Association between circulating fibroblast growth factor 21 and mortality in end-stage renal disease.

Fibroblast growth factor 21 (FGF21) is an endocrine factor that regulates glucose and lipid metabolism. Circulating FGF21 predicts cardiovascular events and mortality in type 2 diabetes mellitus, including early-stage chronic kidney disease, but its impact on clinical outcomes in end-stage renal disease (ESRD) patients remains unclear. This study enrolled 90 ESRD patients receiving chronic hemodialysis who were categorized into low- and high-FGF21 groups by the median value. We investigated the association between circulating FGF21 levels and the cardiovascular event and mortality during a median follow-up period of 64 months. A Kaplan-Meier analysis showed that the mortality rate was significantly higher in the high-FGF21 group than in the low-FGF21 group (28.3% vs. 9.1%, log-rank, P = 0.034), while the rate of cardiovascular events did not significantly differ between the two groups (30.4% vs. 22.7%, log-rank, P = 0.312). In multivariable Cox models adjusted a high FGF21 level was an independent predictor of all-cause mortality (hazard ratio: 3.98; 95% confidence interval: 1.39-14.27, P = 0.009). Higher circulating FGF21 levels were associated with a high mortality rate, but not cardiovascular events in patient with ESRD, suggesting that circulating FGF21 levels serve as a predictive marker for mortality in these subjects.

Prevalence of Fabry disease in dialysis patients: Japan Fabry disease screening study (J-FAST).

BACKGROUND: In Fabry disease, progressive glycolipid accumulation leads to damage in kidney and other organs. This study was designed to determine the prevalence rate of Fabry disease in Japanese dialysis patients. METHODS: All dialysis patients agreeing to Japan Fabry disease screening study (J-FAST) with informed consent were selected except for Fabry disease. The screening was performed by a method of measuring plasma and/or leukocytes lysosomal α-galactosidase A protein level and α-galactosidase A activity. If positive, genetic analysis was carried out upon patient's agreement. RESULTS: J-FAST dealt with 8547 patients (male 5408, female 3139). At the tertiary examination, 26 out of 8547 patients were found to be positive. Six out of 26 patients could not accept genetic analysis because of death. Remaining 20 patients agreed with genetic analysis; then 2 patients (male 2, female 0) had a variation of the α-Gal gene and 11 patients showed E66Q variations. Therefore, the frequency of Fabry disease in J-FAST was 0.04 % (2/5408) in males and 0 % (0/3139) in females, and then 0.02 % (2/8547) in all patients. The presumptive clinical diagnoses of end-stage kidney disease (ESKD) were 10 chronic glomerulonephritis, 7 diabetic nephropathy, 3 unknown etiology, 3 nephrosclerosis, 1 gouty nephropathy, 1 autosomal dominant polycystic kidney disease and 1 renal tuberculosis among 26 tertiary positive patients. Two male Fabry patients were initially diagnosed as nephrosclerosis and chronic glomerulonephritis. CONCLUSIONS: The prevalence rate of Fabry disease in J-FAST was 0.02 %. Moreover, Fabry disease could not be ruled out as the clinical diagnosis of ESKD.

[Comparison of benefits to non-dialysis CKD patients between darbepoetin alpha and epoetin beta pegol].

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients. METHODS: This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated. RESULTS: No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA. CONCLUSIONS: It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients.

Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7 ± 5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309-449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all-cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29-13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality.

Effect of chitosan chewing gum on reducing serum phosphorus in hemodialysis patients: a multi-center, randomized, double-blind, placebo-controlled trial.

BACKGROUND: HS219 (40 mg chitosan-loaded chewing gum) is designed to bind salivary phosphorus as an add-on to available phosphorus binders. We performed a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of HS219 in hemodialysis (HD) patients with hyperphosphatemia as an add-on to phosphorus binders. METHODS: Sixty-eight HD patients who were maintained on calcium carbonate (n=33) or sevelamer hydrochloride (n=35) were enrolled. The primary end point was a change in serum phosphorus levels. Secondary end points included changes in levels of salivary phosphorus, serum calcium, parathyroid hormone (PTH), and intact fibroblast growth factor (iFGF) 23. RESULTS: Sixty-three patients chewed either HS219 (n=35) or placebo (n=28) for 30 min, three times a day, for 3 weeks. HS219 was well tolerated and safe. However, HS219 was not superior to placebo with additional reduction of serum phosphorus with respect to phosphorus binders at the end of the chewing period. There were no significant effects of HS219 on reduction of salivary phosphorus, serum calcium, iPTH, or iFGF23 levels. CONCLUSIONS: The chitosan-loaded chewing gum HS219 does not affect serum and salivary phosphorus levels in Japanese HD patients with hyperphosphatemia. Our findings do not support previous findings that 20 mg of chitosan-loaded chewing gum reduces serum and salivary phosphorus levels. TRIAL REGISTRATION: [corrected] ClinicalTrials.gov NCT01039428, 24 December, 2009.

Spontaneous spinal epidural hematoma as a potentially important stroke mimic.

Hemiparesis develops in response to a wide range of neurological disorders, such as stroke, neoplasms and several inflammatory processes. Occasionally, it may also occur due to a lesion located in the high cervical spinal cord. In this concise review, we describe the features of spontaneous spinal epidural hematoma, which should be included in the large list of stroke mimics. Various concerns regarding the diagnostic and therapeutic conundrums relating to the condition are also discussed.

Fabry disease: experience of screening dialysis patients for Fabry disease.

The prevalence rate for Fabry disease is conventionally considered to be 1 case in 40,000; however, due to increased screening accuracy, reports now suggest that prevalence is 1 case in 1,500 among male children, and it is likely that the clinical importance of the condition will increase in the future. In dialysis patients to date, prevalence rates are between 0.16 and 1.2 %. Globotriaosylsphingosine (Lyso-GL-3), which is a substrate of α-galactosidase A (α-Gal A), has surfaced as a new biomarker, and is also effective in the determination and monitoring of the effects of enzyme replacement therapy. In terms of genetic abnormalities, the E66Q mutation has recently become a topic of discussion, and although doubts have been expressed over whether or not it is the gene responsible for Fabry disease, there is still a strong possibility that it is a functional genetic polymorphism. At present, the standard treatment for Fabry disease is enzyme replacement therapy, and in order to overcome the problems involved with this, a method of producing recombinant human α-Gal A using methanol-assimilating yeast, and chemical or medicinal chaperone treatment are of current interest. Migalastat hydrochloride is known as a pharmacological chaperone, but is currently in Phase III global clinical trials. Adding saposin B to modified α-N-acetyl galactosaminidase is also under consideration as a treatment method.

The origin of idiopathic renal arteriovenous malformation with giant twin aneurysms.

A 50-year-old female patient who presented with intermittent gross hematuria was referred to our hospital. Three-dimensional computed tomography (3D-CT) revealed a left renal arteriovenous malformation (AVM). Because she declined to undergo additional therapy including surgical treatment, we observed the clinical course of renal AVM for 7 years using 3DCT. When the 3D-CT showed gradual enlargement of the aneurysms concurrent with the onset of clinical symptoms (cardiomegaly and hypertension), we performed simple left nephrectomy. After the operation, the cardiomegaly and hypertension returned to normal, and gross hematuria did not recur. Based on the macro-anatomical findings of the resected kidney and the observation of the natural course, this case strongly supported the hypothesis that the renal AVM had existed from birth and enlarged gradually to eventually produce the typical signs and symptoms.

Effect of continuous positive airway pressure on proteinuria in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is common in patients with renal disease, and an association between OSA and proteinuria has been proposed. However, the effect on proteinuria of OSA treatment with continuous positive airway pressure (CPAP) is unknown. We experienced a case of severe OSA, where proteinuria was clearly improved after CPAP initiation without any changes of medication or body weight. The remarkable reduction of repetitive apnea and hypopnea by CPAP might ameliorate proteinuria by lessening renal hypoxia and sympathetic nerve activation. This case suggests that CPAP is a promising option for OSA with proteinuria.

Sleep-disordered breathing predicts cardiovascular events and mortality in hemodialysis patients.

BACKGROUND: Sleep-disordered breathing (SDB), characterized by repetitive apnea and hypopnea during sleep, is a risk factor for cardiovascular disease. However, the links between SDB and cardiovascular events in hemodialysis (HD) patients have not been clearly evaluated. METHODS: We followed the clinical outcome of 94 HD patients, who underwent overnight pulse oximetry on dialysis day. The SDB group was defined as 3% oxygen desaturation index (ODI) over five events per hour, and the others were the normal group. The primary outcome was cardiovascular events and death. We used Kaplan-Meier curve and Cox proportional hazard model for survival analyses. RESULTS: Forty-four patients (46.8%) were classified into the SDB group. Body mass index, diabetes mellitus, 3% ODI and Epworth sleepiness scale were significantly higher, and duration of dialysis, Kt/V, normalized protein catabolism rate and hemoglobin were lower in the SDB group than in the normal group. During a median 55 months of follow-up, Kaplan-Meier analysis revealed that the SDB group had a significantly higher rate of cardiovascular events and all-cause mortality than the normal group. Age, cardiothoracic ratio, serum albumin and 3% ODI were predictors of cardiovascular events and all-cause mortality at univariate Cox regression analysis. In the adjusted analysis, SDB is an independent predictor of increased cardiovascular events (hazard ratio 3.10; 95% confidence interval (CI), 1.35-7.12; P = 0.008) and all-cause mortality (hazard ratio 2.81; 95% CI, 1.07-7.41; P = 0.037). CONCLUSIONS: SDB is an independent risk factor for cardiovascular events and mortality in HD patients. Effective and earlier treatment for these patients is needed to improve clinical outcome.

Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease.

AIMS: AST-120, an oral adsorbent currently on-label only in Asian countries with phase III trials ongoing in the US, slows renal disease progression in patients with diabetes and advanced-stage chronic kidney disease (CKD). The objective of this study is to evaluate the cost-effectiveness of using AST-120 to treat patients with type 2 diabetes and advanced-stage CKD. METHODS: We used Markov model simulating the progression of diabetic nephropathy. Data were obtained from randomized trials estimating the progression of diabetic nephropathy with and without AST-120, and published literature. The base population was patients 60 years of age with type 2 diabetes and Stages 3 and 4 CKD. RESULTS: Treating patients with diabetes and advanced-stage CKD was found to be a dominant strategy, and quality of life improved further and more money was saved (0.22 quality-adjusted life years [QALYs] and $15,019 per patient) using AST-120 than the control strategy. Sensitivity analysis results were robust with regard to cost, adherence, and quality of life associated with AST-120 therapy, as well as age at diagnosis. The model was relatively sensitive to the effectiveness of AST-120. CONCLUSIONS: Treating patients with type 2 diabetes and advanced-stage CKD with AST-120 appears to extend life and reduce costs.

Independent and joint associations of nutritional status indicators with mortality risk among chronic hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

OBJECTIVE: To consider the Kidney Disease Outcomes Quality Initiative recommendation of using multiple nutritional measurements for patients on maintenance dialysis, we explored data for independent and joint associations of nutritional indicators with mortality risk among maintenance hemodialysis patients treated in 12 countries. SETTING: Dialysis units in seven European countries, the United States, Canada, Australia, New Zealand, and Japan. MAIN OUTCOME: Mortality risk. METHODS: We conducted a prospective cohort study of 40,950 patients from phases I to III of the Dialysis Outcomes and Practice Patterns Study (1996-2008). Independent and joint effects (interactions) of nutritional indicators (serum creatinine, serum albumin, normalized protein catabolic rate, body mass index [BMI]) on mortality risk were assessed by Cox regression with adjustments for demographics, years on dialysis, and comorbidities. RESULTS: Important variations in nutritional indicators were seen by country and patient characteristics. Poorer nutritional status assessed by each indicator was independently associated with higher mortality risk across regions. Significant multiplicative interactions (each p < or = 0.01) between indicators were also observed. For example, by using patients with serum creatinine 7.5-10.5 mg/dL and BMI 21-25 kg/m(2) as referent, BMI <21 kg/m(2) was associated with lower mortality risk among patients with creatinine >10.5 mg/dL (relative risk = 0.68) but with higher mortality risk among those with creatinine <7.5 mg/dL (relative risk = 1.38). The association of lower albumin concentration with higher mortality risk was stronger for patients with lower BMI or lower creatinine. CONCLUSION: The joint effects of nutritional indicators on mortality indicate the need to use multiple measurements when assessing the nutritional status of hemodialysis patients.

Depressive symptoms predict the subsequent risk of bodily pain in dialysis patients: Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Bodily pain and psychiatric distress are common symptoms in patients with dialysis. However, the temporal relationships have not yet been investigated. Objective. To evaluate the longitudinal association between depressive symptoms and subsequent risk of developing severe bodily pain in dialysis patients. Design. Prospective cohort study. METHODS: We assessed bodily pain using a self-reported questionnaire and depressive symptoms using scores from the short version of Center for Epidemiological Studies Depression Screening Index (CES-D) from 531 participants showing no/mild bodily pain at baseline, based on the Japan Dialysis Outcomes and Practice Patterns Study, a cohort study of hemodialysis patients. To evaluate the relationship between depressive symptoms and development of severe bodily pain, multivariable logistic regression analysis was performed. RESULTS: The 531 patients had a mean age of 57.9 years, 61.4% were male, and 33.1% had depressive symptoms. Logistic regression analysis revealed that depressive symptoms at baseline were significantly associated with higher odds of developing severe bodily pain during a 0.5- to 2.5-year follow-up period (adjusted odds ratio [AOR] = 2.13, 95% confidence interval [CI]: 1.36-3.33, P = 0.001). Further, patients with higher CES-D scores were likely to develop severe bodily pain (AOR = 1.09, 95% CI: 1.04-1.15, P = 0.001). CONCLUSIONS: Results of this study suggest that depressive symptoms measured by CES-D predict the future risk of developing severe bodily pain in dialysis patients.

Beta-blocker prescription and outcomes in hemodialysis patients from the Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND/AIMS: Given the clear benefits of mortality reduction observed for most beta-blockers in clinical trials, they are relatively underused in hemodialysis patients. Since the outcomes associated with the use of beta-blockers are not fully known, we investigated their effect on mortality among a cohort of hemodialysis patients. METHODS: Data were analyzed from the Dialysis Outcomes and Practice Patterns Study phase II for 2,286 randomly selected patients on hemodialysis in Japan. Treatment with beta-blockers was the major predictor variable. The main outcome measure was all-cause mortality. Cox regression analysis was used to assess an association between treatment with beta-blockers and the risk of death. RESULTS: 247 patients (11.9%) were administered beta-blockers and 1,828 patients (88.1%) were not. Whereas patients treated with beta-blockers had a higher prevalence of hypertension and coronary heart disease, Kaplan-Meier analysis revealed that all-cause mortality rates were significantly (p < 0.007) decreased in patients treated with beta-blockers compared to those without. In multivariable, fully adjusted models, treatment with beta-blockers was also independently associated with reduced all-cause mortality (hazard ratio = 0.48; p = 0.02). CONCLUSION: This study indicated a possible association between the use of beta-blockers and reduced risk of mortality in hemodialysis patients. These results should be confirmed in further randomized controlled trials.

Impact of early referral to nephrologist on mental health among hemodialysis patients: a Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Pre-dialysis early referral is associated with improved survival in patients on dialysis. Here, we examined the association between pre-dialysis early referral and post-dialysis Mental Health (MH) in hemodialysis patients. METHODS: We examined data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective and observational study of hemodialysis patients, by performing a cross-sectional and longitudinal analysis of DOPPS data from Japan. The outcome measure was analyzed from the MH subscale of the Medical Outcomes Study Short Form-36 Item Health Survey. Predictors of mean MH were identified using analysis of covariance. The variables evaluated in the multivariate models included age, sex, duration of dialysis and diabetes. RESULTS: A total of 552 patients under hemodialysis participated in the study, with a late referral prevalence of 34.2% (189/552). The estimated mean MH score was 60.7 (95% confidence interval (CI) 57.5-63.8) and 65.6 (95% CI 63.2-68.1) in late and early referrals, respectively. A statistically significant difference in mean MH score of 4.9 was observed between late and early referral groups (p = 0.01). The mean MH score for late referral was significantly lower than that for early referral in the 6-12 and 12-18 month groups. CONCLUSIONS: Pre-dialysis early referral is a modifiable and important factor and is associated with improved MH of post-dialysis patients.

Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial.

BACKGROUND: The carbonaceous oral adsorbent AST-120 slows the deterioration of kidney function in patients with advanced chronic kidney disease (CKD). However, information about AST-120 in patients with less severe stages of CKD is lacking. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 75 medical facilities, 460 patients with CKD with serum creatinine (sCr) concentrations less than 5.0 mg/dL (not undergoing dialysis). INTERVENTION: Random assignment to either a low-protein diet and antihypertensive medication in the control group or that treatment combined with AST-120 (6 g/d). OUTCOMES & MEASUREMENTS: Composite primary end point: doubling of sCr level, increase in sCr level to 6.0 mg/dL or more, need for dialysis or transplantation, or death. SECONDARY OUTCOMES: adverse events and changes in estimated creatinine clearance (CCr) rate, proteinuria (protein in milligrams per day), and quality of life. RESULTS: Mean sCr level was 2.66 mg/dL and estimated CCr was 22.4 mL/min in both groups. During 56 weeks, numbers of primary end-point events (43 for control versus 42 for AST-120) and event-free survival (P = 0.9) did not differ between groups. Gastrointestinal adverse events were less common in the control group than the AST-120 group (2 versus 32 events). Estimated CCr decreased more in the control group than in the AST-120 group (-15% per year versus -12% per year, relative to the baseline value; [corrected] P = 0.001). Median proteinuria changed from protein of 1,162 to 1,167 mg/d in the control group versus 1,102 to 906 mg/d in the AST-120 group (P = 0.2). LIMITATION: Infrequent primary end-point events. CONCLUSION: AST-120 did not substantially slow the progression of kidney disease in patients with moderate to severe CKD during 1 year.

Physicians make different decisions from nephrologists at serum creatinine 2.0 mg/dl.

BACKGROUND: It is very important, but not clear, how physicians differ from nephrologists in treatment of renal insufficiency. AIM: To demonstrate differences in decision-making in treatment of renal insufficiency between physicians and nephrologists. DESIGN OF STUDY: Postal questionnaire. SETTING: All physicians were graduates from one medical school and certified by the Japanese Society of Internal Medicine. Nephrologists were certified by the Society and the Japanese Society of Nephrology. METHOD: Questionnaires were sent to 1,395 physicians and 385 nephrologists, including audit of serum creatinine concentration that would indicate referral to nephrologist, audit of continuation of angiotensin converting enzyme inhibitor (ACEI) for a case of renal insufficiency and mild hyperkalemia due to ACEI. Outputs were proportion that selected "serum creatinine 177 micromol/l (2.0 mg/dl) and over" as a referral point to the nephrologist, and proportion that chose "suspend ACEI" for a case of renal insufficiency and mild hyperkalemia due to ACEI. RESULTS: Six hundred and fourteen physicians replied (44%), and 111 certified in internal medicine were extracted from them. One hundred and eighty-six certified nephrologists replied (47%), and 114 certified in internal medicine were extracted. The proportion that chose "177 micromol/l" as a referral point to the nephrologist was 20% for physicians and 61% for nephrologists (P < 0.0001). An additional 17% of nephrologists recommended creatinine concentration below 177 micromol/l, whereas no such opinion was found among physicians. The proportion that chose "suspend ACEI" was 45% for physicians and 16% for nephrologists (P < 0.0001). CONCLUSION: There is significant difference between decisions made by physicians and nephrologists regarding treatment for patients with serum creatinine concentration of 177 micromol/l.