BACKGROUND AND OBJECTIVES The Oxford classification of IgA nephropathy (IgAN) includes mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis (S), and tubular ...atrophy/interstitial fibrosis (T) as prognosticators. The value of extracapillary proliferation (Ex) was not addressed. Because the Oxford classification excludes patients with urinary protein <0.5 g/d and eGFR <30 ml/min per 1.73 m(2) at biopsy, the significance of Ex should be confirmed by validation cohorts that include more rapidly progressive cases. We present such a study.
The significance of pathologic features for development end-stage renal failure (ESRF) was examined by multivariate analysis in 702 patients with IgAN. The association of Ex with kidney survival was examined by univariate analysis in 416 patients who met the Oxford criteria and 286 who did not, separately.
In a multivariate model, S and T were significantly associated with ESRF. With addition of Ex, not S but Ex was significant for ESRF. In univariate analysis, kidney survival was significantly lower in patients with Ex than in those without, in patients who did not meet the Oxford criteria, but such a difference was not found in patients who met it.
The prognostic significance of Ex was evident in our cohort. It seems that Ex did not emerge from the Oxford classification as a prognosticator because of exclusion of severe cases (eGFR <30 ml/min per 1.73 m(2)). We suggest that extracapillary proliferation be included in the next version of the Oxford classification of IgAN to widen the scope of the classification.
The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in ...haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ - 421.36 (- 778.94 to - 63.78, p = 0.02) and - 0.83% (- 1.61 to - 0.05, p = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment.
Background Hemodialysis patients are at increased risk for bone fracture and sarcopenia. There is close interplay between skeletal muscle and bone. However, it is still unclear whether lower skeletal ...muscle mass increases the risk for bone fracture. Study Design Cross-sectional study and prospective longitudinal cohort study. Setting & Participants An independent cohort of 78 hemodialysis patients in the cross-sectional study and 3,030 prevalent patients undergoing maintenance hemodialysis prospectively followed up for 4 years. Predictor Skeletal muscle mass measured by bioelectrical impedance analysis (BIA) and modified creatinine index, an estimate of skeletal muscle mass based on age, sex, Kt/V for urea, and serum creatinine level. Outcomes Bone fracture at any site. Results In the cross-sectional study, modified creatinine index was significantly correlated with skeletal muscle mass measured by BIA. During a median follow-up of 3.9 years, 140 patients had bone fracture. When patients were divided into sex-specific quartiles based on modified creatinine index, risk for bone fracture estimated by a Fine-Gray proportional subdistribution hazards model with all-cause death as a competing risk was significantly higher in the lower modified creatinine index quartiles (Q1 and Q2) compared to the highest modified creatinine index quartile (Q4) as the reference value in both sexes (multivariable-adjusted HRs for men were 7.81 95% CI, 2.63-23.26, 5.48 95% CI, 2.08-14.40, 2.24 95% CI, 0.72-7.00, and 1.00 P for trend < 0.001, and for women were 4.44 95% CI, 1.50-13.11, 2.33 95% CI, 0.86-6.31, 1.96 95% CI, 0.82-4.65, and 1.00 P for trend = 0.007 for Q1, Q2, Q3, and Q4, respectively). Limitations One-time assessment of modified creatinine index; no data for residual kidney function and fracture sites and causes. Conclusions Modified creatinine index was correlated with skeletal muscle mass measured by BIA. Lower modified creatinine index was associated with increased risk for bone fracture in male and female hemodialysis patients.
Background Cardiothoracic ratio by chest radiography is commonly used to assess volume status. Little is known about the relationships between cardiothoracic ratio and the incidence of clinical ...outcomes in patients undergoing hemodialysis (HD). Study Design Prospective cohort study. Setting & Participants 3,436 participants in the Q-Cohort Study 18 years or older who underwent maintenance HD in Japan. Predictor Cardiothoracic ratio. Outcomes & Measurements All-cause mortality and cardiovascular disease (CVD) events. Results During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed CVD events. From baseline cardiothoracic ratios, participants were categorized into sex-specific quartiles because cardiothoracic ratio distribution differed by sex. The 4-year event-free survival rate, in terms of all-cause mortality and CVD events, was significantly lower with higher cardiothoracic ratios. Compared to the lowest cardiothoracic ratio (quartile 1), multivariable-adjusted HRs for all-cause mortality were 0.89 (95% CI, 0.66-1.20), 1.41 (1.08-1.86), and 1.52 (1.17-2.00) in patients from quartiles 2, 3, and 4, respectively. Similarly, in comparison to quartile 1, multivariable-adjusted HRs for CVD events were 1.00 (95% CI, 0.77-1.31), 1.18 (0.92-1.53), and 1.37 (1.07-1.76) in patients from quartiles 2, 3, and 4, respectively. Furthermore, the combination of higher cardiothoracic ratio and normohypotension (systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg) was associated with higher risk for CVD events. Limitations Single measurement of all variables, potentially less-heterogeneous patient population, and limited ascertainment of cardiac parameters and the outcomes. Conclusions Higher cardiothoracic ratio is associated with higher risk for both all-cause mortality and CVD events in patients undergoing HD.
The identification of malnutrition-inflammation-complex (MIC) and functional status (FS) is key to improving patient experience on hemodialysis (HD). We investigate the association of MIC and FS ...combinations with mortality in HD patients. We analyzed data from 5630 HD patients from 9 countries in DOPPS phases 4-5 (2009-2015) with a median follow-up of 23 IQR 11, 31 months. MIC was defined as serum albumin < 3.8 g/dL and serum C-reactive protein > 3 mg/L in Japan and > 10 mg/L elsewhere. FS score was defined as the sum of scores from the Katz Index of Independence in Activities of Daily Living and the Lawton-Brody Instrumental Activities of Daily Living Scale. We investigated the association between combinations of MIC (+/-) and FS (low < 11/high ≥ 11) with death. Compared to the reference group (MIC-/high FS), the adjusted hazard ratios HR (95% CI) for all-cause mortality were 1.82 (1.49, 2.21) for MIC-/low FS, 1.57 (1.30, 1.89) for MIC+/high FS, and 3.44 (2.80, 4.23) for MIC+/low FS groups. Similar associations were observed with CVD-related and infection-related mortality. The combination of MIC and low FS is a strong predictor of mortality in HD patients. Identification of MIC and poor FS may direct interventions to lessen adverse clinical outcomes in the HD setting.
Background
Coronary artery calcification (CAC) is predictive of cardiovascular events. We assessed whether a non-calcium-based phosphate binder, lanthanum carbonate (LC), could delay CAC progression ...compared with a calcium-based phosphate binder, calcium carbonate (CC), in hemodialysis patients.
Methods
This was a subsidiary of the LANDMARK study, which is a multicenter, open-label, randomized control study comparing LC and CC for cardiovascular events among Japanese hemodialysis patients with hyperphosphatemia who were at risk of vascular calcification. Participants were randomly assigned (1:1) to receive LC or CC. The changes in the total Agatston score of CAC 2 years from baseline were the primary outcome. Secondary outcomes included the changes in the total Agatston score at 1 year from baseline and the changes in serum phosphate, corrected calcium, and intact parathyroid hormone concentrations.
Results
Of 239 patients, 123 comprised the full analysis set. The median daily drug dose (mg) was 750 interquartile range (IQR), 750‒1500 in the LC group and 3000 (IQR, 3000‒3000) in the CC group; it remained constant throughout the study period. There was no significant difference in the change in total Agatston score from baseline to 2 years between the LC and CC groups 368 (95% confidence interval, 57–680) in the LC group vs. 611 (105–1118) in the CC group; difference, 243 (− 352–838).
Conclusions
LC-based treatment for hyperphosphatemia did not delay CAC for 2 years compared with CC-based treatment in hemodialysis patients with at least one risk factor for vascular calcification.
Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD.
A phase 3, multicenter, randomized, double blind, placebo-controlled study ...investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m(2)) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5-4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment.
The mean change in serum phosphate was -1.29 mg/dl (95% confidence interval, -1.63 to -0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, -0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline median, -142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo.
In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.
Background
Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study ...aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.
Methods
Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis 285 patients were excluded mainly due to lack of hemoglobin (Hb) values. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.
Results
The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15–900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein–creatinine ratio were independently associated with better initial response to DA (
P
= < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively).
Conclusions
Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.
Enarodustat (JTZ‐951) is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease. Two open‐label, uncontrolled phase 3 studies evaluated ...the 52‐week safety and efficacy of enarodustat in Japanese anemic patients with chronic kidney disease not on dialysis (n = 132) SYMPHONY ND‐Long study or on maintenance hemodialysis (n = 136) SYMPHONY HD‐Long study. The most frequent adverse events were viral upper respiratory tract infection (25.8%) followed by chronic kidney disease (8.3%) in the SYMPHONY ND‐Long study, and viral upper respiratory tract infection (49.3%) followed by contusion (16.9%) and diarrhea (16.9%) in the SYMPHONY HD‐Long study. The incidence of any adverse events did not increase over time. Mean hemoglobin levels and 95% confidence intervals were maintained within the target range (10.0–12.0 g/dl) over 52 weeks in both studies. The long‐term safety and efficacy of enarodustat were confirmed in Japanese anemic patients with chronic kidney disease.
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