediation by magnesium excretion, protein intake and diabetes. Conclusions In the general population, we observed an inverse association of educational level with CKD. Diabetes and the modifiable risk factors smoking, poor diet, BMI, WHR and hypertension are suggested to underlie this association. These findings provide support for targeted preventive policies to reduce socioeconomic disparities in kidney disease.