Serum alkaline phosphatase and infection-related mortality in hemodialysis patients: ten-year outcomes of the Q-cohort study.

BACKGROUND: High serum alkaline phosphatase (ALP) levels are associated with excess all-cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the long-term relationship between serum ALP levels and infection-related mortality remains unclear. METHODS: A total of 3502 maintenance HD patients were registered in the Q-Cohort Study, an observational cohort study in Japan. The primary outcome was infection-related mortality during a 10-year follow-up period. The covariate of interest was serum ALP levels at baseline. The association between serum ALP levels and infection-related mortality was calculated using a Cox proportional hazards model and a Fine-Gray subdistribution hazards model with non-infection-related death as a competing risk. RESULTS: During the follow-up period, 446 patients died of infection. According to their baseline serum ALP levels, the patients were categorized into sex-specific quartiles (Q1-Q4). Compared with patients in the lowest serum ALP quartile (Q1), those in the highest quartile (Q4) had a significantly higher multivariable-adjusted hazard ratio (HR) of 1.70 [95% confidence interval (CI) 1.24-2.32] for infection-related mortality. Furthermore, the HR for every 50 U/L increase in serum ALP levels was 1.24 (95% CI 1.12-1.36) for infection-related mortality. These associations remained consistent in the competing risk model: subdistribution HR, 1.47; 95% CI 1.07-2.03 for Q4 compared with Q1. CONCLUSION: Higher serum ALP levels were significantly associated with a higher risk of infection-related mortality in patients undergoing HD.

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.

High low-density lipoprotein cholesterol as an independent risk factor for coronary restenosis in hemodialysis patients undergoing percutaneous coronary interventions.

HD patients have been reported to have a higher risk of restenosis after percutaneous coronary intervention (PCI). The aim of this study was to investigate the risk factors of coronary restenosis in HD patients. We enrolled 54 HD patients (mean age: 66.5 ± 10.1 years; 72.2% men; mean HD duration: 3.7 years), who received PCI and follow-up coronary angiography. Of the patients, 22 (40.7%) had restenosis within 3 to 12 months of PCI. Univariate logistic analysis showed low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, LDL-C, non-HDL-C, and history of major adverse cardiovascular events were significantly associated with coronary restenosis (OR]: 1.89, 1.27, 1.22, and 5.79, respectively). Multivariate analysis showed that LDL-C was significantly associated with coronary restenosis (OR: 1.43). These data suggest that LDL-C is an independent risk factor for coronary restenosis in HD patients undergoing PCI, and strict lipid management may be required.

Higher Cholesterol Level Predicts Cardiovascular Event and Inversely Associates With Mortality in Hemodialysis Patients: 10-Year Outcomes of the Q-Cohort Study.

The prevalence of atherosclerotic diseases is higher in hemodialysis patients. The aim of the current study was to investigate associations between cholesterol level and the incidences of cardiovascular disease (CVD) and mortality in hemodialysis patients. A total of 3517 participants undergoing maintenance hemodialysis were followed up for 10 years. Total cholesterol (TC) level was divided into quartile in baseline data. The multivariate analyses were calculated by a Cox proportional hazards model. The incidences of ischemic heart disease (IHD), peripheral artery disease (PAD), and CVD were significantly positively associated with higher cholesterol levels after adjustment for confounding factors (P < 0.01, P = 0.04, and P < 0.01, respectively). Furthermore, the incidences of cancer-associated mortality and all-cause mortality were significantly positively associated with lower cholesterol levels after adjustment for confounding factors (both P < 0.01). The lowest TC level at all-cause mortality risk was 179 mg/dL. From these results, higher TC predicts IHD, PAD, and CVD events, and lower TC predicts cancer-associated mortality and all-cause mortality in patients undergoing maintenance hemodialysis.

Modified creatinine index and risk for cardiovascular events and all-cause mortality in patients undergoing hemodialysis: The Q-Cohort study.

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.

Hemoglobin concentration and the risk of hemorrhagic and ischemic stroke in patients undergoing hemodialysis: the Q-cohort study.

Background: The contribution of the hemoglobin concentration to the incidence of hemorrhagic or ischemic stroke in patients undergoing hemodialysis is unclear. Methods: In total, 3436 patients undergoing prevalent hemodialysis were followed up for 4 years. The primary outcome was the first development of hemorrhagic or ischemic stroke. The baseline hemoglobin concentration was divided into quartiles [hemoglobin (g/dL): Q1, ≤9.7; Q2, 9.8-10.5; Q3, 10.6-11.1; Q4, ≥11.2]. The association between the hemoglobin concentration and each type of stroke was examined using the Kaplan-Meier method and a Cox proportional hazards model. Results: During the follow-up period, 76 (2.2%) patients developed hemorrhagic stroke and 139 (4.0%) developed ischemic stroke. The 4-year incidence rate of hemorrhagic stroke was significantly higher in patients with lower hemoglobin concentrations. Compared with the quartile of patients with the highest hemoglobin concentrations (Q4), the multivariable-adjusted hazard ratios for hemorrhagic stroke were 1.18 (95% confidence interval, 0.56-2.51), 1.59 (0.82-3.21) and 2.31 (1.16-4.73) in patients in Q3, Q2 and Q1, respectively. No association was identified between the 4-year incidence rate of ischemic stroke and the hemoglobin concentration. Compared with the quartile of patients with the lowest hemoglobin concentrations (Q1), the multivariable-adjusted hazard ratios for ischemic stroke were 1.17 (95% confidence interval, 0.73-1.89), 0.88 (0.51-1.51) and 1.10 (0.66-1.83) in patients in Q2, Q3 and Q4, respectively. Conclusions: Our results suggest that low hemoglobin concentrations are associated with a high risk of hemorrhagic stroke, but not of ischemic stroke, in patients undergoing hemodialysis.

Cardiothoracic Ratio and All-Cause Mortality and Cardiovascular Disease Events in Hemodialysis Patients: The Q-Cohort Study.

BACKGROUND: Cardiothoracic ratio by chest radiography is commonly used to assess volume status. Little is known about the relationships between cardiothoracic ratio and the incidence of clinical outcomes in patients undergoing hemodialysis (HD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,436 participants in the Q-Cohort Study 18 years or older who underwent maintenance HD in Japan. PREDICTOR: Cardiothoracic ratio. OUTCOMES & MEASUREMENTS: All-cause mortality and cardiovascular disease (CVD) events. RESULTS: During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed CVD events. From baseline cardiothoracic ratios, participants were categorized into sex-specific quartiles because cardiothoracic ratio distribution differed by sex. The 4-year event-free survival rate, in terms of all-cause mortality and CVD events, was significantly lower with higher cardiothoracic ratios. Compared to the lowest cardiothoracic ratio (quartile 1), multivariable-adjusted HRs for all-cause mortality were 0.89 (95% CI, 0.66-1.20), 1.41 (1.08-1.86), and 1.52 (1.17-2.00) in patients from quartiles 2, 3, and 4, respectively. Similarly, in comparison to quartile 1, multivariable-adjusted HRs for CVD events were 1.00 (95% CI, 0.77-1.31), 1.18 (0.92-1.53), and 1.37 (1.07-1.76) in patients from quartiles 2, 3, and 4, respectively. Furthermore, the combination of higher cardiothoracic ratio and normohypotension (systolic blood pressure < 140mmHg and diastolic blood pressure < 90mmHg) was associated with higher risk for CVD events. LIMITATIONS: Single measurement of all variables, potentially less-heterogeneous patient population, and limited ascertainment of cardiac parameters and the outcomes. CONCLUSIONS: Higher cardiothoracic ratio is associated with higher risk for both all-cause mortality and CVD events in patients undergoing HD.

Assessment of urinary angiotensinogen as a marker of podocyte injury in proteinuric nephropathies.

Urinary protein (UP) is widely used as a clinical marker for podocyte injury; however, not all proteinuric nephropathies fit this model. We previously described the elevation of urinary angiotensinogen (AGT) accompanied by AGT expression by injured podocytes in a nitric oxide inhibition rat model (Eriguchi M, Tsuruya K, Haruyama N, Yamada S, Tanaka S, Suehiro T, Noguchi H, Masutani K, Torisu K, Kitazono T. Kidney Int 87: 116-127, 2015). In this report, we performed the human and animal studies to examine the significance and origin of urinary AGT. In the human study, focal segmental glomerulosclerosis (FSGS) patients presented with higher levels of urinary AGT, corrected by UP, than minimal-change disease (MCD) patients. Furthermore, AGT was evident in podocin-negative glomerular segmental lesions. We also tested two different nephrotic models induced by puromycin aminonucleoside in Wistar rats. The urinary AGT/UP ratio and AGT protein and mRNA expression in sieved glomeruli from FSGS rats were significantly higher than in MCD rats. The presence of AGT at injured podocytes in FSGS rats was detected by immunohistochemistry and immunoelectron microscopy. Finally, we observed the renal tissue and urinary metabolism of exogenous injected human recombinant AGT (which is not cleaved by rodent renin) in FSGS and control rats. Significant amounts of human AGT were detected in the urine of FSGS rats, but not of control rats. Immunostaining for rat and human AGT identified that only rat AGT was detected in injured podocytes, and filtered human AGT was seen in superficial proximal tubules, but not in injured podocytes, suggesting AGT generation by injured podocytes. In conclusion, the urinary AGT/UP ratio represents a novel specific marker of podocyte injury.

New-onset systemic lupus erythematosus in a long-term hemodialysis patient with acute pleuritis and pneumonitis.

A 61-year-old woman, with a 25-year history of maintenance hemodialysis due to end-stage renal disease of unknown causes, was admitted because of systemic joint pain and inflammatory response of unknown etiology that persisted for 1 month. Laboratory data on admission revealed leukocytopenia, lymphocytopenia, high serum C-reactive protein, and positivity for antinuclear antibody (ANA) and anti-double strand DNA. After admission, she progressively developed cough and dyspnea. A chest radiograph revealed bilateral ground glass opacity and pleural effusion. A thoracentesis revealed lupus erythematosus cells, suggesting lupus pleuritis. A chest computed tomography showed a pattern of diffuse alveolar damage compatible with acute lupus pneumonitis. She fulfilled the American Rheumatism Association diagnostic criteria for systemic lupus erythematosus (SLE). Methylprednisolone pulse therapy followed by oral prednisone treatment improved the clinical symptoms and laboratory abnormalities. ANA was negative 25 years earlier when she first started hemodialysis and she had neither clinical nor serological abnormalities related to SLE during the last 25 years. Further, she had neither received drugs that can cause drug-induced SLE, nor had a history of ultraviolet ray exposure, pregnancy, blood transfusion, trauma and smoking. This report suggests that new-onset SLE can develop in patients undergoing long-term dialysis. Hence, when we encounter dialysis patients with arthralgia and/or respiratory disorders, we should consider the possibility of new-onset SLE.