Significance Statement: Developing strategies for managing coronary artery calcification (CAC) in patients with CKD remains a clinical challenge. Previous experimental studies showed that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. In a 2-year, open-label, randomized, controlled trial with a two-by-two factorial design, the authors investigated whether oral magnesium oxide or the oral carbon adsorbent AST-120 affected CAC progression in patients with stage 3−4 CKD with risk factors for CAC. In an interim analysis with 125 enrolled patients (96 of whom completed the trial), patients taking magnesium oxide experienced a significantly smaller percentage change in CAC score compared with controls (11.3% versus 39.5%). AST-120 was not associated with a similar significant slowing of CAC. Larger-scale trials are warranted to confirm these findings. Background: Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. Methods: To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3−4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. Results: We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group’s dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. Conclusions: MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.

Significance Statement: Although both short-acting and long-acting erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients undergoing hemodialysis, the relative effects on survival of these ESA types are unknown. In this nationwide, registry-based cohort study enrolling 194,698 patients on hemodialysis, the authors found that long-acting ESA users showed a 13% higher rate of death than short-acting ESA users (P<0.001) during the 2-year follow-up period. The difference in risk was pronounced among patients receiving high doses of ESA, for whom the adjusted 2-year number needed to harm for death was 30.8. Survival of long-acting ESA users who achieved more optimal hemoglobin levels was inferior to that of short-acting ESA users. Among patients on hemodialysis, long-acting ESA use might be associated with an increased rate of death compared with short-acting ESA use. Background: Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown. Methods: To compare the mortality risk associated with use of short-acting ESAs versus long-acting ESAs, we conducted a nationwide cohort study of 194,698 hemodialysis patients in Japan who received either a short-acting (epoetin α/β or epoetin κ) or a long-acting (darbepoetin or epoetin β pegol) ESA. Study outcomes were 2-year all-cause and cause-specific mortality. In addition to Cox proportional hazards models, we performed an instrumental variable analysis in which facility-level long-acting ESA prescription rates were taken as the instrumental variable. Results: During the 2-year follow-up period, 31,557 deaths occurred. In a multivariable Cox model, long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users, a significant difference (P<0.001). Similar results were obtained in other analyses. This difference in risk was pronounced among patients receiving high doses of ESA (for whom the adjusted 2-year number needed to harm for death was 30.8). Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection, and malignancies. In the instrumental variable analysis, long-acting ESA users remained at a significantly higher risk of death. Compared with anemic (hemoglobin 9.0–9.9 g/dl) short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels (10.0–10.9 g/dl) showed a higher mortality rate. Conclusions: Among patients undergoing hemodialysis, use of long-acting ESAs might be associated with a higher risk of death than use of short-acting ESAs.

Magnesium is an essential mineral for bone metabolism. However, little is known about the relationship between magnesium and the risk of fractures. In this cohort study, we elucidated the association between serum magnesium level and the risk of incident hip fracture among patients undergoing hemodialysis. We identified 113,683 patients undergoing hemodialysis with no history of hip fracture from a nation-wide database of patients undergoing dialysis in Japan. During a 2-year follow-up, a total of 2305 (2%) new hip fractures occurred. The crude incidence rate was significantly higher among patients in the lower quartiles of serum magnesium levels (2.63%, 2.08%, 1.76%, and 1.49% in Q1–Q4, respectively; P<0.001 for trend). The range of serum magnesium levels (in milligrams per deciliter) in each quartile was as follows: Q1, 2.9. After adjustment for demographic and clinical factors, patients in Q1 had a 1.23-fold higher risk for hip fracture than those in Q4 (95% confidence interval, 1.06 to 1.44; P<0.01). Similarly, an inverse probability weighting analysis showed an increased risk of hip fracture among patients in the lower magnesium quartiles. We did not observe significant effect modifications in subgroup analyses. The population-attributable fraction of serum magnesium level for incident hip fractures was 13.7% (95% confidence interval, 3.7% to 22.7%), which was much higher than that of serum calcium, serum phosphate, and parathyroid hormone levels. Thus, mild hypermagnesemia is associated with a lower risk of hip fracture among patients undergoing hemodialysis.

Increasing evidence has suggested a clinical relevance of magnesium in the context of vascular calcification and mortality among patients with CKD. Hypomagnesemia is not rare among non-dialysis CKD patients despite their decreased glomerular filtration rates; the prevalence rate was about 15% even in CKD stages G4 and G5. Among several potential causes of hypomagnesemia, tubular dysfunction/interstitial fibrosis may play a pivotal role in the development of hypomagnesemia in CKD, which impairs tubular magnesium reabsorption. Magnesium deficiency may, in turn, be involved in the progression of CKD. An in vitro study has revealed that magnesium deficiency aggravates tubular cell death and inflammation induced by phosphate load. In a cohort study of patients with CKD, low-serum magnesium levels enhanced the risk of end-stage kidney disease related to high-serum phosphate levels, suggesting a close relationship between magnesium deficiency and phosphate toxicity. More importantly, magnesium has a potent capacity to inhibit the calcification of vascular smooth muscle cells induced by phosphate. A randomized trial has shown the efficacy of oral magnesium oxide in retarding the progression of coronary artery calcification among non-dialysis CKD patients. Thus, magnesium might provide better cardiovascular prognosis; indeed, hemodialysis patients with mild hypermagnesemia exhibited the lowest mortality rate. Further randomized trials are needed to assess the impact of magnesium in terms of hard clinical outcomes among CKD patients.

Dietary protein restriction has long been a cornerstone of nutritional therapy for patients with chronic kidney diseases (CKD). However, the recommended amount of dietary protein intake is different across guidelines. This is partly because previous randomized controlled trials have reported conflicting results regarding the efficacy of protein restriction in terms of kidney outcomes. Interestingly, a vegetarian, very low protein diet has been shown to reduce the risk of kidney failure among patients with advanced CKD, without increasing the incidence of hyperkalemia. This finding suggests that the source of protein may also influence the kidney outcomes. Furthermore, a plant-dominant low-protein diet (PLADO) has recently been proposed as an alternative dietary therapy for patients with CKD. There are several potential mechanisms by which plant-based diets would benefit patients with CKD. For example, plant-based diets may reduce the production of gut-derived uremic toxins by increasing the intake of fiber, and are useful for correcting metabolic acidosis and hyperphosphatemia. Plant proteins are less likely to induce glomerular hyperfiltration than animal proteins. Furthermore, plant-based diets increase magnesium intake, which may prevent vascular calcification. More evidence is needed to establish the efficacy, safety, and feasibility of PLADO as a new adjunct therapy in real-world patients with CKD.