Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce.

Patients receiving hemodialysis with values outside of target levels for parathyroid hormone (PTH: 150–600 pg/mL), calcium (Ca: 8.4–10.2 mg/dL), and phosphate (P: 3.5–5.5 mg/dL) are at elevated morbidity and mortality risk. We examined whether patients receiving care in dialysis facilities where greater proportions of patients have at least two values out of target have a higher risk of adverse clinical outcomes.

Aim: The objective of this study was to examine the time-varying relationship of chronic kidney disease-mineral bone disorder (CKD-MBD) related biochemical parameters (parathyroid hormone (PTH), calcium, phosphate) over a 12-month period. Material and methods: Using data from a large US provider of dialysis services from 2010 through 2012, we constructed a cohort of adult patients receiving in-center hemodialysis who had biochemical parameters measured at both baseline and 12 months of follow-up. We used descriptive statistics to assess the overall distributions of the biochemical parameters at both measurements, to examine how patients transitioned between categories for each biochemical parameter, and to evaluate how the biochemical parameters changed with respect to each other. Results: Among the 132,087 patients included in our analyses, the cross-sectional distributions for the combined categories of 150 - < 300 and 300 - < 600 pg/mL for PTH between the two measurements remained unchanged (67% of patients). For calcium and phosphate, the distributions across all categories also remained largely unchanged. Considering within-patient changes over time. however, a majority (74%) of patients who initially had a PTH < 150 pg/mL transitioned to a higher category, while a majority (56%) of patients who initially had a PTH > 600 pg/mL transitioned to a lower category. We observed that phosphate values on average directly trended with PTH values over the follow-up period. Conclusion: We found that while calcium showed relatively little variation, parallel bidirectional variation in PTH and phosphate over time was quite common among adult patients receiving hemodialysis. Optimal control of phosphate is likely to be dependent not only on consistent adherence to dietary restrictions and phosphate binders, but may additionally rely on adequate and sustained control of PTH.

PurposeCinacalcet is indicated for treatment of secondary hyperparathyroidism in patients receiving hemodialysis. Cinacalcet reduces serum calcium concentrations by decreasing parathyroid hormone secretion, but the frequency and degree of calcium reduction following cinacalcet initiation, subsequent physician response, and ultimate calcium recovery in clinical practice are not well described.MethodsPatients receiving hemodialysis at a large dialysis organization who enrolled in the organization's prescription benefits service and initiated cinacalcet at serum calcium 8.4mg/dL were studied (N=13723). Patients were categorized by whether they experienced a reduction in calcium to <8.4mg/dL and to what level (<7.5, 7.5-7.9, and 8.0-8.3mg/dL). Baseline characteristics, frequency of subsequent intervention, and calcium recovery were compared.ResultsOf those who experienced a reduction in calcium to <8.4mg/dL (n=6437 [46.9%]), 6.6% had calcium <7.5mg/dL and 24.5% had calcium 7.5-7.9mg/dL, while the majority (68.9%) had a level of 8-8.3mg/dL. Higher baseline parathyroid hormone and alkaline phosphatase were associated with lower resultant calcium. Among patients with calcium reductions, 45.6-63.5% received one or more directed clinical therapeutic responses, including 15.6-28.4% for whom cinacalcet was discontinued; the majority of patients recovered to calcium 8.4mg/dL within 90days of first detection. Only modest differences in recovery were noted between patients who did and did not receive any therapeutic response and patients who did and did not discontinue cinacalcet.ConclusionSerum calcium reductions following cinacalcet initiation were common; declines <7.5mg/dL were infrequent. Calcium recovery occurred in the majority of patients, with or without therapeutic intervention. Copyright (c) 2015 John Wiley & Sons, Ltd.

BACKGROUND Some US dialysis facilities have reduced default dialysate calcium concentrations from 2.5 mEq/L to lower levels. There has been no rigorous systematic examination of the effects of such a reduction on clinical and biochemical outcomes. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS Medicare-eligible patients who received in-center hemodialysis at a large dialysis organization in January 2008 to December 2010. PREDICTOR Facility conversion from predominant use (≥75% patients) of 2.50-mEq/L dialysate calcium to predominant use of lower dialysate calcium concentrations versus maintenance of predominant use of 2.50-mEq/L dialysate calcium. OUTCOMES All-cause and cause-specific mortality and hospitalization, laboratory markers of metabolic bone disease, and drug utilization. MEASUREMENTS Hierarchical mixed linear and Poisson models were fit to compare pre- to postconversion differences in outcomes between converter and matched control facilities. Results, expressed as relative rate ratios (RRRs) and delta-delta (change in mean values), were estimated for early (months 0-2) and late (months 3-12) postconversion to allow for possible latent effects. RESULTS Facility conversion was associated with greater rates of hospitalization for heart failure exacerbation (late RRR, 1.27 [95% CI, 1.06-1.51]), hypocalcemia (early RRR, 1.19 [95% CI, 1.05-1.35]; late RRR, 1.39 [95% CI, 1.20-1.60]), and intradialytic hypotension (early RRR, 1.07 [95% CI, 1.02-1.11]; late RRR, 1.05 [95% CI, 1.01-1.10]), but no differences were observed for all-cause mortality or hospitalization rates. Facility conversion was also associated with comparative temporal decreases in serum calcium level, increases in serum phosphate and parathyroid hormone levels, and increases in use of phosphate binders, vitamin D, and calcimimetics. LIMITATIONS Possible residual confounding, generalizability beyond Medicare patients uncertain. CONCLUSIONS There are potential safety concerns associated with the default use of dialysate calcium concentrations < 2.50 mEq/L, as well as biochemical evidence of poorer disease control despite associated greater medication use. Individualization of dialysate calcium concentration rather than predominant use of dialysate calcium concentrations < 2.50 mEq/L should be considered.

BACKGROUND:Little is known about changes in parathyroid hormone (PTH), calcium and phosphorous levels after parathyroidectomy in hemodialysis patients. We studied the effects of parathyroidectomy on these biochemical values in a large cohort of patients receiving maintenance hemodialysis.METHODS:This retrospective cohort study included patients identified in both the United States Renal Data System and the database of a large dialysis organization who underwent parathyroidectomy in 2007-09, were aged ≥ 18 years, had Medicare Parts A and B as primary payer and had received hemodialysis for ≥ 1 year pre-parathyroidectomy. Descriptive statistics were calculated for continuous variables; categorical variables were used to characterize the population and evaluate monthly laboratory and medication use; median values were calculated for laboratory measures.RESULTS:Among 1402 parathyroidectomy patients, mean age was 48.9 years, 52.4% were males, 58.8% were African American and mean dialysis duration was 7.5 years. Median PTH levels increased over the year before parathyroidectomy from 1039 to 1661 pg/mL and decreased afterward to 98 pg/mL at 1 month; levels remained ≥ 897 pg/mL for 10% of patients. Median calcium levels fell from 9.6 mg/dL before to 7.9 mg/dL 1 month after parathyroidectomy; levels were ≤ 7.1 mg/dL for 25% and remained ≤ 7.2 mg/dL for the lowest 25% at 3 months. Median phosphorous level was 6.8 mg/dL immediately before parathyroidectomy, decreased to 3.8 mg/dL immediately after and reached 5.8 mg/dL at 1 year.CONCLUSIONS:While PTH levels dropped after parathyroidectomy for most patients, surgery was sometimes ineffective in reducing levels and sometimes led to over-suppression. Hypocalcemia could be profound and long lasting, suggesting the need for prolonged vigilance.

Cinacalcet reduces parathyroid hormone (PTH) levels in patients receiving hemodialysis, but no non-experimental studies have evaluated the association between changes in PTH levels following cinacalcet initiation and clinical outcomes. We assessed whether short-term change in PTH levels after first cinacalcet prescription could serve as a surrogate marker for improvements in longer-term clinical outcomes.

The international burden of secondary hyperparathyroidism (SHPT) is unknown, but it may be estimable through the available chronic kidney disease and SHPT literature. Structured reviews of biomedical literature and online data systems were performed for selected countries to ascertain recent estimates of the incidence, prevalence, and survival of individuals with CKD and SHPT. International societies of nephrology were contacted to seek additional information regarding available data. Estimates were abstracted from 35 sources reporting estimates of CKD in 25 countries. Population prevalence estimates of CKD stages 3–5 in adults ranged from approximately 1 to 9% (China, Mexico, resp.). Estimates of the population prevalence of maintenance dialysis therapy ranged from 79 per million population (pmp; China) to 2385 pmp (Japan); incidence rates ranged from 91 pmp (United Kingdom) to 349 pmp (United States). Prevalence of SHPT among stage 5D populations was highly variable and dependent upon the disease definition used. Among the few nations reporting, approximately 30–50% of stage 5D patients had serum parathyroid hormone levels >300 pg/mL. Reported incidence and prevalence estimates across the individual nations were variable, likely reflecting differing population demographics, risk factors, etiologies, and availability of treatment through all stages of CKD.

BACKGROUND:It is important to identify an easily defined subset of patients at increased risk of adverse clinical outcomes associated with mineral and bone disorder (MBD) biomarkers (parathyroid hormone, calcium and phosphate).METHODS:Observational cohort study of 26 221 prevalent hemodialysis patients in Davita clinics as of 31 August 2005 and followed up until 31 December 2006 (16 months). Predictors were 12 possible definitions of 'clinically important' MBD based on all 3 biomarkers, and 18 alternative definitions based on only 1 or 2 biomarkers. Events were death alone and a composite of cardiovascular hospitalization or death. Excess events were calculated based on a multivariate Cox model using 5224 patients in target for all MBD biomarkers and applied to 20 997 patients out of target for at least one biomarker. Excess events attributable to MBD were estimated by subtracting the multivariate model-derived predicted number from the actual number. Outcomes were the proportion of excess events attributable to MBD captured by each definition (threshold ≥70%) and the reduction in the population size considered to have clinically important MBD (threshold ≥30%). The excess fraction was excess events divided by actual events.RESULTS:Patients with more biochemical markers out of target tended to be younger, black and have longer times since starting dialysis. The excess fraction associated with MBD ranged from ∼10 to 26% depending on the clinical endpoint and definition. The only definition to meet the thresholds required at least two of the three MBD biomarkers to be out of target (high or low). It captured 82% of excess composite endpoints and 74% of excess deaths and reduced the at-risk population by 46%.CONCLUSIONS:Patients with at least two of three MBD biomarkers out of target represent a subgroup of patients at elevated risk of adverse clinical events.

BACKGROUND:Cinacalcet is used to treat secondary hyperparathyroidism among hemodialysis patients. Large-scale epidemiologic studies describing patterns of cinacalcet use, effects on parathyroid hormone (PTH), calcium, and phosphorous levels, and predictors of discontinuation have not been previously reported.METHODS:This retrospective cohort study used a clinical database of a large U.S. dialysis provider (2007-2010) merged with administrative data from the United States Renal Data System. Among new users of cinacalcet with Medicare coverage, trends in PTH, calcium, and phosphorus were measured in 30-day intervals following cinacalcet initiation.RESULTS:Seventeen thousand seven hundred sixty-three eligible initiators contributed 111,047 30-day follow-up intervals. Of these, 56 % discontinued cinacalcet by month 4. Of those discontinuing, 76.3 % reinitiated. Mean values of PTH, calcium, and phosphorus decreased to recommended levels within 4 months following initiation. Proximal PTH levels < 150 pg/mL were associated with discontinuation: HR = 1.23 (95 % CI: 1.12, 1.36), whereas low calcium (< 7.5 mg/dL) was suggestive of an association, HR = 1.09 (95 % CI 0.91, 1.32). Being in the Part D gap period increased discontinuation risk: HR = 1.09 (95 % CI: 1.03, 1.16). Low-income subsidy status decreased discontinuation risk: HR = 0.77 (95 % CI 0.69, 0.86). Predictors of reinitiation included low-income subsidy, HR = 1.32 (95 % CI 1.22, 1.43); higher albumin level, HR = 1.23 (95 % CI 1.10, 1.36) and higher calcium level, HR = 1.26 (95 % CI 1.19, 1.33).CONCLUSIONS:Substantial and expected declines in laboratory values occurred following cinacalcet initiation. Early discontinuation and reinitiation of cinacalcet were common and may have occurred for clinical and economic reasons.

BACKGROUND AND OBJECTIVES:Patients receiving dialysis undergo parathyroidectomy to improve laboratory parameters in resistant hyperparathyroidism with the assumption that clinical outcomes will also improve. However, no randomized clinical trial data demonstrate the benefits of parathyroidectomy. This study aimed to evaluate clinical outcomes up to 1 year after parathyroidectomy in a nationwide sample of patients receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using data from the US Renal Data System, this study identified prevalent hemodialysis patients aged ≥18 years with Medicare as primary payers who underwent parathyroidectomy from 2007 to 2009. Baseline characteristics and comorbid conditions were assessed in the year preceding parathyroidectomy; clinical events were identified in the year preceding and the year after parathyroidectomy. After parathyroidectomy, patients were censored at death, loss of Medicare coverage, kidney transplant, change in dialysis modality, or 365 days. This study estimated cause-specific event rates for both periods and rate ratios comparing event rates in the postparathyroidectomy versus preparathyroidectomy periods. RESULTS:Of 4435 patients who underwent parathyroidectomy, 2.0% died during the parathyroidectomy hospitalization and the 30 days after discharge. During the 30 days after discharge, 23.8% of patients were rehospitalized; 29.3% of these patients required intensive care. In the year after parathyroidectomy, hospitalizations were higher by 39%, hospital days by 58%, intensive care unit admissions by 69%, and emergency room/observation visits requiring hypocalcemia treatment by 20-fold compared with the preceding year. Cause-specific hospitalizations were higher for acute myocardial infarction (rate ratio, 1.98; 95% confidence interval, 1.60 to 2.46) and dysrhythmia (rate ratio 1.4; 95% confidence interval1.16 to 1.78); fracture rates did not differ (rate ratio 0.82; 95% confidence interval 0.6 to 1.1). CONCLUSIONS:Parathyroidectomy is associated with significant morbidity in the 30 days after hospital discharge and in the year after the procedure. Awareness of clinical events will assist in developing evidence-based risk/benefit determinations for the indication for parathyroidectomy.

Context: Sclerostin, a protein secreted by osteocytes, inhibits bone formation. Individuals with genetic mutations that decrease the availability of sclerostin have very high bone mass.Objective: The aim of this study was to examine the hypothesis that elevated serum sclerostin levels are associated with increased risk of hip fracture in older women.Design, Setting, and Participants: This was a case-cohort study of a prospective, community-based cohort of 9704 women aged 65 yr or older. Sclerostin levels were measured in serum collected in 1989-1990 in 228 women with incident hip fractures and 227 women in a randomly selected sample; average follow-up time was 9.8 yr.Results: Serum sclerostin levels were correlated with total hip bone mineral density (BMD; r = 0.27, P < 0.001). The risk of hip fracture increased across quartiles of serum sclerostin (test for trend, P < 0.001) and was significantly elevated among those in the fourth quartile (hazard risk 3.4, 95% confidence interval 1.7-7.0) compared with women in the lowest quartile, after adjusting for age, body mass index, estrogen use, history of fracture since age 50 yr, and total hip BMD. When dividing the cohort into eight groups by sclerostin quartile and median hip BMD, women with lower total hip BMD in the highest sclerostin quartile had a 22.3-fold (95% confidence interval 5.8-86.3) increased risk of fracture compared with women with higher total hip BMD in the lowest sclerostin quartile.Conclusions: We conclude that higher serum sclerostin levels are associated with a greater risk of hip fractures in older women. In addition, the risk of hip fracture is amplified when high sclerostin levels are combined with lower BMD. (J Clin Endocrinol Metab 97: 2027-2032, 2012)

BACKGROUND AND PURPOSE:A variety of risk factors have been hypothesized to contribute to the development of fracture-healing complications; however, population-based estimates of the strength of these risk factors are limited. In this case-control study, we evaluated patient-related risk factors for fracture-healing complications.METHODS:Using the United Kingdom General Practice Research Database, we identified patients with a fracture-healing complication (delayed union, nonunion, or malunion) between 1988 and 2008. 4 controls (i.e. patients with normal healing) were matched to each case on general practice, fracture site, fracture date, and length of history in the database. We used conditional logistic regression to estimate odds ratios (ORs) of various risk factors, including demographics, comorbidities, and medication use.RESULTS:Diabetes and use of non-steroidal anti-inflammatory drugs (NSAIDs) within 12 months before the initial fracture were associated with a higher odds of a fracture-healing complication (type-I diabetes: adjusted OR = 2.3, 95% CI: 1.3-3.8; type-II diabetes: adjusted OR = 2.3, CI: 1.4-3.7; NSAIDs: adjusted OR = 2.6, CI: 2.1-3.2). Patients who had a motor vehicle accident recorded within 1 month before their initial fracture were also at increased odds of a fracture-healing complication (adjusted OR = 2.6, CI: 1.2-5.4).INTERPRETATION:Diabetes, NSAID use, and a recent motor vehicle accident were most consistently associated with an increased risk of a fracture-healing complication, regardless of fracture site or specific fracture-healing complication. This analysis suggests that certain patient-related characteristics influence the development of fracture-healing complications in general, even though specific healing complications may differ by their mechanism.