Renal Failure Without Hemodialysis Is a Risk Factor for Postoperative Complications in Colorectal Cancer Surgery.

Background/Aim: Surgical outcomes of colorectal cancer (CRC) in patients with renal failure (RF) remain to be clarified. The objective of this research was to investigate how RF impacts the surgical outcomes in patients with CRC. Patients and Methods: A retrospective analysis was performed on clinical data from 633 patients who underwent colorectal resection for CRC between January 2017 and December 2021. Outcomes of the patients with and without RF were compared. RF was defined as estimated Glomerular Filtration Rate less than 30. Results: Forty-five (7%) patients with RF were identified. RF was a significant risk factor for postoperative complications after colorectal cancer surgery (odds ratio=2.19, 95% confidence interval=1.08-4.42, p=0.0284). The patients with RF had significantly more comorbidity (p=0.016), and higher American Society of Anesthesiologists physical status (p<0.01). Hemoglobin level (p<0.01) and PNI (p<0.01) were significantly lower in those with RF. Postoperative complications were significantly higher (p=0.016), and the postoperative hospital stay was significantly longer (p<0.01) among patients with RF compared to those without RF. Patients with RF, excluding those undergoing hemodialysis, had significantly more complications compared to those without RF (p=0.004). Conclusion: Careful attention should be paid to perioperative management in RF colorectal cancer patients.

History of fragility fracture is associated with cardiovascular mortality in hemodialysis patients: the Q-Cohort study.

INTRODUCTION: In patients undergoing dialysis, major bone fracture is associated with a high risk of mortality, including death of cardiovascular (CV) origin. In the present study, we aimed to determine whether a history of fragility fracture is a predictor of CV death in patients undergoing hemodialysis with long-term follow-up. MATERIALS AND METHODS: In total, 3499 patients undergoing hemodialysis were analyzed for 10 years. We evaluated the history of fragility fracture in each patient at enrollment. The primary outcome was CV death. A Cox proportional hazard model and a competing risk approach were applied to determine the association between a history of fragility fracture and CV death. RESULTS: A total of 346 patients had a history of fragility fracture at enrollment. During a median follow-up of 8.8 years, 1730 (49.4%) patients died. Among them, 621 patients experienced CV death. Multivariable Cox analyses after adjustment for confounding variables showed that a history of fragility fracture was associated with CV death (hazard ratio, 1.47; 95% confidence interval, 1.16-1.85). In the Fine-Gray regression model, a history of fragility fracture was an independent risk factor for CV death (subdistribution hazard ratio, 1.36; 95% confidence interval, 1.07-1.72). CONCLUSION: In a large cohort of patients undergoing hemodialysis, a history of fragility fracture was an independent predictor of CV death.

Phase 2 study of upacicalcet in Japanese haemodialysis patients with secondary hyperparathyroidism: an intraindividual dose-adjustment study.

Background: Upacicalcet is a novel small-molecule calcimimetic agent developed for intravenous injection. Here, we evaluated the long-term efficacy and safety of upacicalcet treatment via intraindividual dose adjustment in haemodialysis patients with secondary hyperparathyroidism (SHPT). Methods: A phase 2, multicentre, open-label, single-arm study was conducted. Upacicalcet was administered for 52 weeks; the starting dose was 50 µg thrice a week, and then adjusted to 25, 50, 100, 150, 200, 250, or 300 µg, according to the dose-adjustment method set in the protocol. The primary endpoint was the percentage of patients with serum intact parathyroid hormone (iPTH) level achieving a target range of 60-240 pg/mL (target achievement rate) at week 18. Results: A total of 58 patients were administered upacicalcet. The target achievement rate of serum iPTH level at week 18 was 57.9%, which increased to 80.8% at week 52. The serum-corrected calcium (cCa) level decreased immediately after upacicalcet administration, but no further decrease was observed. Adverse events were observed in 94.8% of patients, and adverse drug reactions (ADRs) occurred in 20.7% of patients. The most common ADR was decreased adjusted calcium in eight patients; dizziness occurred as a serious ADR in one patient. The serum cCa level of patients who interrupted upacicalcet treatment at a serum cCa level of <7.5 mg/dL recovered to ≥7.5 mg/dL immediately after the interruption. Conclusions: In haemodialysis patients with SHPT, upacicalcet doses of 25-300 µg for 52 weeks were found to be highly effective and well-tolerated, with minor safety concerns.

Prevalence of hyponatremia and associated factors in patients with chronic kidney disease: the Fukuoka Kidney Disease Registry (FKR) study.

BACKGROUND: Hyponatremia is a common and important electrolyte disorder. However, the prevalence and factors associated with hyponatremia in patients with chronic kidney disease (CKD) are unknown. METHODS: We studied the factors associated with hyponatremia (< 135 mEq/L) in CKD patients registered in the Fukuoka Kidney Disease Registry (FKR) study using a logistic regression model variable selected using the variable reduction method. RESULTS: We analyzed the baseline characteristics of 4367 participants with CKD (age, 64 ± 16 years; male, 56.1%). Hyponatremia was detected in 2.0% of the patients at baseline, and multivariate logistic analysis showed that the independent factors for hyponatremia were body mass index (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.85-0.97), prescription of benzodiazepine (OR 2.31; 95% CI 1.39-3.86), blood hemoglobin level (OR 0.76; 95% CI 0.65-0.88), and serum C-reactive protein level (OR 1.27; 95% CI 1.04-1.54). CONCLUSION: The cross-sectional analysis using baseline data from the FKR study revealed independent factors associated with hyponatremia in patients with decreased kidney function. Longitudinal analyses of the FKR cohort are needed to evaluate the effects of these factors on the prognosis of hyponatremia in patients with CKD.

Angiotensin II receptor blockers and bone fracture in chronic kidney disease patients: the Fukuoka kidney disease Registry Study.

BACKGROUND: Angiotensin II receptor blockers (ARBs) reportedly reduce the risk of developing bone fractures; however, this association remains unclear among patients with chronic kidney disease (CKD). METHODS: This was a cross-sectional study of 3380 CKD patients enrolled in the Fukuoka Kidney disease Registry Study, a multicenter prospective observational cohort study of non-dialysis-dependent CKD patients. The patients were divided into two groups, those taking ARBs and those who were not. Logistic regression models were used to examine the association between ARBs and bone fracture. RESULTS: Approximately 67.0% of the participants were on ARBs, and 6.3% had a history of bone fracture. The history of bone fracture was significantly lower in patients with prescribed ARB and remained significant even after multivariable adjustment (odds ratio, 0.68; 95% confidence interval, 0.51-0.93). Other antihypertensive drugs, such as thiazide diuretics, which were reportedly helpful in preventing fractures, did not alter the bone fracture history and did not change among ARB users and non-users. CONCLUSIONS: The present study showed that administering ARB was significantly associated with a lower frequency of bone fracture history.

Direct and indirect effects of fibroblast growth factor 23 on the heart.

Fibroblast growth factor (FGF)23 is a bone-derived phosphotropic hormone that regulates phosphate and mineral homeostasis. Recent studies have provided evidence that a high plasma concentration of FGF23 is associated with cardiac disease, including left ventricular hypertrophy (LVH), heart failure, atrial fibrillation, and cardiac death. Experimental studies have shown that FGF23 activates fibroblast growth factor receptor 4 (FGFR4)/phospholipase Cγ/calcineurin/nuclear factor of activated T-cells signaling in cardiomyocytes and induces cardiac hypertrophy in rodents. Activation of FGFR4 by FGF23 normally requires the co-receptor α-klotho, and klotho-independent signaling occurs only under conditions characterized by extremely high FGF23 concentrations. Recent studies have demonstrated that FGF23 activates the renin-angiotensin-aldosterone system (RAAS) and induces LVH, at least in part as a result of lower vitamin D activation. Moreover, crosstalk between FGF23 and RAAS results in the induction of cardiac hypertrophy and fibrosis. In this review, we summarize the results of studies regarding the relationships between FGF23 and cardiac events, and describe the potential direct and indirect mechanisms whereby FGF23 induces LVH.

Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway.

Background: Patients with chronic kidney disease (CKD) have a high risk of left ventricular hypertrophy (LVH). Fibroblast growth factor 23 (FGF23) and indoxyl sulfate (IS) are associated with LVH in patients with CKD, but the interactions between these molecules remain unknown. We investigated whether IS contributes to LVH associated with FGF23 in cultured cardiomyocytes and CKD mice. Methods and results: In cultured rat cardiac myoblast H9c2 cells incubated with IS, mRNA levels of the LVH markers atrial natriuretic factor, brain natriuretic peptide, and ß-myosin heavy chain were significantly upregulated. Levels of mRNA of the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which regulates FGF23 O-glycosylation, and FGF23 were also upregulated in H9c2 cells. Intact FGF23 protein expression and fibroblast growth factor receptor 4 (FGFR4) phosphorylation were increased in cell lysates by IS administration. In C57BL/6J mice with heminephrectomy, IS promoted LVH, whereas the inhibition of FGFR4 significantly reduced heart weight and left ventricular wall thickness in IS-treated groups. While there was no significant difference in serum FGF23 concentrations, cardiac FGF23 protein expression was markedly increased in IS-injected mice. GALNT3, hypoxia-inducible factor 1 alpha, and FGF23 protein expression was induced in H9c2 cells by IS treatment and suppressed by the inhibition of Aryl hydrocarbon receptor which is the receptor for IS. Conclusion: This study suggests that IS increases FGF23 protein expression via an increase in GALNT3 and hypoxia-inducible factor 1 alpha expression, and activates FGF23-FGFR4 signaling in cardiomyocytes, leading to LVH.

Association between prevalence of laxative use and history of bone fractures and cardiovascular diseases in patients with chronic kidney disease: the Fukuoka Kidney disease Registry (FKR) study.

BACKGROUND: Constipation is a common complication in patients with chronic kidney disease (CKD) and is involved in the pathogenesis of dysbiosis and progression of CKD. However, little is known about its association with disorders of the bone-cardiovascular axis in patients with CKD. METHODS: We performed a cross-sectional analysis of 3878 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main exposure of interest was constipation defined as use of at least one type of laxative. The main outcomes were the histories of bone fractures and cardiovascular diseases (CVDs) as manifestations of disorders of the bone-cardiovascular axis. RESULTS: The prevalences of laxative use and histories of bone fractures and CVDs increased as kidney function declined. Among the 3878 patients, 532 (13.7%) patients used laxatives, 235 (6.1%) patients had prior bone fractures, and 1001 (25.8%) patients had prior CVDs. Histories of bone fractures and CVDs were significantly more prevalent among laxative users (P < 0.05). Multivariable-adjusted logistic regression analysis revealed that patients with laxatives had a significantly higher odds ratios for histories of bone fractures and CVDs than those without laxatives [adjusted odds ratios (95% confidence intervals) 1.67 (1.20-2.31) and 1.70 (1.30-2.22), respectively, P < 0.05]. CONCLUSIONS: These results suggest that constipation indicated by laxative use is associated with increased prevalences of historical bone fractures and CVDs in pre-dialysis patients with CKD.

Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidism.

The dosage of evocalcet required to control serum parathyroid hormone (PTH) levels varies among secondary hyperparathyroidism (SHPT) patients. This post hoc analysis evaluated the dose-dependent efficacy of evocalcet on serum intact PTH (iPTH) levels, corrected calcium (Ca) and phosphate (P) levels, and safety, in an evaluation period (week 28 to week 30) by stratifying the previous phase 3 data with the final evocalcet dosages (low 1-2 mg [131 patients], medium 3-4 mg [90 patients], high 5-8 mg [92 patients]), and identified pre-treatment patient characteristics predicting the use of higher final evocalcet dosages via univariate and multivariate logistic regression models. At the end of the study at week 30, the median serum iPTH level was higher and the achievement ratio for the target range of Japanese Society for Dialysis Therapy (60-240 pg/mL) was lower in the final high-dose subgroup (216 pg/mL and 58%, respectively) than in the other subgroups (low: 149 pg/mL and 79%; medium: 149 pg/mL and 73%, respectively). Among the three subgroups, the mean serum corrected Ca and P levels demonstrated similar trends, and similar ratio of patients achieved the target range (corrected Ca, 8.4-10 mg/dL; P, 3.5-6.0 mg/dL) from week 28 to week 30. No dose-dependent safety concerns were identified. Younger age, prior cinacalcet use, higher serum levels of iPTH and corrected Ca, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with final high-dose evocalcet (p < 0.05 in all cases). Patients requiring final high-dose evocalcet had pre-treatment characteristics indicating severe SHPT, leading to a lower final achievement rate for the target PTH levels of Japanese Society for Dialysis Therapy. Therefore, the early initiation of evocalcet treatment for SHPT is critical. Trial registration: This trial was registered as follows: ClinicalTrials.gov: NCT02549391 and JAPIC: JapicCTI-153013.

Malnutrition-Inflammation Complex Syndrome and Bone Fractures and Cardiovascular Disease Events in Patients Undergoing Hemodialysis: The Q-Cohort Study.

Rationale & Objective: Malnutrition-inflammation complex syndrome (MICS) is common in patients receiving hemodialysis and increases the risks of morbidity and mortality. However, few studies have examined the overall impact of MICS on disorders of the bone-cardiovascular axis. Study Design: Prospective, multicenter, observational cohort study. Setting & Participants: A total of 3,030 patients receiving maintenance hemodialysis registered in the Q-Cohort Study. Predictors: A newly developed score for MICS composed of elements chosen from 8 baseline parameters related to nutrition and inflammation by bootstrap resampling, multivariable-adjusted Cox proportional hazard risk analysis for all-cause mortality, and the risk prediction rule. ß-coefficients of each element analyzed in the multivariable-adjusted model were used for the creation of the MICS score. Outcomes: Bone fractures, cardiovascular disease events, and the composite outcome of bone fractures and cardiovascular disease events. Analytical Approach: Cox proportional hazard regression and Fine-Gray proportional subdistribution hazards regression. Results: During a median follow-up of 4 years, 140 patients developed bone fractures and 539 developed cardiovascular disease events. Age; serum levels of creatinine, albumin, and C-reactive protein; and body mass index were selected for the creation of the MICS score. The median (IQR) MICS score was 196 (181-212). The multivariable-adjusted Cox proportional hazard risk model and the competing risk model showed that a higher MICS score was incrementally associated with elevated risks of bone fractures, cardiovascular disease events, and the composite outcome; hazard risks (95% CIs) of fractures, cardiovascular disease events, and the composite outcome for each 10-point increase in the MICS score were 1.18 (1.01-1.38), 1.16 (1.07-1.26), and 1.15 (1.07-1.24), respectively. Limitations: One-time measurement of the parameters used for the creation of the MICS score. Conclusions: Malnutrition and inflammation represented by the MICS score were associated with increased risks of bone-cardiovascular axis disorders in patients receiving maintenance hemodialysis.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

Serum Alkaline Phosphatase Levels and Increased Risk of Brain Hemorrhage in Hemodialysis Patients: The Q-Cohort Study.

AIM: Elevated serum alkaline phosphatase (ALP) levels have been associated with increased risks of all-cause and cardiovascular mortality in patients receiving hemodialysis. However, little is known about the impact of serum ALP levels on the development of stroke, such as brain hemorrhage and infarction. METHODS: A total of 3,497 patients receiving maintenance hemodialysis registered in the multicenter observational Q-Cohort Study were analyzed. The primary outcomes were the incidences of brain hemorrhage and infarction. The covariate of interest was serum ALP levels. Patients were divided into tertiles based on their serum ALP levels (U/L) at baseline (T1, ＜69.3; T2, 69.3-98.4; T3, ＞98.4). The risks of brain hemorrhage, brain infarction, and composite stroke were estimated using Cox proportional hazards models and competing risk models with all-cause death as a competing risk. RESULTS: A total of 89 patients developed brain hemorrhage and 195 patients developed brain infarction during the 4-year follow-up period. The risk of brain hemorrhage in the highest tertile (T3) was significantly higher than that in the lowest tertile (T1) (multivariable-adjusted hazard ratio [95% confidence interval], 1.93 [1.12-3.35], subdistribution hazard ratio, 1.91 [1.10-3.30]). However, there was no significant association between serum ALP levels and the risk of brain infarction or composite stroke. CONCLUSIONS: Higher serum ALP levels are associated with an increased risk of brain hemorrhage, but not brain infarction, in patients receiving maintenance hemodialysis. High serum ALP level is thus an important risk factor for brain hemorrhage in hemodialysis patients.

A case of a hemodialysis patient with secondary hyperparathyroidism who was resistant to etelcalcetide treatment but not to cinacalcet hydrochloride.

Although both cinacalcet and etelcalcetide are calcimimetics that directly inhibit parathyroid hormone (PTH) secretion by activating the calcium (Ca)-sensing receptor (CaSR), their binding sites are different. We report a first case of a hemodialysis (HD) patient with secondary hyperparathyroidism (SHPT), in whom cinacalcet, but not etelcalcetide, could reduce serum intact PTH (i-PTH) levels. A HD patient received total parathyroidectomy (PTx) with auto-transplantation 16 years earlier. Due to SHPT relapse, cinacalcet was started at 7 years after PTx. His i-PTH levels had been controlled with both 75-100 mg of cinacalcet and 4.5 µg/week of calcitriol for a year before switching from cinacalcet to etelcalcetide. At 1 month following the switch, his serum i-PTH level increased to 716 pg/mL. The dose of etelcalcetide was gradually increased and finally reached the maximal dose of 45 mg/week. Because even the maximal dose of etelcalcetide for > 4 months did not reduce his serum i-PTH levels to < 700 pg/mL, etelcalcetide was switched to 50 mg/day of cinacalcet, which reduced the levels to 208 pg/mL at 2 months after the switch. Genomic sequencing test using whole blood revealed no mutation in the portion including Cys 482 of CaSR gene. The patient was resistant to etelcalcetide treatment but not to cinacalcet, suggesting the possibility that the enlarged parathyroid gland has some change in the portion including Cys 482 in the CaSR gene. Therefore, considering the possibility of etelcalcetide resistance during SHPT treatment should be kept in mind.

Non-invasive fibrosis assessments of non-alcoholic fatty liver disease associated with low estimated glomerular filtration rate among CKD patients: the Fukuoka Kidney disease Registry Study.

BACKGROUND: A growing body of evidence has shown that non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). Non-invasive fibrosis assessments of NAFLD such as Fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS) have been developed to substitute liver biopsy. Little is known about the association between FIB-4 index or NFS and the components of CKD. METHODS: In the present cross-sectional study, we assessed of 3640 Japanese CKD patients. We examined the association between FIB-4index or NFS and the odds of having low estimated glomerular filtration rate (eGFR) defined as eGFR < 60 mL/min/1.73 m2 or albuminuria defined as urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Patients were divided into quartiles according to their baseline FIB-4 index and NFS levels. Linear and logistic regression analysis were conducted, with adjustment for potential confounding factors. RESULTS: FIB-4 index and NFS were negatively associated with eGFR, but not UACR, after adjustment for potential confounding factors. Both FIB-4 index and NFS were significantly associated with low eGFR after adjustment for potential confounding factors. Meanwhile, in the multivariable-adjusted model, no associations were found between FIB-4 index or NFS and albuminuria. The addition of FIB-4 index or NFS to the established clinical CKD risk factors improved diagnostic accuracy of prevalence of low eGFR. We also found that there was a significant trend of higher FIB-4 index and NFS with more advanced renal fibrosis using the kidney biopsy data. CONCLUSIONS: Higher non-invasive fibrosis assessments of NAFLD were associated with higher odds of decreased eGFR.

Associations Between Surrogates of Skeletal Muscle Mass and History of Bone Fracture in Patients with Chronic Kidney Disease: The Fukuoka Kidney disease Registry (FKR) Study.

Patients with chronic kidney disease (CKD) are at increased risks of both sarcopenia and fragility fractures. However, information on the association between skeletal muscle mass (SMM) and the risk of bone fractures in patients with CKD is lacking. We performed a cross-sectional analysis of 4146 patients with CKD using the baseline dataset of the Fukuoka Kidney disease Registry Study, as a multicenter, prospective cohort study of pre-dialysis CKD patients. The main measure was estimated SMM (eSMM) calculated using an equation validated by bioelectrical impedance analysis with two independent datasets of 100 and 81 CKD patients. The main outcome was historical bone fractures. The associations between sex-specific quartiles (Q1-Q4) of eSMM and fracture history were assessed by logistic regression analyses. The prevalence of a history of fractures increased and eSMM decreased with progressive CKD stages. Among the 4146 patients, 249 had prior bone fractures, including 111 patients in Q1 (lowest quartile), 65 in Q2, 46 in Q3, and 27 in Q4 (highest quartile). A multivariable-adjusted model revealed that patients in Q1 had a significantly higher odds ratio (95% confidence interval) for bone fracture history than those in Q4 (reference): Q1, 2.77 (1.32-5.80); Q2, 1.95 (1.05-3.65); and Q3, 1.57 (0.90-2.75) (P-value for trend < 0.001). Similar associations were obtained when other skeletal muscle surrogates were applied: serum creatinine to serum cystatin C and daily urinary creatinine excretion. These results suggest that a lower eSMM is associated with an increased prevalence of historical bone fractures in pre-dialysis CKD patients.

Association of hyperphosphatemia with an increased risk of sudden death in patients on hemodialysis: Ten-year outcomes of the Q-Cohort Study.

BACKGROUND AND AIMS: Sudden death is one of the most common causes of death among patients on hemodialysis. Although hyperphosphatemia is a well-known risk factor for cardiovascular and all-cause deaths, the studies focusing on the relationship between serum phosphate levels and the risk of sudden death are limited. This study aimed to clarify the relationship between serum phosphate levels and the risk of sudden death in patients on hemodialysis. METHODS: This is a multicenter, longitudinal, and observational study. A total of 3505 patients, registered in the Q-Cohort Study, who underwent maintenance hemodialysis, and were followed up for 10 years, were included. Patients were divided into quartiles on the basis of baseline serum phosphate levels: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 908), 4.9-5.6 mg/dL; and Q4 (n = 874), ≥5.7 mg/dL. Associations between baseline serum phosphate levels and sudden death were analyzed using the Cox proportional hazards model and the Fine-Gray regression model. RESULTS: During the follow-up period, 227 patients died from sudden death. The risk for sudden death was significantly higher in the highest quartile (Q4) than in the lowest quartile (Q1) as the reference group (multivariable-adjusted hazard ratios and 95% confidence intervals: Q1, 1.00; Q2, 1.15 [0.77-1.70], Q3, 1.31 [0.89-1.93], and Q4, 1.72 [1.14-2.59]; hazard ratio for every 1-mg/dL increase in the serum phosphate level, 1.23 [1.09-1.39]; p < 0.001). CONCLUSIONS: Hyperphosphatemia is independently associated with an elevated risk of sudden death in patients on hemodialysis.

Impact of Multivascular Disease on Cardiovascular Mortality and Morbidity in Patients Receiving Hemodialysis: Ten-Year Outcomes of the Q-Cohort Study.

AIM: Multivascular disease, indicating concurrent arteriosclerotic lesions in a number of different vascular beds, is an independent risk factor for recurrent ischemic events in the general population. However, the impact of multivascular disease on the risk of developing cardiovascular disease has not been fully evaluated in patients receiving hemodialysis. METHODS: A total of 3,504 hemodialysis patients were prospectively followed for 10 years. In this study, multivascular disease was defined as the coexistence of coronary artery disease and stroke. We examined the relationship between multivascular disease and the occurrence of composite cardiovascular endpoint, consisting of cardiovascular death, nonfatal coronary artery disease, nonfatal stroke, and peripheral artery disease. RESULTS: The proportion of participants with multivascular disease was 5.7% (n=200) at baseline. During follow-up (median, 106.6 months; interquartile range, 50.1-121.8 months), 1,311 patients experienced the composite endpoint, which was defined as at least one of the following: cardiovascular death (n=620), nonfatal coronary artery disease (n=318), nonfatal stroke (n=340), and peripheral artery disease (n=257). Compared with the group with no history of cardiovascular disease, the risk of experiencing the composite endpoint increased significantly with higher numbers of injured vascular beds in patients with single vascular disease (hazard ratio, 1.68; 95% confidence interval, 1.49-1.89) and in those with multivascular disease (hazard ratio, 2.11; 95% confidence interval, 1.71-2.60). In a multivariable analysis, multivascular disease was an independent predictor of cardiovascular events, in addition to diabetes, aging, and hypertension. CONCLUSIONS: This study clearly demonstrated that multivascular disease was a powerful predictor for cardiovascular mortality and morbidity in patients receiving hemodialysis.

Association of normalized protein catabolic rate (nPCR) with the risk of bone fracture in patients undergoing maintenance hemodialysis: The Q-Cohort Study.

BACKGROUND & AIMS: Normalized protein catabolic rate (nPCR) is used as a surrogate for daily dietary protein intake and nutritional status in patients receiving maintenance hemodialysis. It remains uncertain whether the nPCR level is associated with the incidence of bone fracture. METHODS: A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective, observational study, were followed up for 4 years. The primary outcome was bone fracture at any site. The main exposure was the nPCR level at baseline. Patients were assigned to four groups based on their baseline nPCR levels (G1: <0.85, G2: 0.85≤, <0.95, G3: 0.95≤, <1.05 [reference], G4: ≥1.05 g/kg/day). We examined the relationship between the nPCR levels and the risk for bone fracture using Cox proportional hazards models. RESULTS: During the follow-up period, 136 patients experienced bone fracture at any site. In the multivariable analyses, the risk for bone fracture was significantly higher in the lowest (G1) and highest (G4) nPCR groups than the reference (G3) group (hazard ratio [95% confidence intervals]: G1, 1.93 [1.04-3.58]; G2, 1.27 [0.67-2.40]; G3 1.00 (reference); G4, 2.21 [1.25-3.92]). The association remained almost unchanged, even when patients were divided into sex-specific nPCR quartiles, when analysis was limited to patients with a dialysis vintage ≥2 years, assumed to have lost residual kidney function, or when a competing risk model was applied. CONCLUSIONS: Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients.

Association Between Plasma Intact Parathyroid Hormone Levels and the Prevalence of Atrial Fibrillation in Patients With Chronic Kidney Disease　- The Fukuoka Kidney Disease Registry Study.

BACKGROUND: Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD).Methods and Results:The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-Q4) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016). CONCLUSIONS: Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

Association of serum phosphate concentration with the incidence of intervention for peripheral artery disease in patients undergoing hemodialysis: 10-year outcomes of the Q-Cohort Study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) is mainly caused by atherosclerosis and is a critical cardiovascular complication in patients undergoing hemodialysis. Although hyperphosphatemia is a risk factor for cardiovascular events, whether serum phosphate concentration is associated with PAD remains unclear. This study was performed to clarify the relationship between serum phosphate concentration and the risk of intervention for PAD in patients undergoing hemodialysis. METHODS: In total, 3505 patients undergoing hemodialysis registered in the Q-Cohort Study were followed up for 10 years. The primary outcome was the incidence of major adverse limb events (MALE) as a surrogate endpoint of intervention for PAD. The patients were divided into quartiles according to the baseline serum phosphate concentration: Q1 (n = 886), <4.2 mg/dL; Q2 (n = 837), 4.2-4.8 mg/dL; Q3 (n = 909), 4.9-5.6 mg/dL; and Q4 (n = 873), ≥5.7 mg/dL. A multivariable-adjusted Cox proportional hazards risk model was employed to examine the association between the serum phosphate concentration and the risk of MALE. RESULTS: During a median follow-up period of 8.2 years, 257 patients required intervention with MALE. The Cox proportional hazards risk model showed that the risk of MALE in Q4 was significantly higher than that in Q1 (hazard ratio, 1.81; 95% confidence interval, 1.25-2.63). Every 1-mg/dL increase in serum phosphate concentration was also significantly associated with the increased incidence of MALE (hazard ratio, 1.24; 95% confidence interval, 1.10-1.39). CONCLUSIONS: An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.