Jessica E. Miller

Predictors of Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Hemodialysis Patients

BACKGROUND Identification of predictors of hyporesponsiveness to erythropoietin-stimulating agents (ESAs) in hemodialysis (HD) patients may help improve anemia management and reduce hemoglobin level variability. STUDY DESIGN We conducted repeated-measure and logistic regression analyses in a retrospective cohort of long-term HD patients to examine the association of iron markers and measures of renal osteodystrophy with ESA responsiveness. The ESA response coefficient at the individual level, ie, the least confounded dose-response association, was separated from the population level, assumed to represent confounding by medical indication. SETTING/PARTICIPANTS The national database of a large dialysis organization (DaVita Inc, El Segundo, CA) with 38,328 surviving prevalent HD patients during 12 months who received ESA for at least 3 consecutive calendar quarters was examined. PREDICTORS Serum levels of ferritin, iron saturation ratio, intact parathyroid hormone, and alkaline phosphatase. OUTCOMES/OTHER MEASUREMENTS: The main outcome was case-mix-adjusted hemoglobin response to quarterly averaged ESA dose at the individual level. The odds ratio (OR) of the greatest versus poorest ESA-response quartile at the patient level was calculated. OR less than 1.0 indicated ESA hyporesponsiveness, and OR greater than 1.0, enhanced responsiveness. RESULTS Mean ESA-response coefficients of the least to most responsive quartiles were 0.301 +/- 0.033 (SD), 0.344 +/- 0.004, 0.357 +/- 0.004, and 0.389 +/- 0.026 g/dL greater hemoglobin level per 1,000 U/wk greater ESA dose in each quarter, respectively. The ORs of greatest versus poorest ESA responsiveness at the patient level were serum ferritin level less than 200 ng/mL (0.77; 95% confidence interval [CI], 0.70 to 0.86; reference, 200 to 500 ng/mL), iron saturation ratio less than 20% (0.54; 95% CI, 0.49 to 0.59; reference, 20% to 30%), intact parathyroid hormone level of 600 pg/mL or greater (0.54; 95% CI, 0.49 to 0.60; reference, 150 to 300 pg/mL), and alkaline phosphatase level of 160 IU/L or greater (0.64; 95% CI, 0.58 to 0.70; reference, 80 to 120 IU/L). Lower estimated dietary protein intake and serum levels of nutritional markers were also associated with greater risk of ESA hyporesponsiveness. LIMITATIONS Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different associations than targeted hemoglobin level. CONCLUSIONS In long-term HD patients, low iron stores, hyperparathyroidism, and high-turnover bone disease are associated with significant ESA hyporesponsiveness. Prospective studies are needed to verify these associations.

Association of hemodialysis treatment time and dose with mortality and the role of race and sex.

BACKGROUND The association of survival with characteristics of thrice-weekly hemodialysis (HD) treatment, including dose or duration of treatment, has not been completely elucidated, especially in different race and sex categories. STUDY DESIGN We examined associations of time-averaged and quarterly varying (time-dependent) delivered HD dose and treatment time and 5-year (July 2001-June 2006) survival. SETTING & PARTICIPANTS 88,153 thrice-weekly-treated HD patients from DaVita dialysis clinics. PREDICTORS HD treatment dose (single-pool Kt/V) and treatment time. OUTCOMES & OTHER MEASUREMENTS 5-Year mortality. RESULTS Thrice-weekly treatment time < 3 hours (but > or = 2.5 hours) per HD session compared with > or = 3.5 hours (but < 5 hours) was associated with increased death risk independent of Kt/V dose. The greatest survival gain of higher HD dose was associated with a Kt/V approaching the 1.6-1.8 range, beyond which survival gain was minimal, nonexistent, or even tended to reverse in African American men and those with 4-5 hours of HD treatment. In non-Hispanic white women, Kt/V > 1.8 continued to show survival advantage trends, especially in time-dependent models. LIMITATIONS Our results may incorporate uncontrolled confounding. Achieved Kt/V may have different associations than targeted Kt/V. CONCLUSIONS HD treatment dose and time appear to have different associations with survival in different sex or race groups. Randomized controlled trials may be warranted to examine these associations across different racial and demographic groups.

Impact of race on hyperparathyroidism, mineral disarrays, administered vitamin D mimetic, and survival in hemodialysis patients

Blacks have high rates of chronic kidney disease, are overrepresented among the US dialysis patients, have higher parathyroid hormone levels, but greater survival compared to nonblacks. We hypothesized that mineral and bone disorders (MBDs) have a bearing on survival advantages of black hemodialysis patients. In 139,328 thrice‐weekly treated hemodialysis patients, including 32% blacks, in a large dialysis organization, where most laboratory values were measured monthly for up to 60 months (July 2001 to June 2006), we examined differences across races in measures of MBDs and survival predictabilities of these markers and administered the active vitamin D medication paricalcitol. Across each age increment, blacks had higher serum calcium and parathyroid hormone (PTH) levels and almost the same serum phosphorus and alkaline phosphatase levels and were more likely to receive injectable active vitamin D in the dialysis clinic, mostly paricalcitol, at higher doses than nonblacks. Racial differences existed in mortality predictabilities of different ranges of serum calcium, phosphorus, and PTH but not alkaline phosphatase. Blacks who received the highest dose of paricalcitol (>10 µg/week) had a demonstrable survival advantage over nonblacks (case‐mix‐adjusted death hazard ratio = 0.87, 95% confidence level 0.83–0.91) compared with those who received lower doses (<10 µg/week) or no active vitamin D. Hence, in black hemodialysis patients, hyperparathyroidism and hypercalcemia are more prevalent than in nonblacks, whereas hyperphosphatemia or hyperphosphatasemia are not. Survival advantages of blacks appear restricted to those receiving higher doses of active vitamin D. Examining the effect of MBD modulation on racial survival disparities of hemodialysis patients is warranted.

Association of Cumulatively Low or High Serum Calcium Levels with Mortality in Long-Term Hemodialysis Patients

Background: The outcome-predictability of baseline and instantaneously changing serum calcium in hemodialysis patients has been examined. We investigated the mortality-predictability of time-averaged calcium values to reflect the ‘cumulative’ effect of calcium burden over time. Methods: We employed a Cox model using up-to-5-year (7/2001–6/2006) time-averaged values to examine the mortality-predictability of cumulative serum calcium levels in 107,200 hemodialysis patients prior to the use of calcimimetics, but during the time where other calcium-lowering interventions, including lower dialysate calcium, were employed. Results: Both low (<9.0 mg/dl) and high (>10.0 mg/dl) calcium levels were associated with increased mortality (reference: 9.0 to <9.5 mg/dl). Whereas mortality of hypercalcemia was consistent, hypocalcemia mortality was most prominent with higher serum phosphorus (>3.5 mg/dl) and PTH levels (>150 pg/ml). Higher paricalcitol doses shifted the calcium range associated with the greatest survival to the right, i.e. from 9.0 to <9.5 to 9.5 to <10.0 mg/dl. African-Americans exhibited the highest death hazard ratio of hypocalcemia <8.5 mg/dl, being 1.35 (95% CI: 1.22–1.49). Both a rise and drop in serum calcium over 6 months were associated with increased mortality compared to the stable group. Conclusions: Whereas in hemodialysis patients cumulatively high or low calcium levels are associated with higher death risk, subtle but meaningful interactions with phosphorus, PTH, paricalcitol dose and race exist.

Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia?

Patients with chronic kidney disease (CKD), especially those requiring maintenance hemodialysis treatments, may lose up to 3 g of iron each year because of frequent blood losses. Higher doses of erythropoiesis-stimulating agents (ESAs) may worsen iron depletion and lead to an increased platelet count (thrombocytosis), ESA hyporesponsiveness, and hemoglobin variability. Hence, ESA therapy requires concurrent iron supplementation. Traditional iron markers such as serum ferritin and transferrin saturation ratio (TSAT) (ie, serum iron divided by total iron-binding capacity [TIBC]), may be confounded by non-iron-related conditions. Whereas serum ferritin <200 ng/mL suggests iron deficiency in CKD patients, ferritin levels between 200 and 1,200 ng/mL may be related to inflammation, latent infections, malignancies, or liver disease. Protein-energy wasting may lower TIBC, leading to a TSAT within the normal range, even when iron deficiency is present. Iron and anemia indices have different mortality predictabilities, in that high serum ferritin but low iron, TIBC, and TSAT levels are associated with increased mortality, whereas hemoglobin exhibits a U-shaped risk for death. The increased mortality associated with targeting hemoglobin above 13 g/dL may result from iron depletion-associated thrombocytosis. Intravenous (IV) iron administration may not only decrease hemoglobin variability and ESA hyporesponsiveness, it may also reduce the greater mortality associated with the much higher ESA doses that have been used in some patients when targeting higher hemoglobin levels.

Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia.

BACKGROUND Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length. METHODS We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia. FINDINGS Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39-40 weeks (RR 1·12, 95% CI 1·12-1·13), by 19% for each 500 g reduction in birthweight less than 3000-3500 g (1·19, 1·18-1·21), and by 41% for each 5 cm reduction in birth length less than 45-50 cm (1·41, 1·38-1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st-5th percentile RR 1·15, 95% CI 1·12-1·19, and 1·11, 1·07-1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st-5th percentile RR 1·08, 95% CI 1·04-1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital. INTERPRETATION Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common. FUNDING Australian National Health and Medical Research Council.

Administered paricalcitol dose and survival in hemodialysis patients: A marginal structural model analysis

Several observational studies have indicated that vitamin D receptor activators (VDRA), including paricalcitol, are associated with greater survival in maintenance hemodialysis (MHD) patients. However, patients with higher serum parathyroid hormone, a surrogate of higher death risk, are usually given higher VDRA doses, which can lead to confounding by indication and attenuate the expected survival advantage of high VDRA doses.

Maternal infections during pregnancy and cerebral palsy: a population-based cohort study.

BACKGROUND Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child. METHODS Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models. RESULTS Of the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester. CONCLUSION Genito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP.

Risk of Cerebral Palsy and Childhood Epilepsy Related to Infections before or during Pregnancy

Background and Aim Maternal infections during pregnancy have been associated with several neurological disorders in the offspring. However, given the lack of specificity for both the exposures and the outcomes, other factors related to infection such as impaired maternal immune function may be involved in the causal pathway. If impaired maternal immune function plays a role, we would expect infection before pregnancy to be associated with these neurological outcomes. Methods/Principal Findings The study population included all first-born singletons in Denmark between January 1 1982 and December 31 2004. We identified women who had hospital-recorded infections within the 5 year period before pregnancy, and women who had hospital-recorded infections during pregnancy. We grouped infections into either infections of the genitourinary system, or any other infections. Cox models were used to estimate adjusted hazard ratios (aHRs) with 95% confidence interval (CI). Maternal infection of the genitourinary system during pregnancy was associated with an increased risk of cerebral palsy (aHR = 1.63, 95% CI: 1.34–1.98) and epilepsy (aHR = 1.27, 95% CI: 1.13–1.42) in the children, compared to children of women without infections during pregnancy. Among women without hospital-recorded infections during pregnancy, maternal infection before pregnancy was associated with an increased risk of epilepsy (aHR = 1.35, 95% CI: 1.21–1.50 for infections of the genitourinary system, and HR = 1.12, 95% CI: 1.03–1.22 for any other infections) and a slightly higher risk of cerebral palsy (aHR = 1.20, 95% CI: 0.96–1.49 for infections of the genitourinary system, and HR = 1.23, 95% CI: 1.06–1.43 for any other infections) in the children, compared to children of women without infections before (and during) pregnancy. Conclusions These findings indicate that the maternal immune system, maternal infections, or factors related to maternal immune function play a role in the observed associations between maternal infections before pregnancy and cerebral diseases in the offspring.

Ethnic differences in arm vein diameter and arteriovenous fistula creation rates in men undergoing hemodialysis access

OBJECTIVE The National Kidney Foundation recommends that arteriovenous fistulas (AVFs) be placed in at least 65% of hemodialysis patients. Some studies suggest that African American patients are less likely to receive a first-time AVF than patients of other ethnicities, although the reason for this disparity is unclear. The purpose of our study is to determine (1) whether there are ethnic differences in AVF creation, (2) whether this may be related to differences in vein diameters, and (3) whether AVF patency rates are similar between African American and non-African American male patients. METHODS Consecutive male patients undergoing first-time hemodialysis access from 2006 to 2010 at two institutions were retrospectively reviewed. Data collected included age, ethnicity, weight, height, body mass index, diabetes, hypertension, congestive heart failure, smoking history, intravenous drug abuse, need for temporary access placement, and preoperative venous ultrasound measurements. Categoric variables were compared using χ(2) analysis, and the Wilcoxon rank-sum test was used to compare continuous variables. RESULTS Of 249 male patients identified, 95 were African American. Median age in African American and non-African American patients was 63 years. Hypertension and hyperlipidemia were statistically significantly greater in African American patients. The need for temporary access before hemoaccess was similar between the cohorts. African American patients demonstrated significantly smaller median basilic and cephalic vein diameters at most measured sites. Overall, 221 of 249 (88.8%) underwent AVF first. An AV graft was created in 17.9% of African American patients vs in only 7.1% of non-African Americans (odds ratio, 2.8; 95% confidence interval, 1.3-6.4; P = .009). The difference between median vein diameters used for autologous fistula creation in African American and non-African American patients was not significant. There was no significant difference in the primary patency (80.8% vs 76.2%; P = .4), primary functional patency (73.1% vs 69.2%; P = .5), or secondary functional patency rates (91.0% vs 96.5%; P = .1). Average primary fistula survival time was 257 days in African American and 256 in non-African American patients (P = .2). CONCLUSIONS African American patients are less likely than non-African American patients to undergo AVF during first-time hemodialysis access surgery. This ethnic discrepancy appears to be due to smaller arm vein diameters in African American patients. In African American patients with appropriate vein diameters who do undergo AVF, primary and functional patencies are equivalent to non-African American patients.