Magnesium in Kidney Function and Disease—Implications for Aging and Sex—A Narrative Review

“

TL;DR

This narrative review examines the role of magnesium in kidney function and disease, with a focus on aging and sex differences. The main finding is that low serum magnesium levels are associated with increased mortality and faster kidney function decline in chronic kidney disease patients, while higher magnesium levels appear protective. Clinically, monitoring and managing magnesium status may improve outcomes in elderly CKD patients, though optimal target ranges and supplementation strategies remain undefined.

Full summary

5,559 CHARS

**Background** Magnesium (Mg) is an essential cation involved in energy metabolism, DNA and protein synthesis, and is maintained within a narrow serum range (0.75–0.95 mmol/L) primarily by intestinal absorption and renal excretion. The kidney plays a vital role in Mg balance, with reabsorption occurring in the proximal tubule, loop of Henle (via claudin 16 and 19), and distal convoluted tubule. In chronic kidney disease (CKD), the ability to excrete Mg declines as glomerular filtration rate falls; in stages 1–3, fractional Mg excretion compensates to maintain normal levels, but in stages 4–5, compensatory mechanisms fail, leading to hypermagnesemia. However, dialysis patients may have normal or low Mg due to diet, medications, or dialysate composition. Hypomagnesemia is common and associated with increased vascular calcification, cardiovascular risk, and mortality. Aging itself causes progressive renal structural and functional decline—kidney volume decreases by approximately 16 cm³ per decade after age 60, and nephron loss of 6000–6500 per year after age 30—which may further disrupt Mg homeostasis. Dietary Mg intake is often inadequate in older populations, and factors like reduced intestinal absorption, increased urinary excretion, comorbidities, and polypharmacotherapy (e.g., diuretics, proton-pump inhibitors) contribute to hypomagnesemia. Sex differences in kidney aging and Mg metabolism are also noted, with males experiencing sharper kidney volume decline after age 70 and potential links to anabolic hormones like testosterone.

**Methods** This is a narrative review. Initial searches were conducted in June 2022 in PubMed and Scopus using the terms 'magnesium' and 'ageing'. The search was expanded with Boolean operators to include 'kidney function', 'hypermagnesemia', 'hypomagnesemia', 'gender', 'sex', 'ageing', 'elderly', 'geriatric patient', and 'elderly'. Additional databases (Cochrane) were consulted. The PICO question was: P: Elderly with chronic kidney disease; I: role of Mg; C: sex; O: improvement in kidney function. Inclusion criteria were observational studies or clinical trials evaluating older patients with kidney disease and considering Mg, published between 2012 and 2022. Exclusion criteria included articles outside the study period, those with variables outside scope, not including elderly patients, systematic reviews or articles under review, and non-English/Spanish language. Of 1482 articles initially identified, 10 were finally selected.

**Key Results** All 10 selected studies found a positive relationship between higher serum Mg levels and decreased risk of CKD-related mortality or cardiological complications. Key findings from individual studies include: - Kanbay et al. (2012): Strong positive correlation between flow-mediated dilation and Mg values; higher Mg associated with less endothelial dysfunction (p < 0.001) and better survival. - Wyskida et al. (2012): In 101 hemodialysis patients, mean pre-dialysis serum Mg was 1.32 ± 0.18 mmol/L (48% higher than controls); hypermagnesemia (≥1.5 mmol/L) in 81.2%, with higher prevalence in males (odds ratio = 1.98 [0.64 to 6.13], p = 0.23). - Van Laecke et al. (2013): Low serum Mg predicted higher mortality in CKD, independent of initial renal impairment, and predicted faster kidney function decline. - Sakaguchi et al. (2013): In 142,555 Japanese ESRD patients, lower serum Mg was a significant predictor of cardiovascular mortality; lower Mg associated with older age, lower albumin, calcium, phosphate, hemoglobin, higher CRP and alkaline phosphatase, and higher prevalence of diabetes, CVD, and hip fracture. - Lacson et al. (2015): In 21,534 dialysis patients, increasing serum Mg associated with decreasing 1-year mortality risk; patients with Mg > 2.10 mEq/L had survival advantage (HR 0.89, 95% CI 0.80–0.95). - Rebholz et al. (2016): Low dietary Mg intake associated with rapid kidney function decline (eGFR 100 vs. 94 mL/min/1.73 m²; p < 0.001). - Ferrè et al. (2017): Low serum Mg independently associated with higher all-cause death risk in early-stage CKD. - Farhadnejad et al. (2016): Higher Mg intake associated with lower CKD risk (OR 0.41, 95% CI 0.22–0.76); protective effect of Mg (estimated average requirement 581 mg) decreased CKD risk by 60%. - Azem et al. (2020): U-shaped association between serum Mg and mortality (HR 1.23, 95% CI 1.03–1.48 for both hypo- and hypermagnesemia); no association with eGFR decline. - Galán Carrillo et al. (2021): Calcitriol associated with higher Mg (p = 0.029), calcium supplements (p = 0.038) and proton-pump inhibitors (p = 0.026) with lower Mg; loop diuretics positively associated with Mg (p < 0.001); hypermagnesemia (Mg > 2.2 mg/dL) associated with higher cardiovascular event risk (p = 0.028).

**Clinical Implications** The review underscores that Mg status is a modifiable factor influencing outcomes in CKD, particularly in the elderly. Hypomagnesemia is linked to increased mortality, faster renal decline, and cardiovascular complications, while hypermagnesemia also carries risks (U-shaped association). Monitoring serum Mg and addressing deficiencies through diet or supplementation may improve prognosis, but optimal target ranges and standardized approaches are not yet established. Sex differences in kidney aging and Mg metabolism suggest that personalized strategies considering age and sex could be beneficial. The authors call for well-designed prospective clinical trials to determine indications for Mg supplementation, taking age and sex into account.