Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .

Executive summary of the Japan Osteoporosis Society Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

With the aging of society, the number of osteoporosis-related fractures is increasing. Prevention of osteoporosis and maintenance of the quality of life of osteoporosis patients require early diagnosis, effective treatment, and highly precise treatment monitoring. Although bone biopsy is clinically one of the essential techniques for diagnosis of osteoporosis, it is invasive and difficult to perform in general clinical practice. Bone mineral density measurement is another essential technique available in clinical practice that provides good precision. However, it is not effective for determining the appropriate treatment options or evaluating short-term treatment efficacy. On the other hand, bone turnover markers (BTMs) have gained attention because they provide information that is valuable for both the selection of treatment and short-term monitoring. BTMs are now positioned to become a tool for clinically assessing bone turnover outcomes. Since the Japan Osteoporosis Society issued its Guidelines for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis in 2012, new drugs, drug formulations, and combination drug therapies have been approved; therefore, we updated the 2012 guidelines in the Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.

Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan.

Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12-month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; ≥ 90, ≥ 60 to < 90, or ≥ 30 to < 60 mL/min/1.73 m2). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 ± 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non-vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited.

Risedronate therapy in patients with mild-to-moderate chronic kidney disease with osteoporosis: post-hoc analysis of data from the risedronate phase III clinical trials.

BACKGROUND: The clinical effect of bisphosphonate treatment has not been clearly evaluated by kidney function in Japanese Chronic Kidney Disease (CKD) patients with osteoporosis. This study analyzed the data from three risedronate Japanese phase III trials. The clinical effect of risedronate therapy was evaluated in CKD patients with osteoporosis. METHODS: The Japanese clinical trials involved 852 subjects who received risedronate (2.5 mg once daily or 17.5 mg once weekly) and whose estimated glomerular filtration rate (eGFR) were calculable and at ≥ 30 mL/min. The subjects were divided into subgroups according to the eGFR level: ≥ 90 mL/min/1.73 m2, ≥ 60 to < 90 mL/min/1.73 m2, ≥ 30 to < 60 mL/min/1.73 m2. Lumbar spine bone mineral density (BMD), bone turnover markers (BTMs) and adverse events were evaluated at 48 weeks. RESULTS: Adverse event incidence was similar among three subgroups. There was also no exacerbation of impaired kidney function associated with risedronate administration in the subjects with eGFR above 30 mL/min/1.73 m2. Risedronate administration induced a significant increase in lumbar spine BMD and significant inhibition of BTMs in three subgroups. CONCLUSIONS: The risedronate therapy showed similar clinical effects in CKD patients with osteoporosis compared to those without CKD.

Effect of Predialysis Recombinant Human Erythropoietin on Early Survival After Hemodialysis Initiation in Patients With Chronic Kidney Disease: Co-JET Study.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Efficacy and Safety of Risedronate in Osteoporosis Subjects with Comorbid Diabetes, Hypertension, and/or Dyslipidemia: A Post Hoc Analysis of Phase III Trials Conducted in Japan.

Many osteoporotics have comorbid diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL). However, whether such comorbidities alter response to anti-osteoporotic treatment is unknown. We did post hoc analyses of combined data from three risedronate Japanese phase III trials to determine whether the presence of DM, HT, or DL affects its efficacy and safety. Data from 885 subjects who received 48-week treatment with risedronate were collected and combined from the three phase III trials. They were divided into two groups by the presence or absence of comorbidities: DM (n = 53) versus non-DM (n = 832); HT (n = 278) versus non-HT (n = 607); and DL (n = 292) versus non-DL (n = 593). Bone mineral density (BMD), urinary type 1 collagen N-telopeptide (uNTX), and serum bone-specific alkaline phosphatase (BAP) were measured at baseline and sequentially until 48 weeks. BMD or bone markers were not different between any of the two groups. Overall, BMD was increased by 5.52%, and uNTX and BAP were decreased by 35.4 and 33.8%, respectively. Some bone markers were slightly lower in DM and DL subjects, but the responses to risedronate were not significantly different. Statin users had lower uNTX and BAP, but showed no difference in the treatment response. All the other medications had no apparent effect. Adverse event incidence was marginally higher in DL compared with non-DL (Relative risk 1.06; 95% confidence interval 1.01-1.11), but was not related to increase in any specific events. Risedronate shows consistent safety and efficacy in suppressing bone turnover and increasing BMD in osteoporosis patients with comorbid DM, HT, and/or DL.

A Prospective Observational Survey on the Long-Term Effect of LDL Apheresis on Drug-Resistant Nephrotic Syndrome.

BACKGROUND/AIMS: LDL apheresis (LDL-A) is used for drug-resistant nephrotic syndrome (NS) as an alternative therapy to induce remission by improvement of hyperlipidemia. Several clinical studies have suggested the efficacy of LDL-A for refractory NS, but the level of evidence remains insufficient. A multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was conducted to evaluate its clinical efficacy with high-level evidence. METHODS: Patients with NS who showed resistance to primary medication for at least 4 weeks were prospectively recruited to the study and treated with LDL-A. The long-term outcome was evaluated based on the rate of remission of NS 2 years after treatment. Factors affecting the outcome were also examined. RESULTS: A total of 58 refractory NS patients from 40 facilities were recruited and enrolled as subjects of the POLARIS study. Of the 44 subjects followed for 2 years, 21 (47.7%) showed remission of NS based on a urinary protein (UP) level <1.0 g/day. The UP level immediately after LDL-A and the rates of improvement of UP, serum albumin, serum creatinine, eGFR, and total and LDL cholesterol after the treatment session significantly affected the outcome. CONCLUSIONS: Almost half of the cases of drug-resistant NS showed remission 2 years after LDL-A. Improvement of nephrotic parameters at termination of the LDL-A treatment was a predictor of a favorable outcome.

Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naïve galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis.

Endocrine and metabolic changes affecting cardiovascular disease in dialysis patients.

Protein-energy wasting plays an important role in the increased risk of mortality from cardiovascular disease in people with end-stage renal disease. Because protein-energy wasting is a condition of imbalance between anabolism and catabolism, endocrine and metabolic alterations that regulate such balance should be the possible target of intervention. Subjects with end-stage renal disease exhibit various changes in thyroid function, gonadal hormones, adrenal androgen, glucose metabolism, dyslipidemia, fatty acid composition, cholesterol absorption, and vitamin D. In this article, we briefly review the association of these alterations with mortality and cardiovascular disease in hemodialysis patients. Although some of them may be the adaptive response to the catabolic condition, these observational data are useful for risk stratification of patients and also for providing new ideas for possible prevention.

Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5 mg daily for 8 weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12 months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N-terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat-treatment group was limited.

Immediate therapeutic efficacy of low-density lipoprotein apheresis for drug-resistant nephrotic syndrome: evidence from the short-term results from the POLARIS Study.

BACKGROUND: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan. METHOD: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. RESULTS: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. CONCLUSIONS: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.

Serum ß2-microglobulin correlates positively with left ventricular hypertrophy in long-term hemodialysis patients.

BACKGROUND/AIMS: ß2-Microglobulin (ß2-MG) is a major protein component of dialysis-related amyloidosis. In long-term hemodialysis (HD) patients, ß2-MG amyloid deposits not only in osteoarticular tissues, but also in systemic tissues, including the heart. The purpose of this study was to investigate the relationship between serum ß2-MG concentrations and echocardiographic parameters in long-term HD patients in a cross-sectional study. METHODS: Measurement of serum ß2-MG concentrations and echocardiography were performed in 251 patients who had undergone HD therapy for more than 10 years. RESULTS: The left ventricular mass index (LVMI) of the higher serum ß2-MG (≥30 mg/l) group was significantly higher than that of the lower serum ß2-MG (<30 mg/l) group (151.5 ± 45.7 vs. 137.0 ± 44.5 g/m(2), p = 0.020). In simple regression analyses, serum ß2-MG concentrations correlated significantly and positively with interventricular septum thickness (IVST) (r = 0.215, p < 0.001), posterior left ventricular wall thickness (PWT) (r = 0.249, p < 0.001), left ventricular wall thickness (LVWT) (r = 0.252, p < 0.001), relative wall thickness (RWT) (r = 0.153, p = 0.015) and LVMI (r = 0.171, p = 0.007). Multiple regression analyses revealed that serum ß2-MG concentrations correlated significantly and positively with IVST, PWT, LVWT and RWT. CONCLUSION: Serum ß2-MG concentrations correlated significantly and positively with the echocardiographic parameters of left ventricular hypertrophy (LVH) in long-term HD patients. Thus, deposition of ß2-MG amyloid in the heart may be associated with LVH progression.

Significant association between bone-specific alkaline phosphatase and vascular calcification of the hand arteries in male hemodialysis patients.

BACKGROUND/AIMS: Bone-specific alkaline phosphatase (BAP) hydrolyzes pyrophosphate, which inhibits vascular calcification. We examined association between serum BAP and vascular calcification of male hemodialysis patients. METHODS: Hand roentgenography of 167 male maintenance hemodialysis patients was conducted, and visible vascular calcification of the hand arteries was evaluated. Serum levels of 3 bone formation markers (BAP, osteocalcin, and N-terminal propeptide of type I collagen) and 2 bone resorption markers (C-terminal telopeptide of type I collagen, and cross-linked N-telopeptide of type I collagen) were measured, along with serum intact parathyroid hormone (PTH). RESULTS: Of 167 patients, visible vascular calcification was seen in 37 patients. Among the bone formation and resorption markers, serum BAP was significantly higher in patients with vascular calcification than in those without (p<0.05); although the other 5 serum bone markers were not significantly different between them. Multivariate logistic regression analyses revealed that log [BAP] was significantly associated with vascular calcification after adjustment for age, hemodialysis duration, presence of diabetes, log [intact PTH] and each of the other 5 bone markers (p<0.0001). CONCLUSIONS: Higher serum BAP, but not other bone markers, is significantly associated with the presence of vascular calcification in male hemodialysis patients.

Relationship between serum sclerostin, bone metabolism markers, and bone mineral density in maintenance hemodialysis patients.

BACKGROUND: Sclerostin, which is secreted exclusively by osteocytes, is a negative regulator of bone formation. The role of sclerostin in chronic kidney disease-mineral and bone disorder is not well known. In the present study, we examined the relationship between serum sclerostin levels, bone turnover markers, and bone mineral density (BMD) of the radius in maintenance hemodialysis patients. METHODS: This was a cross-sectional study that analyzed sclerostin, bone alkaline phosphatase (a bone formation marker), and tartrate-resistant acid phosphatase 5b (a bone resorption marker) in stored serum samples from 181 hemodialysis patients (age, 68 ± 11 y; 105 males and 76 females; hemodialysis duration, 6.9 ± 5.9 y). The BMD in the distal one-third of the radius and in the ultradistal radius, which are enriched with cortical and cancellous bone, respectively, was examined by dual-energy x-ray absorptiometry. RESULTS: Serum sclerostin was 125 ± 53 pmol/L (mean ± SD). Serum sclerostin correlated significantly and negatively with serum bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b (r = -0.265, P < .001; r = -0.218, P < .01, respectively). The BMD in the distal one-third of the radius and in the ultradistal radius both correlated significantly and positively with serum sclerostin levels (r = 0.454, P < .0001; r = 0.329, P < .0001, respectively). In multiple regression analysis, serum sclerostin was associated significantly and independently with BMD of both parts of the radius (ß = 0.200, P < .001; ß = 0.218, P < .05), after adjustment for age, hemodialysis duration, and bone metabolism markers. CONCLUSION: Serum sclerostin was associated significantly, independently, and positively with BMD of both cortical and cancellous bone. Sclerostin is considered to be one of the factors associated with chronic kidney disease-mineral and bone disorder in hemodialysis patients.

Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study.

OBJECTIVE: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. RESULTS: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). CONCLUSIONS: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

Impacts of recombinant human erythropoietin treatment during predialysis periods on the progression of chronic kidney disease in a large-scale cohort study (Co-JET study).

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub-cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability-weighted (IPW) analysis to adjust for time-dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time-dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223-0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53-0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.

Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: randomized controlled trial (PioRAGE).

OBJECTIVE: The receptor for advanced glycation end-products (RAGE) is involved in vascular complications in diabetic patients. Pioglitazone, in contrast to glimepiride, has been shown to be protective against atherosclerotic disorders. In this study, we directly compared the effects of those drugs on RAGE system. METHODS: Sixty-three type 2 diabetic patients (age 20-80 years, hemoglobin A1c 6.4-10.3%) being treated with sulfonylurea (glimepiride 0.5-2.0 mg/day, glyclazide 20-80 mg/day, glibenclamide 1.25-5.0 mg/day), or with nateglinide or metiglynide were randomly assigned to receive either pioglitazone (n = 31) or glimepiride (n = 32). Levels in plasma of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), and RAGE expression in peripheral mononuclear cells were determined at 0, 12, and 24 weeks. RESULTS: Twenty-seven patients in the pioglitazone group (15-30 mg) and 30 in the glimepiride group (0.5-4 mg) completed the 24-week trial. Increases in plasma esRAGE were significantly greater in the pioglitazone group (12 weeks: 55 ± 15 pg/mL, p = 0.018; 24 weeks: 90 ± 14 pg/mL, p = 0.003) as compared to the glimepiride group (12 weeks: 12 ± 9 pg/mL; 24 weeks: 29 ± 14 pg/mL). Increases in plasma sRAGE were also significantly (p = 0.037) higher in the pioglitazone group at 24 weeks (170 ± 166 vs.74 ± 171 pg/mL). Furthermore, RAGE expression in mononuclear cells was significantly (p = 0.008) decreased to a greater degree in the pioglitazone group at 24 weeks (-7.39 ± 5.18 vs. -3.39 ± 5.72 MFI). Changes in HbA1c, IRI, and insulin resistance index (HOMA) at 24 weeks were not significantly different between the groups. CONCLUSION: Pioglitazone suppresses RAGE expression and increases circulating sRAGE/esRAGE, and those activities are not necessarily dependent on plasma glucose or insulin resistance levels. CLINICAL TRIAL NO: UMIN000002055.

Low hemoglobin levels and hypo-responsiveness to erythropoiesis-stimulating agent associated with poor survival in incident Japanese hemodialysis patients.

Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57-2.77; P < 0.0001). Moreover, the 3-year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥ 9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13-2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10,310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.

Hair magnesium, but not serum magnesium, is associated with left ventricular wall thickness in hemodialysis patients.

BACKGROUND: Extracellular magnesium (Mg) accounts for approximately 1% of the total body Mg. Clinically, serum Mg concentration is measured, but it does not necessarily reflect total body Mg status. Although relationships have been reported between reduced Mg and cardiovascular disease in non-dialysis patients, there have been few such studies in hemodialysis patients. It was hypothesized that reduced Mg, as represented by lower Mg concentration in the hair, would be associated with echocardiographic parameters in chronic hemodialysis patients. METHODS AND RESULTS: Hair Mg concentration was measured in 79 male hemodialysis patients using inductively coupled plasma mass spectrometry, and the relationships between hair Mg concentration and echocardiographic parameters were investigated. There was no significant correlation between Mg concentration in the hair and in serum. Hair Mg concentration in the patients with high-left ventricular mass index (LVMI) was significantly lower than that in the low-LVMI patients. Hair Mg concentration correlated significantly and negatively with posterior left ventricular wall thickness, interventricular septum thickness, left ventricular wall thickness (LVWT), and relative wall thickness. Serum Mg concentration, however, did not correlate with any of these echocardiographic parameters. CONCLUSIONS: In hemodialysis patients, hair Mg concentration is a biomarker, independent of serum Mg concentration. Hair Mg, but not serum Mg, was significantly and negatively associated with LVWT. Reduced tissue Mg concentration, as measured in the hair, may be associated with left ventricular hypertrophy in hemodialysis patients.