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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.

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

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. 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

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.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.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.Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients.

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.

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.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.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).An elevated serum phosphate concentration was associated with an increased risk of MALE in patients undergoing hemodialysis.

Several experimental studies have indicated that increased plasma osmolarity caused by recurrent dehydration is involved in kidney injury via a mechanism, mediated by vasopressin secretion and activation of the aldose reductase pathway. Epidemiologic evidence linking increased plasma osmolarity and the onset of end-stage kidney disease (ESKD), in patients with primary glomerulonephritis, is lacking. We retrospectively examined 663 patients with IgA nephropathy (IgAN) diagnosed by kidney biopsy and evaluated the association between estimated plasma osmolarity and ESKD prevalence, using a Cox proportional hazards model. During follow-up (median 80.4 months; interquartile range 22.2–120.1), 73 patients developed ESKD. In a baseline survey, plasma osmolarity was correlated negatively with the mean value of the estimated glomerular filtration rate, but correlated positively with the mean value of urinary protein excretion, systolic blood pressure, and pathologic severity of extracapillary proliferation, in addition to tissue fibrosis and sclerosis. The incidence rate of ESKD increased linearly with increase in plasma osmolarity (P

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.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.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].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.

Rationale & Objective: The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients. Study Design: Nonrandomized intervention study. Setting & Population: 12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration. Intervention: Use of 2.75-mEq/L dialysate calcium concentration. Outcomes: Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion. Results: Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels. Limitations: Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period. Conclusions: Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors. Funding: None. Trial Registration: University Hospital Medical Information Network, www.umin.ac.jp/english/, R000040105, UMIN000035184. Index Words: Calcium, dialysate calcium concentration, hemodialysis, parathyroid hormone

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.

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.

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

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.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.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).Hyperphosphatemia is independently associated with an elevated risk of sudden death in patients on hemodialysis.

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.

Background and aims The modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr levels, and Kt/V for urea, reflects skeletal muscle mass in patients on hemodialysis. Whether the modified Cr index is associated with cardiovascular events and all-cause mortality remains unknown. Methods A total of 3027 patients registered in the Q-Cohort Study, a multicenter, prospective study of patients on hemodialysis in Japan, were analyzed. The main outcomes were cardiovascular events and all-cause mortality. Associations between sex-specific quartiles of the modified Cr index and outcomes were analyzed by the Cox proportional hazard models and the Fine–Gray proportional subdistribution hazards model. Results The modified Cr index was correlated with known nutritional and inflammatory markers. During a 4-year follow-up, 499 patients died of any cause, 372 experienced heart disease, and 194 developed stroke. The risk for all-cause mortality was significantly higher in the lower quartiles (Q1 and Q2) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals: Q1, 2.65 [1.69–4.25], Q2, 1.92 [1.27–2.94], and Q3, 1.31 [0.87–2.02]). The risk of heart disease was significantly higher in Q1 than in Q4 (hazard ratios and 95% confidence intervals: Q1, 1.64 [1.04–2.61], Q2, 1.34 [0.91–2.00], and Q3, 1.04 [0.71–1.52]). The risk of stroke was not associated with the modified Cr index. Conclusions A lower modified Cr index is associated with an increased risk for heart disease and all-cause mortality, but not with the risk for stroke in patients on hemodialysis.

The use of phosphate (P)-binders allows hemodialysis patients to take in more protein and thus may maintain a good nutritional status. Protein-energy-malnutrition increases the risk of infection-related death. The association between use of P-binders and the relative risks of infection-related death remains unknown in hemodialysis patients. A total of 2926 hemodialysis patients registered to the Q-Cohort Study was followed up for 4-years. The association between use of P-binders and the risks for infection-related and all-cause mortality were estimated by Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score based approaches. During the follow-up period, 106 patients and 492 patients died of infection and any cause, respectively. Cox proportional hazards models with multivariable adjustments including nutritional confounders showed that the incidence of infection-related death was significantly lower in patients with P-binders use compared with those without (hazard ratio [95% confidence interval] for infection-related mortality 0.63 [0.40–0.99]). The results remained significant even after applying four different propensity score-based analyses. Notably, use of P-binders was associated with a lower risk of all-cause mortality. Further studies including randomized controlled clinical trials and observational studies analyzed by an instrumental variable model will provide more robust evidences for the associations observed in our study.

Hemodialysis patients are at increased risk for bone fracture and sarcopenia. There is close interplay between skeletal muscle and bone. However, it is still unclear whether lower skeletal muscle mass increases the risk for bone fracture.Cross-sectional study and prospective longitudinal cohort study.An independent cohort of 78 hemodialysis patients in the cross-sectional study and 3,030 prevalent patients undergoing maintenance hemodialysis prospectively followed up for 4 years.Skeletal muscle mass measured by bioelectrical impedance analysis (BIA) and modified creatinine index, an estimate of skeletal muscle mass based on age, sex, Kt/V for urea, and serum creatinine level.Bone fracture at any site.In the cross-sectional study, modified creatinine index was significantly correlated with skeletal muscle mass measured by BIA. During a median follow-up of 3.9 years, 140 patients had bone fracture. When patients were divided into sex-specific quartiles based on modified creatinine index, risk for bone fracture estimated by a Fine-Gray proportional subdistribution hazards model with all-cause death as a competing risk was significantly higher in the lower modified creatinine index quartiles (Q1 and Q2) compared to the highest modified creatinine index quartile (Q4) as the reference value in both sexes (multivariable-adjusted HRs for men were 7.81 [95% CI, 2.63-23.26], 5.48 [95% CI, 2.08-14.40], 2.24 [95% CI, 0.72-7.00], and 1.00 [P for trend 0.001], and for women were 4.44 [95% CI, 1.50-13.11], 2.33 [95% CI, 0.86-6.31], 1.96 [95% CI, 0.82-4.65], and 1.00 [P for trend = 0.007] for Q1, Q2, Q3, and Q4, respectively).One-time assessment of modified creatinine index; no data for residual kidney function and fracture sites and causes.Modified creatinine index was correlated with skeletal muscle mass measured by BIA. Lower modified creatinine index was associated with increased risk for bone fracture in male and female hemodialysis patients.

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.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 mFIB-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.Higher non-invasive fibrosis assessments of NAFLD were associated with higher odds of decreased eGFR.

Modified creatinine (Cr) index, calculated by age, sex, pre-dialysis serum Cr concentration, and Kt/V for urea, is an indicator of skeletal muscle mass in hemodialysis (HD) patients. It remains unknown whether the modified Cr index predicts infection-related mortality in this population. We investigated the association between the modified Cr index and infection-related mortality. A total of 3046 patients registered in the Q-Cohort Study, a multicenter, observational study of HD patients, were analyzed. Associations between sex-specific quartiles (Q1–Q4) of the modified Cr index and the risk for infection-related mortality were analyzed by Cox proportional hazard model. During a median follow-up of 8.8 years, 387 patients died of infection. The estimated risk for infection-related mortality was significantly higher in the lower quartiles (Q1, Q2, and Q3) than in the highest quartile (Q4) as the reference group (hazard ratios and 95% confidence intervals [CI]: Q1, 2.89 [1.70–5.06], Q2, 2.76 [1.72–4.62], and Q3, 1.79 [1.12–2.99]). The hazard ratio (95% CI) for a 1 mg/kg/day decrease in the modified Cr index was 1.18 (1.09–1.27, P

Although hypercalcemia is a risk factor for all-cause mortality in hemodialysis patients, it remains unknown whether hypercalcemia increases the risk of infection-related death. A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective cohort study of hemodialysis patients, were analyzed. The predictor was albumin-corrected serum calcium level at baseline. The main outcome was infection-related death. Death risk were estimated by multivariable-adjusted Cox proportional hazard risk models and competing risk models. During the follow-up period of 4 years, 107 patients died of infection and 473 died of any cause. The patients were divided into four groups by the serum calcium level at baseline (G1, 5.7–8.9 mg/dL; G2, 9.0–9.4 mg/dL; G3, 9.5–9.9 mg/L; G4 10.0–16.5 mg/dL). In the multivariable-adjusted model, the incidence of infection-related death was significantly higher in the highest serum calcium group (G4) compared with the lowest serum calcium group (G1): hazard ratio [95% confidence interval], 2.34 [1.35–4.04], P = 0.002. Furthermore, higher serum calcium level was significantly associated with increased risk of all-cause death. In conclusion, our data suggest that a higher serum calcium level may be a risk factor for infection-related and all-cause death in hemodialysis patients.

Aim The incidence of sudden death and its risk factors in patients on hemodialysis remain unclear. This study aimed to clarify the incidence of sudden death and its risk factors in Japanese patients on hemodialysis. Methods A total of 3505 patients on hemodialysis aged ≥ 18 years were followed for 10 years. Multivariate-adjusted hazard ratio (HR) with 95% confidence interval (95% CI) of each risk factor of sudden death were calculated using a Cox proportional hazards model. Results During the 10-year follow-up, 1735 patients died, including 227 (13%) sudden deaths. The incidence rate of sudden death was 9.13 per 1000 person-years. In multivariable-adjusted Cox analysis, male sex (HR 1.67; 95% CI 1.20-2.33), age (HR 1.44; 95% CI 1.26-1.65 per 10-year higher), the presence of diabetes (HR 2.45; 95% CI 1.82-3.29), history of cardiovascular disease (HR 1.85; 95% CI 1.38-2.46), cardiothoracic ratio (HR 1.21; 95% CI 1.07-1.39 per 5% higher), serum C-reactive protein (HR 1.11; 95% CI 1.03-1.20 per 1-mg/dL higher), and serum phosphate (HR 1.15; 95% CI 1.03-1.30 per 1-mg/dL higher) were independent predictors of sudden death. A subgroup analysis stratified by sex or age showed that lower serum corrected calcium levels, not using vitamin D receptor activators in women, and a shorter dialysis session length in men or older people (≥ 65 years) increased the risk for sudden death. Conclusions This study clarified the incidence of sudden death and its specific predictors in Japanese patients on hemodialysis.

As fibroblast growth factor 23 (FGF23) has been shown to induce cardiovascular disease directly in patients with chronic kidney disease, identification of factors and treatments that can modulate serum FGF23 (sFGF23) level is clinically important. This retrospective longitudinal study investigated factors that modulate sFGF23 in 49 patients who underwent peritoneal dialysis (PD). sFGF23 ratio (sFGF23 at 18 months/baseline sFGF23) was used as an indicator of changes in sFGF23 level. Total phosphate elimination was the sum of both renal phosphate excretion and dialysate phosphate elimination. In multivariate analysis, log sFGF23 ratio was associated negatively with total phosphate elimination and the use of cinacalcet at baseline, and positively with the use of vitamin D receptor activators at baseline, even after adjusting for potential confounding factors. Our study indicates that maintaining phosphate elimination can prevent increased sFGF23, thereby preventing cardiovascular events in patients who undergo PD.

Chronic kidney disease (CKD) is an established independent risk factor for progression to end-stage renal disease (ESRD) and incidence of cardiovascular disease (CVD). The onset and progression of CKD are associated with both genetic predisposition and various lifestyle-related factors, but little is known about the influence of genetic-environmental interactions on the incidence of ESRD or CVD in patients with CKD. The Fukuoka Kidney disease Registry (FKR) Study is designed as one of the largest prospective, multicenter, observational cohort studies in non-dialysis dependent CKD patients. The FKR Study aims to enroll approximately 5000 individuals at multiple clinical centers and follow them for up to at least 5 years. At baseline, subjects enrolled in the FKR Study will fill out extensive lifestyle-related questionnaires. Further, their health status and treatments will be monitored annually through a research network of nephrology centers. Blood and urine samples, including DNA/RNA, will be collected at the time of enrolment and every 5-years follow-up. The FKR Study will provide many insights into the onset and progression of CKD, which will suggest hypothesis-driven interventional clinical trials aimed at reducing the burden of CKD. The features of the FKR Study may also facilitate innovative research to identify and validate novel risk factors, including genetic susceptibility and biomarkers, using biomaterials by high-throughput omics technologies.

There has been limited data discussing the relationship between apparent treatment-resistant hypertension (ATRH) and cardiovascular disease risk in patients receiving maintenance hemodialysis. We analyzed data for 2999 hypertensive patients on maintenance hemodialysis. ATRH was defined as uncontrolled blood pressure despite the use of three or more classes of antihypertensive medications, or four or more classes of antihypertensive medications regardless of blood pressure level. We examined the relationships between ATRH and cardiovascular events using a Cox proportional hazards model. The proportion of participants with ATRH was 18.0% (539/2999). During follow-up (median: 106.6 months, interquartile range: 51.3–121.8 months), 931 patients experienced cardiovascular events including coronary heart disease (n = 424), hemorrhagic stroke (n = 158), ischemic stroke (n = 344), and peripheral arterial disease (n = 242). Compared with the non-ATRH group, the ATRH group showed a significant increased risk of developing cardiovascular disease (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.08–1.49), coronary heart disease (HR: 1.28; 95% CI: 1.01–1.62), ischemic stroke (HR: 1.31; 95% CI: 1.01–1.69), and peripheral arterial disease (HR: 1.42; 95% CI: 1.06–1.91) even after adjusting for potential confounders. This study demonstrated that ATRH was significantly associated with increased cardiovascular risk in hemodialysis patients.

Recent lines of evidence suggest that, as in other countries, sudden cardiac death (SCD) is more common in the Japanese dialysis clinical setting than we previously thought.Three specific important findings may underlie the increased incidence of SCD in dialysis patients. Even after successful coronary revascularization, hemodialysis (HD) patients continue to have a higher incidence of SCD than the general population. Second, about 70% or more of end-stage kidney disease patients have concentric and eccentric left ventricular hypertrophy, which predisposes many dialysis patients to interstitial fibrosis, decreased coronary perfusion reserve, and decreased ischemia tolerance. Third, mildly impaired left ventricular dysfunction, with an ejection fraction50%, is associated with a greater risk of SCD in dialysis patients. We have believed and accepted a common sense theory that paroxysmal ventricular tachycardia and fibrillation are the central cause of SCD in HD patients, because such cardiac functional morphological abnormalities were observed, and there are many chances for ventricular arrhythmia triggers, such as volume expansion and electrolyte shift, to develop. However, the type of fatal arrhythmia responsible for SCD differs between before and after HD. Sudden cardiac arrest (SCA) from ventricular fibrillation (VF) was more often seen in the post-HD setting, while SCA from non-VF, which may be bradyarrhythmia, was more often seen in the pre-HD setting. This may imply that the causes of SCA are bradyarrhythmia due to hyperkalemia in the pre-HD setting on the day after a long interval, and fatal ventricular arrhythmia due to a prolonged QT interval in the post-HD setting, because some recent evidence suggests that shifts of electrolytes, such as potassium and calcium, during HD cause rapid prolongation of the QT interval after HD, which may lead to the onset of ventricular arrhythmia and SCD. In fact, a higher calcium gradient, defined as the difference between the pre-HD corrected total serum calcium level and the dialysate calcium level, was associated with a higher risk of SCD in HD patients. Key Messages: Further study is needed to determine which combination of calcium, potassium, and bicarbonate concentrations in dialysate is optimal to avoid SCD in high-risk HD patients.

Myostatin is a member of the transforming growth factor-β family, which regulates synthesis and degradation of skeletal muscle proteins and is associated with the development of sarcopenia. It is up-regulated in the skeletal muscle of chronic kidney disease patients and is considered to be involved in the development of uremic sarcopenia. However, serum myostatin levels have rarely been determined, and the relationship between serum myostatin levels with clinical and metabolic factors remains unknown. This cross-sectional study investigated the association between serum myostatin level and clinical factors in 69 outpatients undergoing peritoneal dialysis. Serum myostatin level was determined by commercially available enzyme-linked immunosorbent assay (ELISA). Univariable and multivariable analysis were conducted to determine factors associated with serum myostatin levels. The factors included age, sex, diabetes mellitus, dialysis history, body mass index, residual kidney function, peritoneal dialysate volume, serum biochemistries, and the use of vitamin D receptor activators (VDRAs). Mean serum myostatin level was 7.59 ± 3.37 ng/mL. There was no association between serum myostatin level and residual kidney function. Serum myostatin levels were significantly and positively associated with lean body mass measured by the creatinine kinetic method and negatively associated with the use of VDRAs after adjustment for potential confounding factors. Our study indicated that serum myostatin levels are associated with skeletal muscle mass and are lower in patients treated with VDRAs. Further studies are necessary to determine the significance of measuring serum myostatin level in patients undergoing peritoneal dialysis.

Aims Clinical studies have shown that very low protein diet (VLPD) has negative effects on long-term survival. It remains unclear why VLPD induces premature death. The present study determined the underlying mechanism whereby VLPD exerts its harmful effects on uremic rats. Main methods Rats were divided into four groups and fed a normal diet or diets containing 0.3% adenine and low/normal protein with high/low phosphate. After 6 weeks, body weight, urinary biochemistry (creatinine and phosphate), serum biochemical parameters (urea, creatinine, fibroblast growth factor 23, albumin, and fetuin-A), systemic inflammatory markers (serum tumor necrosis factor-alpha and urinary 8-hydroxy-2′-deoxyguanosine), calcium content in the aorta, and serum calcium-phosphate precipitates were evaluated. Hepatic mRNA levels were also determined. Key findings Rats fed the diet containing 0.3% adenine developed severe azotemia. Rats fed VLPD developed malnutrition (decreases in body weight, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary 8-hydroxy-2′-deoxyguanosine) independent of phosphate status. VLPD decreased the serum fetuin-A level and hepatic fetuin-A synthesis and increased serum calcium-phosphate precipitates, a marker of calciprotein particle. A high-phosphate diet induced arterial medial calcification, which was enhanced by VLPD. Serum calcium-phosphate precipitate levels were correlated with the degree of inflammation, malnutrition, and aortic calcium content. Dietary phosphate restriction prevented VLPD-enhanced vascular calcification, but could not halt inflammation and malnutrition induced by VLPD. Significance VLPD enhances inflammation, malnutrition, and vascular calcification in uremic rats, among which only vascular calcification is prevented by dietary phosphate restriction.

Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control group and four groups of rats with adenine-induced CKD. Three groups were treated with 0, 50, and 100 mg·kg−1·day−1 SPL for 8 wk, and one group was treated with 100 mg·kg−1·day−1 SPL for the last 2 wk of the 8-wk treatment period. After 8 wk, CKD rats developed azotemia and hyperphosphatemia, with increases in the expression of serum and glucocorticoid-regulated kinase-1 and sodium-phosphate cotransporter, in inflammation and oxidative stress level, in osteogenic signaling and apoptosis, and in aortic calcification, compared with control rats. SPL dose dependently decreased these changes in the aortas, concomitant with improvements in renal inflammation, tubulointerstitial nephritis, and kidney function. SPL neither lowered blood pressure level nor induced hyperkalemia. Treatment of CKD rats for the last 2 wk with 100 mg·kg−1·day−1 SPL attenuated VC compared with CKD rats with the same degree of kidney function and hyperphosphatemia. In conclusion, SPL dose dependently inhibits the progression of VC by suppressing MR signaling, local inflammation, osteogenic transition, and apoptosis in the aortas of CKD rats.

Selection of a lower dialysate calcium concentration (DCa) can reduce calcium burden and prevent vascular calcification in hemodialysis patients. However, decreased DCa can worsen mineral and bone disorders. This 1-year retrospective observational study evaluated 121 hemodialysis patients at Fukuoka Renal Clinic who underwent conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. The primary outcomes were changes in serum levels of calcium, phosphate, and parathyroid hormone (PTH). The effects of baseline serum calcium and PTH levels on changes in biochemical parameters were also determined. One year after DCa conversion, mean serum calcium level decreased, while serum phosphate, alkaline phosphatase, and PTH concentrations increased. The rate of achievement of target PTH was higher in patients with lower serum PTH level at baseline, while patients with higher baseline serum PTH level tended to exceed the upper limit of the PTH target range. Patients with higher baseline serum calcium concentration showed a greater decrease in serum calcium level and a greater increase in serum PTH level at 1 year. Patients with a lower baseline serum PTH level can benefit from optimal PTH control following conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. However, secondary hyperparathyroidism may be exacerbated in some patients with higher baseline serum calcium (Ca) and PTH levels. These results indicate that an individualized approach can maximize the benefits of Ca unloading after conversion to lower DCa.

Aim Sclerostin and dickkopf-1 (Dkk-1) are soluble inhibitors of Wnt-β-catenin signaling and are involved in decreased bone formation and bone volume in patients with various bone diseases. The clinical characteristics of sclerostin and Dkk-1 and their impacts on mineral and bone metabolism remain undetermined in patients undergoing peritoneal dialysis (PD). Methods This cross-sectional study investigated the association between serum sclerostin and Dkk-1 levels and mineral disorders in 74 outpatients under PD treatment. Levels of sclerostin and Dkk-1 in serum, urine, and peritoneal dialysate were determined using enzyme-linked immunosorbent assay kits. The associations between serum sclerostin and Dkk-1 levels and biochemical parameters were evaluated by linear regression analyses. Results Median serum sclerostin and Dkk-1 levels were 138 pmol/L (range, 98.3–195.9 pmol/L) and 38.8 pmol/L (range, 28.5–47.1 pmol/L), respectively. Both sclerostin and Dkk-1 were excreted into urine and peritoneal dialysate. Multivariable linear regression analyses showed that serum sclerostin level was significantly associated with age, sex, parathyroid hormone level, and renal Kt/V. In contrast, serum Dkk-1 level was associated with platelet count and serum fibroblast growth factor 23 level but not with any of the bone metabolic markers. Conclusion Serum sclerostin was associated with serum intact parathyroid hormone, while Dkk-1 was associated with serum fibroblast growth factor 23 in patients undergoing PD. The utility of determining soluble Wnt-β-catenin inhibitors levels in patients undergoing PD requires further investigation.

Tuberculosis is one of the common causes of fever of unknown origin in patients with chronic kidney disease (CKD). Extrapulmonary tuberculosis is more common in CKD patients, and is, unfortunately, often underdiagnosed despite extensive assessments. Recently, fluorine-18-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) has been available in the diagnosis of malignancy, inflammatory and infectious diseases, and has become a useful diagnostic tool. Here, we present two cases of endstage kidney disease who presented with fever of unknown origin at the time of dialysis initiation. In both cases, although interferon-gamma-releasing assay was positive, combined conventional diagnostic modalities such as computed tomography and gallium-citrate scintigraphy failed to detect the sites infected with tuberculosis. By contrast, extrapulmonary lesions were detected by FDG-PET/CT and successfully treated with combined anti-tuberculous drugs. Diagnosis of extrapulmonary tuberculosis was confirmed by biopsy of the affected lymph node and lumbar spine, followed by PCR of the biopsied specimen. These cases highlight the importance of considering tuberculosis as one of the differential diagnoses in pre-dialysis CKD patients with persistent fever, and the usefulness of FDG-PET/CT in the detection of infectious sites of extrapulmonary tuberculosis.

Chronic inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester (L-NAME) causes progressive renal injury and systemic hypertension. Angiotensin II (Ang II) has been conventionally regarded as one of the primary causes of renal injury. We reported previously that such renal injury was almost completely suppressed by both an Ang II type I receptor blocker and an aldosterone antagonist. The aldosterone antagonist also inhibited the systemic Ang II elevation. Therefore, it remains to be elucidated whether Ang II or aldosterone directly affects the development of such renal injury. In the present study, we investigated the role of aldosterone in the pathogenesis of renal injury induced by L-NAME-mediated chronic nitric oxide synthase inhibition in male Wistar rats (aged 10 wk). Serial analyses demonstrated that the renal injury and inflammation in L-NAME-treated rats was associated with elevation of both Ang II and aldosterone. To investigate the direct effect of aldosterone on the renal injury, we conducted adrenalectomy (ADX) and aldosterone supplementation in L-NAME-treated rats. In ADX rats, aldosterone was undetectable, and renal injury and inflammation were almost completely prevented by ADX, although systemic and local Ang II and blood pressure were still elevated. Aldosterone supplementation reversed the beneficial effect of ADX. The present study indicates that aldosterone rather than Ang II plays a central and direct role in the pathogenesis of renal injury by L-NAME through inflammation, independent of its systemic hemodynamic effects.

The long-term effect of cinacalcet hydrochloride treatment on parathyroid gland (PTG) volume has been scarcely investigated in patients with moderate to advanced secondary hyperparathyroidism (SHPT). The present study was a prospective observational study to determine the effect of cinacalcet treatment on PTG volume and serum biochemical parameters in 60 patients with renal SHPT, already treated with intravenous vitamin D receptor activator (VDRA). Measurement of biochemical parameters and PTG volumes were performed periodically, which were analyzed by stratification into tertiles across the baseline parathyroid hormone (PTH) level or PTG volume. We also determined the factors that can estimate the changes in PTG volume and the achievement of the target PTH range by multivariable analyses. Two years of cinacalcet treatment significantly decreased the serum levels of PTH, calcium, and phosphate, followed by the improvement of achieving the target ranges for these parameters recommended by the Japanese Society for Dialysis Therapy. Cinacalcet decreased the maximal and total PTG volume by about 30%, and also decreased the serum PTH level independent of the baseline serum PTH level and PTG volume. Ten out of 60 patients showed 30% increase in maximal PTG after 2 years. Multivariable analysis showed that patients with nodular PTG at baseline and patients with higher serum calcium and PTH levels at 1 year were likely to exceed the target range of PTH at two years. In conclusion, cinacalcet treatment with intravenous VDRA therapy decreased both PTG volume and serum intact PTH level, irrespective of the pretreatment PTG status and past treatment history.

BACKGROUND Recent lines of evidence suggest that, as in other countries, sudden cardiac death (SCD) is more common in the Japanese dialysis clinical setting than we previously thought. SUMMARY Three specific important findings may underlie the increased incidence of SCD in dialysis patients. Even after successful coronary revascularization, hemodialysis (HD) patients continue to have a higher incidence of SCD than the general population. Second, about 70% or more of end-stage kidney disease patients have concentric and eccentric left ventricular hypertrophy, which predisposes many dialysis patients to interstitial fibrosis, decreased coronary perfusion reserve, and decreased ischemia tolerance. Third, mildly impaired left ventricular dysfunction, with an ejection fraction

We herein present the case of a patient with myeloma and chronic kidney disease (CKD) who developed rapidly progressive vascular and soft tissue calcification during the course of treatment for severe hypocalcemia induced by the administration of denosumab for myeloma and hypercalcemia. Because a large amount of supplementation with active vitamin D and calcium was required to correct the severe hypocalcemia, rapidly progressive vascular calcification developed. Seeing that patients with CKD are prone to developing severe and prolonged hypocalcemia after denosumab treatment, physicians should closely monitor the patients' serum calcium levels and manage their hypocalcemia appropriately so as to avoid the development of significant ectopic calcification.

The association between blood urea nitrogen to creatinine ratio (UCR) and survival is uncertain in hemodialysis patients. We examined the influence of UCR on mortality and morbidity in hemodialysis patients. A total of 3,401 hemodialysis patients were prospectively followed for 4 years. The association between UCR with overall survival was analyzed using a Cox regression model. During a 4-year follow-up period, 545 patients died from any cause and 582 experienced MACE, 392 with coronary heart disease (CHD), 114 with infection-related death, 77 with hemorrhagic stroke, 141 with ischemic stroke, and 107 with cancer death. Every 1 increase in UCR level was significantly associated with an increased risk for all-cause mortality (hazard ratio [HR] 1.07; 95% confidence interval [CI] 1.03–1.12), CHD (HR 1.08; 95% CI 1.02–1.14), and infection-related death (HR 1.11; 95% CI 1.02–1.21). There was no evidence of a significant association between UCR and death from cancer, and incidence of stroke. A high UCR was significantly associated with an increased risk for all-cause mortality, infection-related death and incidence of CHD in hemodialysis patients.

Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3 % adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75 % adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6 % lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6 % calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated β-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.

Fibroblast growth factor (FGF) 23 plays an important role in regulation of renal phosphate excretion in patients with chronic kidney disease. However, it remains undetermined whether FGF23 is closely linked to renal phosphate handling in patients with low glomerular filtration rate (GFR). The present cross-sectional study included 52 outpatients undergoing peritoneal dialysis with urine volume ≥ 100 mL/day. The primary outcome was level of urinary phosphate excretion, and the secondary outcomes were tubular maximal reabsorption of phosphate normalized to GFR (TmP/GFR), an index of the renal threshold for phosphate excretion, and level of peritoneal phosphate excretion. Variates of interest were serum FGF23 and parathyroid hormone (PTH) levels. The median and interquartile range of serum FGF23 level, TmP/GFR, and total urinary and peritoneal phosphate excretion were 5610 (1493–11 430) ng/mL, 1.30 (0.44–1.86) mg/dL, 117 (40–234) mg/day, and 208 (156–250) mg/day, respectively. Multivariate linear regression analysis revealed that serum FGF23 level was significantly (P

Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of Pioverload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Piloading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different Piconcentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Piconcentration-dependent increases in serum and tissue levels of TNF-α and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by Pioverload. Regression analysis showed that serum Pilevels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pimedium directly increased the expression of TNF-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pioverload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Piloading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.

Fibroblast growth factor 23 (FGF23) levels in dialysis patients are influenced by various factors, including phosphorus load. However, the clinical parameters that determine serum FGF23 levels in patients on peritoneal dialysis (PD) remain unclear. The aim of the present study was to examine the effects of clinical factors, on serum FGF23 levels, with an emphasis on residual renal function (RRF). This cross-sectional study included 56 outpatients undergoing PD therapy. Urine volume ≥ 100 mL/day or renal creatinine (Cr) clearance was used as a surrogate marker for RRF. Clinical characteristics were compared between patients with and without RRF. Linear regression analysis was conducted with serum FGF23 level as the dependent variable and renal Cr clearance as the main independent variable. The median and interquartile range of serum FGF23 levels were 5970 (1451-11,688) pg/mL. Patients with RRF showed higher urinary and total phosphate eliminations, and lower serum FGF23 and phosphate levels than patients without RRF. Multivariate linear regression analysis showed that the renal Cr clearance and serum phosphate and dialysis history were negatively associated with serum FGF23 levels, even after adjusting for potential confounders including peritoneal Cr clearance. Further, the predictabilities of serum FGF23 were comparable among renal Cr clearance, Kt/V for urea, and renal phosphate clearance. RRF determined by renal Cr clearance or residual urine volume is an independent negative determinant of serum FGF23 levels in PD patients.