Low-Dose Continuous Kidney Replacement Therapy and Mortality in Critically Ill Patients With Acute Kidney Injury: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Continuous kidney replacement therapy (CKRT) is preferred when available for hemodynamically unstable acute kidney injury (AKI) patients in the intensive care unit (ICU). The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a delivered CKRT dose of 20-25mL/kg/h; however, in Japan the doses are typically below this recommendation due to government health insurance system restrictions. This study investigated the association between mortality and dose of CKRT. STUDY DESIGN: Single-center retrospective cohort study. SETTING & PARTICIPANTS: Critically ill patients with AKI treated with CKRT at a tertiary Japanese university hospital between January 1, 2012, and December 31, 2021. EXPOSURE: Delivered CKRT doses below or above the median. OUTCOME: 90-day mortality after CKRT initiation. ANALYTICAL APPROACH: Multivariable Cox regression analysis and Kaplan-Meier analysis. RESULTS: The study population consisted of 494 patients. The median age was 72 years, and 309 patients (62.6%) were men. Acute tubular injury was the leading cause of AKI, accounting for 81.8%. The median delivered CKRT dose was 13.2mL/kg/h. Among the study participants, 456 (92.3%) received delivered CKRT doses below 20mL/kg/h, and 204 (41.3%) died within 90 days after CKRT initiation. Multivariable Cox regression analysis revealed increased mortality in the below-median group (HR, 1.73 [95% CI, 1.19-2.51], P=0.004). Additionally, a significant, inverse, nonlinear association between 90-day mortality and delivered CKRT dose was observed using delivered CKRT dose as a continuous variable. LIMITATIONS: Single-center, retrospective, observational study. CONCLUSIONS: A lower delivered CKRT dose was independently associated with higher 90-day mortality among critically ill patients who mostly received dosing below the current KDIGO recommendations. PLAIN-LANGUAGE SUMMARY: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend delivering a continuous kidney replacement therapy (CKRT) dose of 20-25mL/kg/h. However, it is not clear if it is safe to use delivered CKRT doses below this recommendation. In this study, over 90% of the patients received CKRT with a delivered dose below the KDIGO recommendation. We divided these patients into 2 groups based on the median delivered CKRT dose. Our findings show that a delivered CKRT dose below the median was associated with increased risk of death within 90 days. These findings show that a lower delivered CKRT dose was independently associated with higher 90-day mortality among critically ill patients who mostly received dosing below current KDIGO recommendations.

Utility of serum ß2-microglobulin for prediction of kidney outcome among patients with biopsy-proven diabetic nephropathy.

AIM: To examine whether serum ß2-microglobulin (ß2-MG) could improve the prediction performance for kidney failure with replacement therapy (KFRT) among patients with diabetic nephropathy (DN). METHODS: Patients with biopsy-proven DN at Nara Medical University Hospital were included. The exposure of interest was log-transformed serum ß2-MG levels measured at kidney biopsy. The outcome variable was KFRT. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were performed. Model fit by adding serum ß2-MG levels was calculated using the Akaike information criterion (AIC). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indexes were used to evaluate the improvement of predictive performance for 5-year cumulative incidence of KFRT by serum ß2-MG levels. RESULTS: Among 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. A higher serum ß2-MG level (1-unit increase in log-transformed serum ß2-MG level) was associated with a higher incidence of KFRT, even after adjustments for previously known clinical and histological risk factors (hazard ratio [95% confidence interval {CI}]: 3.30 [1.57-6.94] and subdistribution hazard ratio [95% CI]: 3.07 [1.55-6.06]). The addition of log-transformed serum ß2-MG level reduced AIC and improved the prediction of KFRT (NRI and IDI: 0.32 [0.09-0.54] and 0.03 [0.01-0.56], respectively). CONCLUSIONS: Among patients with biopsy-proven DN, serum ß2-MG was an independent predictor of KFRT and improved prediction performance. In addition to serum creatinine, serum ß2-MG should probably be measured for DN.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

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.

Differential impact of glomerular and tubule-interstitial histological changes on kidney outcome between non-proteinuric and proteinuric diabetic nephropathy.

BACKGROUND: Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN. METHODS: Patients diagnosed with DN by renal biopsy during 1981-2014 were divided into non-proteinuric (UP ≤ 0.5 g/day) and proteinuric (UP > 0.5 g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders. RESULTS: The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67-5.36] and 3.82 [2.06-7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0-2.48] and 4.98 [1.33-18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01). CONCLUSIONS: IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN.

Cigarette smoking and progression of kidney dysfunction: a longitudinal cohort study.

INTRODUCTION: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established. METHOD: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis. RESULTS: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16-1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001). CONCLUSION: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria.

Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies.

BACKGROUND: Hypertension or elevated blood pressure (BP) is an important risk factor for aortic dissection (AD); however, few prospective studies on this topic have been published. We investigated the association between hypertension/elevated BP and AD in 2 cohorts and conducted a meta-analysis of published prospective studies, including these 2 studies. METHODS: We analyzed data from the J-SHC study (Japan-Specific Health Checkups) and UK Biobank, which prospectively followed up 534 378 and 502 424 participants, respectively. Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for the association of hypertension/elevated BP with AD incidence in the UK Biobank and AD mortality in the J-SHC Study. In the meta-analysis, summary relative risks were calculated with random-effects models. A potential nonlinear dose-response relationship between BP and AD was tested with fractional polynomial models, and the best-fitting second-order fractional polynomial regression model was determined. RESULTS: In the J-SHC study and UK Biobank, there were 84 and 182 ADs during the 4- and 9-year follow-up, and the adjusted hazard ratios of AD were 3.57 (95% CI, 2.17-6.11) and 2.68 (95% CI, 1.78-4.04) in hypertensive individuals, 1.33 (95% CI, 1.05-1.68) and 1.27 (95% CI, 1.11-1.48) per 20-mm Hg increase in systolic BP (SBP), and 1.67 (95% CI, 1.40-2.00) and 1.66 (95% CI, 1.46-1.89) per 10-mm Hg increase in diastolic BP (DBP), respectively. In the meta-analysis, the summary relative risks were 3.07 (95% CI, 2.15-4.38, I2=76.7%, n=7 studies, 2818 ADs, 4 563 501 participants) for hypertension and 1.39 (95% CI, 1.16-1.66, I2=47.7%, n=3) and 1.79 (95% CI: 1.51-2.12, I2 = 57.0%, n=3) per 20-mm Hg increase in SBP and per 10-mm Hg increase in DBP, respectively. The AD risk showed a strong, positive dose-response relationship with SBP and even more so with DBP. The risk of AD in the nonlinear dose-response analysis was significant at SBP >132 mm Hg and DBP >75 mm Hg. CONCLUSIONS: Hypertension and elevated SBP and DBP are associated with a high risk of AD. The risk of AD was positively dose dependent, even within the normal BP range. These findings provide further evidence for the optimization of BP to prevent AD.

Predictors of Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients with Non-Dialysis-Dependent Chronic Kidney Disease (RADIANCE-CKD Study).

INTRODUCTION: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance during ESA administration would be very useful in deciding on a treatment plan. METHODS: Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post hoc sub-analysis of a randomized controlled trial. RESULTS: The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI: 0.711-0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status, and hypertensive retinopathy) with the largest χ2 statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634-0.799). To the six existing risk factors, five serum test items that affect anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI: 0.655-0.817), sufficient to predict ESA resistance. CONCLUSIONS: Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.

Kidney function at 3 months after acute kidney injury is an unreliable indicator of subsequent kidney dysfunction: the NARA-AKI Cohort Study.

BACKGROUND: The relationship between kidney function at 3 months after acute kidney injury (AKI) and kidney function prognosis has not been characterized. METHODS: This retrospective cohort study included adults who underwent noncardiac surgery under general anesthesia. Exclusion criteria included obstetric or urological surgery, missing data and preoperative dialysis. Linear mixed-effects models were used to compare estimated glomerular filtration rate (eGFR) slopes in patients with and without AKI. Multivariable Cox proportional hazard models were used to examine the associations of AKI with incident chronic kidney disease (CKD) and decline in eGFR ≥30%. RESULTS: Among 5272 patients, 316 (6.0%) developed AKI. Among 1194 patients with follow-up creatinine values, eGFR was stable or increased in patients with and without AKI at 3 months postoperatively and declined thereafter. eGFR decline after 3 months postoperatively was faster among patients with AKI than among patients without AKI (P = .09). Among 938 patients without CKD-both at baseline and at 3 months postoperatively-226 and 161 developed incident CKD and a decline in eGFR ≥30%, respectively. Despite adjustment for eGFR at 3 months, AKI was associated with incident CKD {hazard ratio [HR] 1.73 [95% confidence interval (CI) 1.06-2.84]} and a decline in eGFR ≥30% [HR 2.41 (95% CI 1.51-3.84)]. CONCLUSIONS: AKI was associated with worse kidney outcomes, regardless of eGFR at 3 months after surgery. Creatinine-based eGFR values at 3 months after AKI might be affected by acute illness-induced loss of muscle mass. Kidney function might be more accurately evaluated much later after surgery or using cystatin C values.

Association between hyporesponsiveness to erythropoiesis-stimulating agents and risk of brain hemorrhage in patients undergoing hemodialysis: the Q-Cohort Study.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with increased risks of all cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the impact of the hematopoietic response to ESAs on the development of stroke, including brain hemorrhage and infarction, remains unclear. METHODS: In total, 2886 patients undergoing maintenance HD registered in the Q-Cohort Study who were treated with ESAs were prospectively followed up for 4 years. The hematopoietic response to ESAs was evaluated by the erythropoietin resistance index (ERI), calculated by dividing the weekly dose of ESA by post-HD weight and hemoglobin (U/kg/week/g/dL). The primary outcomes were the incidences of brain hemorrhage and infarction. Patients were divided into quartiles based on their ERI at baseline (Q1, ≤ 4.1; Q2, 4.2-7.0; Q3, 7.1-11.2; and Q4, ≥ 11.3). The risks of brain hemorrhage and infarction were estimated using Cox proportional hazards models, adjusting for potential confounders. RESULTS: During the 4 year follow-up period, 71 patients developed brain hemorrhage and 116 developed brain infarction. In the multivariable analysis, the incidence of brain hemorrhage in the highest quartile (Q4) was significantly higher than that in the lowest quartile (Q1) (hazard ratio [95% confidence interval], 2.18 [1.08-4.42]). However, the association between the ERI and the incidence of brain infarction was not significant. CONCLUSIONS: A higher ERI was associated with an increased risk of brain hemorrhage, but not brain infarction, in patients undergoing maintenance HD. A high ERI is thus an important risk factor for brain hemorrhage in these patients.

Association between microscopic hematuria and albuminuria in patients with chronic kidney disease caused by diabetes and hypertension: the Fukuoka Kidney disease Registry Study.

BACKGROUND: The association between microscopic hematuria (MH) and albuminuria in patients with chronic kidney disease (CKD) caused by diabetes and hypertension remains unclear. METHODS: The Fukuoka Kidney disease Registry Study is a Japanese multicenter prospective cohort study of 4476 patients with non-dialysis-dependent CKD. In this cohort, we conducted a cross-sectional study in 994 patients with diabetic nephropathy and hypertensive nephrosclerosis. Patients were divided into three groups according to erythrocyte count in urine sediment [T1: < 5/high power field (HPF); T2: 5-9/HPF; T3: ≥ 10/HPF]. Macroalbuminuria was defined as urinary albumin-creatinine ratio > 300 mg/g. Associations between the degree of MH (T1-T3) and the prevalence of macroalbuminuria were analyzed using logistic regression. RESULTS: The prevalence of macroalbuminuria was 50.8%, 50.4%, and 67.4% in T1 (n = 725), T2 (n = 226), and T3 (n = 43), respectively. The multivariable-adjusted odds ratios for the presence of macroalbuminuria were 0.95 [95% confidence interval (CI) 0.65-1.39; P = 0.86] and 2.50 (95% CI 1.15-5.47; P = 0.022) for patients in T2 and T3, respectively, compared with patients in T1. CONCLUSIONS: MH with erythrocytes ≥ 10/HPF was significantly associated with increased prevalence of macroalbuminuria in patients with non-dialysis-dependent CKD caused by diabetes and hypertension.

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.

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.

Sex differences in the association between urate metabolism and kidney outcomes in patients with chronic kidney disease.

BACKGROUND: The association between serum uric acid (SUA) concentration and kidney outcomes in patients with chronic kidney disease (CKD) is controversial. Furthermore, there are no reports regarding the association of clearance of uric acid (CUA) with kidney outcomes. We aimed to determine whether SUA or CUA was associated with kidney outcomes in patients with CKD stratified by sex. METHODS: The present prospective study was conducted in 815 patients (523 men and 292 women) with CKD. The participants were divided into quartiles (Q1-Q4) of SUA or CUA for each sex. Endpoints were defined as a composite of doubling of serum creatinine (SCr), end-stage kidney disease (ESKD), or death (outcome 1) and a composite of doubling of SCr or ESKD (outcome 2). RESULTS: During a median follow-up of 2.5 years, outcomes 1 and 2 occurred in 363 and 321 patients, respectively. Multivariable-adjusted Cox analyses showed that in men, the hazard ratios (95% confidence intervals) for outcome 1 of Q1, Q2, and Q3 of CUA were 2.08 (1.18-3.70), 2.03 (1.22-3.39), and 1.85 (1.17-2.95), respectively, compared with Q4. Additionally, there were similar associations between lower CUA quartiles and outcome 2 in men. However, no associations between SUA and either outcome were observed in men. Conversely, in women, neither SUA nor CUA was associated with an outcome. CONCLUSION: In CKD, lower CUA was independently associated with poor kidney outcomes only in men, and in both sexes, there was no association of SUA with kidney outcomes.

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.

Trace proteinuria detected via dipstick test is associated with kidney function decline and new-onset overt proteinuria: the Japan Specific Health Checkups (J-SHC) Study.

BACKGROUND: Microalbuminuria is associated with mortality, cardiovascular disease, and end-stage kidney disease. The association between trace proteinuria (detected via dipstick test) and kidney outcomes is unclear. METHODS: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted during 2008-2014. The frequency of trace proteinuria (detected via dipstick test) during first two visits was used as an exposure variable (TrUP 0/2, no trace proteinuria; TrUP 1/2, detected once; TrUP 2/2, detected twice), and kidney outcomes were evaluated. The association between the frequency of trace proteinuria and incidence of 1.5-fold increase in serum creatinine levels and overt proteinuria was analyzed using Cox regression analysis. Trajectories of estimated glomerular filtration rate (eGFR) were compared using a mixed-effect model. RESULTS: Among 306,317 participants, 3188 and 17,461 developed a 1.5-fold increase in serum creatinine levels and new-onset overt proteinuria, respectively, during the median follow-up period of 36.2 months. The adjusted hazard ratio (HR) and 95% confidence interval (CI) for 1.5-fold increase in serum creatinine level in the TrUP 1/2 and TrUP 2/2 groups, compared to TrUP 0/2 group, were 1.23 (1.07-1.42) and 1.39 (1.01-1.92), respectively, and the adjusted HR (95% CI) for overt proteinuria were 2.94 (2.83-3.06) and 5.14 (4.80-5.51), respectively. The eGFR decline rates in the TrUP 1/2 and TrUP 2/2 groups were higher than that in the TrUP 0/2 group (p for interaction < 0.001). CONCLUSIONS: Trace proteinuria (detected via dipstick test) was associated with subsequent kidney function decline and overt proteinuria in the general population.

Synergistic effect of proteinuria on dipstick hematuria-related decline in kidney function: The Japan Specific Health Checkups (J-SHC) Study.

BACKGROUND: The effect of isolated hematuria without proteinuria on kidney function decline, and the modification by the severity of proteinuria in general population are not fully elucidated. METHODS: Participants were included in the Japan Specific Health Checkups Study between 2008 and 2014. The exposure of interest was the frequency of dipstick hematuria during the observation. In each proteinuria frequency category (non-, occasional, persistent), hematuria-related decline in the eGFR rate was examined by analysis of covariance (ANCOVA). eGFR decline trajectories were also assessed using mixed-effects models. RESULTS: Among the 552,951 participants, 146,753 (26.5%) had hematuria, and 56,021 (10.1%) and 8,061 (1.5%) had occasional and persistent proteinuria, respectively. During the median follow-up of 3.0 years, annual change in eGFR decline in participants with hematuria was significantly faster than in those without hematuria (mean [95% confidence interval]: - 0.95 [- 0.98 to - 0.92] vs - 0.86 [- 0.87 to - 0.84] mL/min/1.73 m2/year; P < 0.001). In ANCOVA, the hematuria-related annual eGFR decline rate increased as proteinuria frequency categories increased (differences in annual eGFR decline rate between participants with and without hematuria: 0.08 [0.06 to 0.09] in participants with non-proteinuria category, 0.17 [0.15 to 0.18] in occasional proteinuria category, and 0.68 [0.65 to 0.71] mL/min/1.73 m2/year in persistent proteinuria category; P for interaction < 0.001). Similar results were obtained by the linear mixed-effect model. CONCLUSIONS: Proteinuria has a synergistic effect on dipstick hematuria-related decline in kidney function. Among the general population without proteinuria throughout the observational period, the "isolated hematuria"-related eGFR decline was statistically significant but the difference was small.

Association between Serum C-Reactive Protein Concentrations and Risk of Cancer-Related Mortality in Patients Undergoing Hemodialysis: 10-Year Outcomes of the Q-Cohort Study.

INTRODUCTION: Cancer constitutes a major source of morbidity and mortality among people undergoing hemodialysis (HD). A systemic inflammatory response is associated with the incidence and prognosis of cancer in the general population. However, the effect of systemic inflammation on cancer-related mortality in patients undergoing HD remains unclear. METHODS: We analyzed 3,139 patients registered in the Q-Cohort Study, which is a multicenter, observational cohort study of patients on hemodialysis in Japan. The primary outcome was cancer-related mortality during a 10-year follow-up. The covariate of interest was serum C-reactive protein (CRP) concentrations at baseline. The patients were divided into tertiles based on their serum CRP concentrations at baseline (tertile [T] 1: ≤0.07; T2: 0.08-0.24; and T3: ≥0.25). The association between serum CRP concentrations and cancer-related mortality was calculated using the Cox proportional hazards model and the Fine-Gray subdistribution hazards model with non-cancer-related death as a competing risk. RESULTS: During the 10-year follow-up, 216 patients died of cancer. In the multivariable analysis, the risk of cancer-related mortality in the highest tertile (T3) of serum CRP concentrations was significantly higher than that in the lowest tertile (T1) (multivariable-adjusted hazard ratio [95% confidence interval]: 1.68 [1.15-2.44]). This association remained consistent in the competing risk model, in which the subdistribution hazard ratio was 1.47 and the 95% confidence interval was 1.00-2.14 for T3 compared with T1. CONCLUSION: Higher serum CRP concentrations are associated with an increased risk of cancer-related mortality in patients undergoing maintenance HD.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

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.