Yusuke Sakaguchi

Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis

Although previous studies in the general population showed that hypomagnesemia is a risk for cardiovascular diseases (CVD), the impact of magnesium on the prognosis of patients on hemodialysis has been poorly investigated. To gain information on this we conducted a nationwide registry-based cohort study of 142,555 hemodialysis patients to determine whether hypomagnesemia is an independent risk for increased mortality in this population. Study outcomes were 1-year all-cause and cause-specific mortality with baseline serum magnesium levels categorized into sextiles. During follow-up, a total of 11,454 deaths occurred, of which 4774 had a CVD cause. In a fully adjusted model, there was a J-shaped association between serum magnesium and the odds ratio of all-cause mortality from the lowest to highest sextile, with significantly higher mortality in sextiles 1-3 and 6. Similar associations were found between magnesium and both CVD and non-CVD mortality. The proportion of patients with a baseline intact parathyroid hormone level under 50 pg/ml was significantly higher in the highest sextile; however, after excluding these patients, the CVD mortality risk in the highest sextile was attenuated. Thus, hypomagnesemia was significantly associated with an increased risk of mortality in hemodialysis patients. Interventional studies are needed to clarify whether magnesium supplementation is beneficial for improving patient prognosis.

High Prevalence of Obstructive Sleep Apnea and Its Association with Renal Function among Nondialysis Chronic Kidney Disease Patients in Japan: A Cross-Sectional Study

BACKGROUND AND OBJECTIVES Obstructive sleep apnea (OSA) affects one of five adults in the general population. Although a high prevalence of OSA has been reported among dialysis patients, the association between nondialysis chronic kidney disease (CKD) and OSA has not been fully investigated. This cross-sectional study aimed to investigate the prevalence of OSA among nondialysis CKD patients in Japan and the association between renal function and OSA. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Consecutive nondialysis CKD patients hospitalized mainly for CKD educational program, regardless of their sleep complaints, were enrolled. The diagnosis of OSA and its severity were measured using a type 3 portable monitor. RESULTS Overall (n=100, 68.0% male, median age 66.5 years, body mass index [BMI] 23.1 kg/m(2), estimated GFR [eGFR] 28.5 ml/min per 1.73 m(2)), 65% were diagnosed as OSA: mild OSA (apnea-hypopnea index [AHI] 5.0 to 14.9) in 32%, moderate OSA (AHI 15.0 to 29.9) in 25%, and severe OSA (AHI ≥ 30.0) in 8%. Multivariate logistic regression analysis revealed that a 10-ml/min per 1.73 m(2) decrease in eGFR was associated with a 42% increased odds of OSA after adjustment for age, BMI, and diabetes mellitus. Moreover, in a generalized linear model, eGFR was inversely correlated with AHI after adjustment for covariates. CONCLUSIONS This study demonstrated a high prevalence of OSA among nondialysis CKD patients in Japan and that the increased risk of OSA was significantly associated with decreased GFR among these patients. Further investigations are warranted to determine OSAs direct influence on cardiovascular disease.

Hypomagnesemia in Type 2 Diabetic Nephropathy A novel predictor of end-stage renal disease

OBJECTIVE There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy. RESEARCH DESIGN AND METHODS This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level ≤1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point. RESULTS Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28–3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70–1.90; P = 0.57). CONCLUSIONS Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy.

Magnesium Modifies the Cardiovascular Mortality Risk Associated with Hyperphosphatemia in Patients Undergoing Hemodialysis: A Cohort Study

Background In vitro studies have shown inhibitory effects of magnesium (Mg) on phosphate-induced calcification of vascular smooth muscle cells, raising the possibility that maintaining a high Mg level may be useful for reducing cardiovascular risks of patients with hyperphosphatemia. We examined how serum Mg levels affect the association between serum phosphate levels and the risk of cardiovascular mortality in patients undergoing hemodialysis. Methods A nationwide register-based cohort study was conducted using database of the Renal Data Registry of the Japanese Society for Dialysis Therapy in 2009. We identified 142,069 patients receiving in-center hemodialysis whose baseline serum Mg and phosphate levels were available. Study outcomes were one-year cardiovascular and all-cause mortality. Serum Mg levels were categorized into three groups (lower, <2.7 mg/dL; intermediate, ≥2.7, <3.1 mg/dL; and higher, ≥3.1 mg/dL). Results During follow-up, 11,401 deaths occurred, out of which 4,751 (41.7%) were ascribed to cardiovascular disease. In multivariable analyses, an increase in serum phosphate levels elevated the risk of cardiovascular mortality in the lower- and intermediate-Mg groups, whereas no significant risk increment was observed in the higher-Mg group. Moreover, among patients with serum phosphate levels of ≥6.0 mg/dL, the cardiovascular mortality risk significantly decreased with increasing serum Mg levels (adjusted odds ratios [95% confidence intervals] of the lower-, intermediate-, and higher-Mg groups were 1.00 (reference), 0.81 [0.66–0.99], and 0.74 [0.56–0.97], respectively.). An interaction between Mg and phosphate on the risk of cardiovascular mortality was statistically significant (P = 0.03). Conclusion Serum Mg levels significantly modified the mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis.

Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study

BACKGROUND Hepcidin is a central regulator of iron homeostasis. Increased hepcidin concentrations could cause iron-restricted erythropoiesis in chronic kidney disease (CKD)-associated anemia. This cross-sectional observational study was conducted to evaluate the association between hepcidin and CKD-associated anemia in non-dialysis CKD patients. METHODS A total of 505 non-dialysis CKD patients not treated with parenteral iron were recruited, and serum hepcidin-25 levels were measured by liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was used to examine the relationship between hepcidin and glomerular filtration rate (GFR) and the relationship between hemoglobin concentration and predictors including the hepcidin level. RESULTS The median hepcidin level among the 505 CKD patients was 15.4 ng/mL (interquartile range, 5.5-33.6 ng/mL). Although hepcidin level significantly increased according to the CKD stage, multivariate analysis did not reveal an association of GFR with the hepcidin level. Hepcidin level was a significant predictor of hemoglobin concentration after the adjustment for confounders, and a significant interaction between hepcidin and ferritin was found. After stratifying at the median ferritin level, 91 ng/mL, we found a negative association between hepcidin level and hemoglobin in the high-ferritin group. A trend toward a negative association between hepcidin level and mean corpuscular volume was observed in the high-ferritin group. CONCLUSIONS Serum hepcidin-25 levels were negatively associated with hemoglobin concentrations in non-dialysis CKD patients with sufficient iron stores. We found that ferritin modified the association between hepcidin level and hemoglobin concentration. In addition, our results confirmed that the serum hepcidin level is not associated with GFR.

Association of Nocturnal Hypoxemia with Progression of CKD

BACKGROUND AND OBJECTIVES Nocturnal hypoxemia is highly prevalent among patients with CKD. Nocturnal hypoxemia contributes to systemic inflammation, oxidative stress, endothelial cell dysfunction, and activation of the renin-angiotensin system, which are common pathologic mechanisms of CKD progression. This study investigated whether nocturnal hypoxemia is independently associated with CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This two-center retrospective cohort study included 161 patients with stages 3-4 CKD enrolled from January of 2009 to July of 2011 with a body mass index less than 25.0 kg/m(2). The 4% oxygen desaturation index, the number of events per hour in which oxygen saturation decreases by >4% during sleep, was measured, and the declining rate of the estimated GFR was followed over 1 year. The severity of nocturnal hypoxemia was categorized as none (oxygen desaturation index<5.0), mild (5.0≤oxygen desaturation index<15.0), or moderate to severe (15.0≤oxygen desaturation index). RESULTS The mean estimated GFR of the total cohort at baseline was 31 ml/min per 1.73 m(2). Eighty patients (49.7%) were diagnosed with nocturnal hypoxemia; 64 patients were diagnosed with mild nocturnal hypoxemia, and 16 patients were diagnosed with moderate-to-severe nocturnal hypoxemia. The estimated GFR declined three- to fourfold faster in patients with moderate-to-severe nocturnal hypoxemia than patients with no or mild nocturnal hypoxemia (the mean values [95% confidence intervals] were -2.14 [-1.06 to -3.21], -3.02 [-1.31 to -4.74], and -8.59 [-2.00 to -15.2] ml/min per 1.73 m(2) per year in the no, mild, and moderate-to-severe nocturnal hypoxemia groups, respectively; P=0.003). Nocturnal hypoxemia remained a significant predictor of decline in estimated GFR after adjustment for various baseline clinical factors. CONCLUSIONS In nonobese patients with CKD, nocturnal hypoxemia is an independent risk factor of a rapid decline in kidney function.

Magnesium modifies the association between serum phosphate and the risk of progression to end-stage kidney disease in patients with non-diabetic chronic kidney disease

It is known that magnesium antagonizes phosphate-induced apoptosis of vascular smooth muscle cells and prevents vascular calcification. Here we tested whether magnesium can also counteract other pathological conditions where phosphate toxicity is involved, such as progression of chronic kidney disease (CKD). We explored how the link between the risk of CKD progression and hyperphosphatemia is modified by magnesium status. A post hoc analysis was run in 311 non-diabetic CKD patients who were divided into four groups according to the median values of serum magnesium and phosphate. During a median follow-up of 44 months, 135 patients developed end-stage kidney disease (ESKD). After adjustment for relevant clinical factors, patients in the lower magnesium-higher phosphate group were at a 2.07-fold (95% CI: 1.23-3.48) risk for incident ESKD and had a significantly faster decline in estimated glomerular filtration rate compared with those in the higher magnesium-higher phosphate group. There were no significant differences in the risk of these renal outcomes among the higher magnesium-higher phosphate group and both lower phosphate groups. Incubation of tubular epithelial cells in high phosphate and low magnesium medium in vitro increased apoptosis and the expression levels of profibrotic and proinflammatory cytokine; these changes were significantly suppressed by increasing magnesium concentration. Thus, magnesium may act protectively against phosphate-induced kidney injury.

Association between Density of Coronary Artery Calcification and Serum Magnesium Levels among Patients with Chronic Kidney Disease

Background The Agatston score, commonly used to quantify coronary artery calcification (CAC), is determined by the plaque area and density. Despite an excellent predictability of the Agatston score for cardiovascular events, the density of CAC has never been studied in patients with pre-dialysis chronic kidney disease (CKD). This study aimed to analyze the CAC density and its association with serum mineral levels in CKD. Methods We enrolled patients with pre-dialysis CKD who had diabetes mellitus, prior cardiovascular disease history, elevated low-density lipoprotein cholesterol levels, or smoking history. The average CAC density was calculated by dividing the Agatston score by the total area of CAC. Results The mean estimated glomerular filtration rate (eGFR) of 109 enrolled patients was 35.7 mL/min/1.73 m2. The correlation of the Agatston score with density was much weaker than that with the total area (R2 = 0.19, P < 0.001; and R2 = 0.99, P < 0.001, respectively). Multivariate analyses showed that serum magnesium level was inversely associated with the density, but not with the total area, after adjustment for demographics and clinical factors related to malnutrition-inflammation-atherosclerosis syndrome and mineral and bone disorders including fibroblast growth factor 23 (P = 0.006). This inverse association was pronounced among patients with higher serum phosphate levels (P for interaction = 0.02). Conclusion CAC density was inversely associated with serum magnesium levels, particularly in patients with higher serum phosphate levels.

Effects of Magnesium on the Phosphate Toxicity in Chronic Kidney Disease: Time for Intervention Studies

Magnesium, an essential mineral for human health, plays a pivotal role in the cardiovascular system. Epidemiological studies in the general population have found an association between lower dietary magnesium intake and an elevated risk of cardiovascular events. In addition, magnesium supplementation was shown to improve blood pressure control, insulin sensitivity, and endothelial function. The relationship between magnesium and cardiovascular prognosis among patients with chronic kidney disease (CKD) has been increasingly investigated as it is becoming evident that magnesium can inhibit vascular calcification, a prominent risk of cardiovascular events, which commonly occurs in CKD patients. Cohort studies in patients receiving dialysis have shown a lower serum magnesium level as a significant risk for cardiovascular mortality. Interestingly, the cardiovascular mortality risk associated with hyperphosphatemia is alleviated among those with high serum magnesium levels, consistent with in vitro evidence that magnesium inhibits high-phosphate induced calcification of vascular smooth muscle cells. Furthermore, a harmful effect of high phosphate on the progression of CKD is also attenuated among those with high serum magnesium levels. The potential usefulness of magnesium as a remedy for phosphate toxicity should be further explored by future intervention studies.

Urine Osmolarity Predicts the Body Weight-Reduction Response to Tolvaptan in Chronic Kidney Disease Patients: A Retrospective, Observational Study

Background/Aims: Tolvaptan, a vasopressin V2 receptor antagonist, promotes the excretion of electrolyte-free water. Patients with heart failure or liver cirrhosis, whose urine osmolarity is high due to increased vasopressin, show a good response to tolvaptan; however, it remains dubious whether tolvaptan is also effective in patients with low urine osmolarity due to decreased renal function. The aim of this study was to investigate whether urine osmolarity predicts the effect of tolvaptan in patients with decreased renal function. Methods: In this retrospective, observational study, 17 overhydrated chronic kidney disease patients with heart failure or liver cirrhosis who were admitted to Osaka University Hospital were included. They were treated with sodium-excreting diuretics first, and then tolvaptan was added. The clinically relevant parameters were evaluated before and after the use of tolvaptan, and they, including urine osmolarity before use of tolvaptan, were compared between the responder group and the non-responder group. The definition of responder was based on the decrease of body weight by ≥5% in one week, which is a more rigorous indicator of the effectiveness of tolvaptan than the increase in urine output. Results: The parameter that showed a significant difference between the responder and non-responder groups was urine osmolarity before the use of tolvaptan. The cut-off point derived from the receiver operating characteristic (ROC) curve analysis was 279 mOsm/kg H2O, with sensitivity of 0.86 and specificity of 0.80. Conclusions: In patients with decreased renal function, urine osmolarity before the use of tolvaptan predicted the effectiveness of diuretics in terms of body weight reduction.