Infectious Risk and Variability of Hemoglobin Level in Patients Undergoing Hemodialysis.

Introduction: In the management of anemia in chronic kidney disease, hemoglobin levels often fall below or exceed target ranges. Past retrospective cohort studies of patients undergoing hemodialysis with conventional erythropoiesis stimulating agents (ESAs) found that hemoglobin level fluctuations predicted mortality and cardiovascular adverse events; long-acting agents were thereafter widely available. An updated validation by a prospective cohort study was needed. Methods: Using Cox regression models, we evaluated associations between hemoglobin variability and all-cause death, hospitalization, and cardiovascular, thrombotic, or infectious adverse event outcomes in 3063 hemodialysis patients' data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) from 2012 to 2018. Results: During a median follow-up time of 2.5 years, all-cause mortality was lowest in the first quartile and tended to be higher in groups with greater hemoglobin variability (hazard ratio [HR]: 95% confidence interval for the fourth quartile of an absolute value of hemoglobin variability: 1.44 [0.99-2.08], P for trend = 0.056). Infectious event incidence in these patients was also lower in the first quartile than for the other quartiles (P for trend < 0.01). The association was more pronounced in patients with lower serum ferritin levels or iron supplementation. Cardiovascular and thrombotic event incidence was not associated with hemoglobin variability. Conclusions: Maintenance hemodialysis patients on ESA treatment with higher hemoglobin variability are at higher risk for all-cause mortality and particularly infectious events.

Changes in 3-month mineral and bone disorder patterns were associated with all-cause mortality in prevalent hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients. METHODS: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures. RESULTS: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group. CONCLUSIONS: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.

Effectiveness of cinacalcet treatment for secondary hyperparathyroidism on hospitalization: Results from the MBD-5D study.

OBJECTIVES: To elucidate the effect of cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. METHODS: We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were cinacalcet-naïve at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill-type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. RESULTS: Among the 3,276 patients, cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). CONCLUSIONS: Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.

Frequent monitoring of mineral metabolism in hemodialysis patients with secondary hyperparathyroidism: associations with achievement of treatment goals and with adjustments in therapy.

Background: Dialysis guidelines in Japan recommend more frequent measurement of mineral metabolism markers than the Kidney Disease: Improving Global Outcomes guidelines. However, the extent to which frequent marker measurement contributes to achievement of target ranges and to therapy adjustment is unknown. Methods: This multicenter cohort study involved 3276 hemodialysis patients with secondary hyperparathyroidism. Data on laboratory measurements and drug prescriptions were collected every 3 months. Main exposures were frequencies of measuring serum calcium and phosphorus [weekly/biweekly/monthly (reference)] and serum parathyroid hormone (PTH) [monthly/bimonthly/trimonthly (reference)] levels. Outcomes were achievement of guideline-specified ranges of mineral metabolism markers when serum levels were over, and maintenance of ranges when levels were already within, respective specified ranges, use of intravenous vitamin D receptor activator (VDRA) and initiation of cinacalcet use. Associations were examined via generalized estimating equations. Results: When serum marker levels exceeded the target range, weekly measurement of calcium and phosphorus was positively associated with achievement of the guideline-specified calcium range [adjusted odds ratio (AOR): 1.57, 95% confidence interval (CI) 1.09-2.26] but not phosphorus range (AOR: 0.99, 95% CI 0.74-1.33). Monthly measurement of PTH was positively associated with achievement of the guideline-specified PTH range (AOR: 1.14, 95% CI 1.01-1.27). When serum marker levels were within the guideline-specified range, increased frequency of measurements was not associated with in-range maintenance of marker levels for any of the three mineral markers assessed. Regarding treatment regimen, relatively frequent measurement of serum calcium and phosphorus was positively associated with cinacalcet initiation and relatively frequent measurement of serum PTH with cinacalcet initiation and intravenous VDRA use. Conclusions: Our results suggest that increasing frequency of measurements is helpful when serum marker levels exceed the target range, partially via adjustment in the therapeutic regimen. We found no evidence that frequent measurements are helpful when mineral levels are already within target ranges.

Abnormal mineral metabolism and mortality in hemodialysis patients with secondary hyperparathyroidism: evidence from marginal structural models used to adjust for time-dependent confounding.

BACKGROUND: Hemodialysis patients with mineral and bone disorders (MBDs) have an abnormally high relative risk of death, but their absolute risk of death is unknown. Further, previous studies have not accounted for possible time-dependent confounding of the association between MBD markers and death due to the effect of markers of MBD on treatments, which subsequently may affect MBD markers. STUDY DESIGN: Multicenter, 3-year, prospective, case-cohort study. SETTING & PARTICIPANTS: 8,229 hemodialysis patients with secondary hyperparathyroidism (parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators) at 86 facilities in Japan. PREDICTORS: Serum phosphorus, calcium, and parathyroid hormone levels. OUTCOME: All-cause mortality. MEASUREMENTS: Marginal structural models were used to compute absolute differences in all-cause mortality associated with different levels of predictors while accounting for time-dependent confounding. RESULTS: The association between phosphorus level and mortality appeared U-shaped, although only higher phosphorus level categories reached statistical significance: compared to those with phosphorus levels of 5.0-5.9 mg/dL (1.61-1.93 mmol/L), patients with the highest (≥9.0 mg/dL [≥2.90 mmol/L]) phosphorus levels had 9.4 excess deaths/100 person-years (rate ratio, 2.79 [95% CI, 1.26-6.15]), whereas no association was found for the lowest phosphorus category (<3.0 mg/dL [<0.97 mmol/L]; rate ratio, 1.54 [95% CI, 0.87-2.71]). Similarly, hypercalcemia (≥10.0 mg/dL [≥2.50 mmol/L]) was associated with excess deaths, and the highest level of hypercalcemia (≥11.0 mg/dL [≥2.75 mmol/L]) was associated with 5.8 excess deaths/100 person-years (rate ratio, 2.38 [95% CI, 1.77-3.21]) compared to those with levels of 9.0-9.4 mg/dL (2.25-2.37 mmol/L). Abnormally high parathyroid hormone levels were not associated with excess deaths. LIMITATIONS: Possible residual confounding. CONCLUSIONS: These results reinforce the idea that serum calcium (in addition to phosphorus) level is an important predictor of the absolute risk of death in hemodialysis patients with secondary hyperparathyroidism.

Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study.

BACKGROUND AND OBJECTIVES: Prescription patterns for hemodialysis patients with secondary hyperparathyroidism have varied widely since market introduction of cinacalcet. This study examined associations between prescription patterns and subsequent laboratory values. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients subcohort, 1716 prevalent hemodialysis patients (4048 sets for repeated measures between January 2008 and July 2009) with an intact parathyroid hormone (iPTH) level >180 pg/ml who used intravenous vitamin D receptor activator (VDRA) without cinacalcet were selected. Prescription patterns were defined based on cinacalcet administration (starting or not) and VDRA dosage change (decreased [<-25%], stable [-25% to 25%], or increased [>25%]). Proportion differences (PDs) were determined for decreasing iPTH levels by at least one category (<180, 180-299, 300-499, and ≥500 pg/ml) and for achieving target phosphorus (3.5-6.0 mg/dl) and calcium (8.4-10.0 mg/dl) levels, adjusting for potential confounders. RESULTS: The starting cinacalcet and increased VDRA patterns were associated with decreasing iPTH levels (PD, 0.25 and 0.13; 95% confidence intervals [95% CIs], 0.19-0.31 and 0.09-0.17, respectively); combination use had an additive association (PD, 0.34; 95% CI, 0.20-0.42). The starting cinacalcet and decreased VDRA combination was associated with simultaneously achieving target phosphorus (PD, 0.12; 95% CI: 0.04-0.20) and calcium (PD, 0.09; 95% CI, 0.01-0.17) levels. CONCLUSIONS: Certain combinations of cinacalcet and VDRA were associated with decreasing iPTH and achieving targets for phosphorus and calcium. Combinations may prove advantageous versus VDRA alone in managing secondary hyperparathyroidism.

Decreases in PTH in Japanese hemodialysis patients with secondary hyperparathyroidism: associations with changing practice patterns.

BACKGROUND AND OBJECTIVES: Control of serum concentrations of calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) is essential for management of secondary hyperparathyroidism (SHPT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a planned interim analysis of a longitudinal cohort study. The settings are dialysis facilities in Japan. Eligible patients comprise all those who were receiving hemodialysis at one of 86 participating facilities and who have SHPT. Using data from a random sample (n = 3276) of the participants from January 2008 through June 2009, we measured changes in the percentages of patients who were within the national guideline-specified target ranges of Ca (8.4 to 10 mg/dl), P (3.5 to 6.0 mg/dl), and intact PTH (iPTH) (60 to 180 pg/ml), and changes in prescriptions of drugs targeting SHPT. We used regression models to identify factors affecting the achievement of the guideline-specified targets. RESULTS: There were no notable changes in the percentage of patients who were within the guideline for Ca, P, or both. The percentage who were within the iPTH guideline increased from 14.5% to 43.3% (P < 0.001). There were no remarkable changes in the percentage of patients receiving vitamin D or phosphate binders. The percentage who received cinacalcet increased from 0% to 29%. Prescription of cinacalcet was associated with improvement or target-achievement for iPTH and for Ca by 16.8 percentage points (95% CI: 8.1 to 17.0) and by 12.6 percentage points (13.7 to 19.9), respectively. CONCLUSIONS: In the routine care of hemodialysis patients, increasing use of cinacalcet was associated with better control of SHPT.