A randomized controlled trial of efficacy and safety of Fecal Microbiota Transplant for preventing recurrent Clostridioides difficile infection.

BACKGROUND: Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated infections in US hospitals with 15%-30% of patients experiencing recurrence. The aim of our randomized, double-blind clinical trial was to assess the efficacy of capsule-delivered fecal microbiota transplantation (FMT) versus placebo in reducing recurrent diarrhea and CDI recurrence. The secondary aim was FMT safety assessment. METHODS: Between 2018 and 2022, Veterans across the Veterans Health Administration system with recurrent CDI who responded to antibiotic treatment were randomized in a 1:1 ratio to oral FMT or placebo capsules. Randomization was stratified by number of prior CDI recurrences (1 or ≥2). The primary endpoint was clinical recurrence by day 56, defined as >3 unformed stools daily for ≥2 days with or without laboratory confirmation of C. difficile, or death within 56 days. RESULTS: The study was stopped due to futility after meeting pre-specified criteria. Of 153 participants (76 FMT, 77 placebo) with an average age of 66.5 years, 25 participants (32.9%) in the FMT arm and 23 (29.9%) in the placebo arm experienced the primary endpoint of diarrhea and possible or definite CDI recurrence or death within 56 days of capsule administration (absolute difference 3.0%; 95% CI [-11.7%, 17.7%]). Stratification by number of recurrences revealed no statistically significant differences. There were no clinically important differences in adverse events. CONCLUSIONS: FMT therapy vs. placebo did not reduce CDI recurrence or death at 56 days. There were no meaningful differences in adverse events between treatment groups.

Microbiota or placebo after antimicrobial therapy for recurrent Clostridioides difficile at home: A clinical trial with novel home-based enrollment.

INTRODUCTION: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant's home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. METHODS: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. RESULTS: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. DISCUSSION: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial.

BACKGROUND/AIMS: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials.

Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury.

BACKGROUND: Assessment of adequacy of intermittent hemodialysis (IHD) is conventionally based upon urea kinetic models for calculation of single pool Kt/Vurea (Kt/V), with 1.2 accepted as minimum adequate clearance for thrice weekly IHD. In the Acute Renal Failure Trial Network (ATN) Study, adequacy of IHD in patients with acute kidney injury (AKI) was assessed using Kt/V. However, equations for Kt/V require volume of distribution of urea, which is highly variable in AKI. Therefore, simpler methods are needed to assess adequacy of IHD in AKI. We assessed correlation of urea reduction ratio (URR) with Kt/V and determined URR thresholds corresponding to Kt/V values to determine if URR could be a simpler means to assess the delivered dose of IHD. METHODS: Using patients who received IHD for 2.5-6 h and with pre-dialysis BUN ≥20 mg/dL, we plotted URR against Kt/V. We determined URR thresholds (0.60 to 0.75) corresponding to Kt/V ≥ 1.2, 1.3, and 1.4. We generated receiver operating characteristic (ROC) curves for increasing URR values for each level of Kt/V to identify the corresponding thresholds of URR. RESULTS: There was strong correlation between URR and Kt/V. ROC curves comparing URR with Kt/V ≥ 1.2, 1.3, and 1.4 had area under the curves (AUC) of 0.99. Sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.2 were 0.769 (95% CI: 0.745 to 0.793) and 0.999 (95% CI: 0.997 to 1.000), respectively and the sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.4 were 0.998 (95% CI: 0.995 to 1.000) and 0.791 (95% CI: 0.771 to 0.811), respectively. CONCLUSIONS: Targeting a URR ≥0.67 provides a simplified means of assessing adequacy of IHD in patients with AKI. Use of URR will enhance ability to assess delivery of small solute clearance and improve adherence with clinical practice guidelines in AKI.

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Long-term persistence of zoster vaccine efficacy.

BACKGROUND: The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. METHODS: Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. RESULTS: The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. CONCLUSIONS: Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.

Safety of zoster vaccine in elderly adults following documented herpes zoster.

BACKGROUND: After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). METHODS: A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. RESULTS: The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed ≥ 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. CONCLUSIONS: These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons ≥ 60 years of age with no contraindications, regardless of a prior history of HZ.

Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications.

BACKGROUND: The Depression Substudy of the Shingles Prevention Study (SPS) was designed to evaluate the association between major depression and immune responses to a high-titer live attenuated varicella zoster virus (VZV) vaccine (zoster vaccine), which boosts cell-mediated immunity (CMI) to VZV and decreases the incidence and severity of herpes zoster (HZ). The Depression Substudy was a 2-year longitudinal cohort study in 92 community-dwelling adults≥60 years of age who were enrolled in the SPS, a large, double-blind, placebo-controlled Veterans Affairs Cooperative zoster vaccine efficacy study. METHODS: Forty subjects with major depressive disorder, stratified by use of antidepressant medications, and 52 age- and sex-matched controls with no history of depression or other mental illness had their VZV-CMI measured prior to vaccination with zoster vaccine or placebo and at 6 weeks, 1 year, and 2 years postvaccination. RESULTS: Depressed subjects who were not treated with antidepressant medications had lower levels of VZV-CMI following administration of zoster vaccine than nondepressed controls or depressed subjects receiving antidepressants even when antidepressant medications failed to alter depressive symptom severity (P<.005). Similar results were obtained taking into account the time-varying status of depression and use of antidepressant medications, as well as changes in depressive symptoms, during the postvaccination period. CONCLUSIONS: Depressed patients have diminished VZV-CMI responses to zoster vaccine, and treatment with antidepressant medication is associated with normalization of these responses. Because higher levels of VZV-CMI correlate with lower risk and severity of HZ, untreated depression may increase the risk and severity of HZ and reduce the efficacy of zoster vaccine.

25-OHD response to vitamin D supplementation in children: effect of dose but not GC haplotype.

OBJECTIVE: GC/DBP effects on response to vitamin D supplementation have not been well-studied. Thus we assessed free and total 25-OHD after vitamin D treatment across the six common GC haplotypes. DESIGN: This double-blind, randomized study compared two vitamin D3 doses in healthy, urban-dwelling 6-month to 10-year-old children at-risk for vitamin D deficiency. Randomization was stratified by GC haplotype. METHODS: Children were randomized to receive 2800 or 7000 International Units of vitamin D3 weekly. 25-OHD and 1,25(OH)2D were sampled at baseline and after 1-6 months of supplementation. RESULTS AND CONCLUSIONS: One hundred ninety-two of 225 enrolled subjects completed the study. After one month, total 25-OHD increased with both doses and were higher with 7000 IU/week (85.5 ± 22.8 nmol/L) compared to 2800 IU/week (76.8 ± 18.0 nmol/L), despite equivalent baseline levels. No further significant increase occurred at 6 months (89.8 ± 35.5 and 74.3 ± 18.3 nmol/L, respectively). Free 25-OHD similarly changed. 25-OHD differed among GC groups at baseline. Although no significant effects of individual GC haplotypes on incremental changes were evident, a trend toward an effect of combined 'at risk' GC alleles on response was evident (P = 0.06). Total 1,25(OH)2D showed modest increases, moreso with the larger dose. In urban-dwelling children at-risk for vitamin D deficiency, 1 month of vitamin D3 2800 IU/week increased 25-OHD across all GC haplotype groups, and somewhat enhanced with 7000 IU/week with no further significant increases after 6 months of supplementation. Free 25-OHD measures offer no monitoring advantage over total 25-OHD.

Relationship of Total and Free 25-Hydroxyvitamin D to Biomarkers and Metabolic Indices in Healthy Children.

CONTEXT: Vitamin D status is usually assessed by serum total 25-hydroxyvitamin D (t25-OHD). Whether free 25-hydroxyvitamin D measures better correlate with various clinical outcomes is unclear. OBJECTIVE: To identify correlations between t25-OHD, calculated and direct measures of free 25-OHD, and to identify associations of these measures with other outcomes in children, across the 6 common GC haplotypes. DESIGN: Healthy urban-dwelling children underwent measurement of relevant variables. SETTING: Academic medical center. PARTICIPANTS: The study included 203 healthy, urban-dwelling children, aged 6 months to 10 years, predominantly of Hispanic background and representative of all common GC haplotypes. INTERVENTION: None. MAIN OUTCOME MEASURES: Total and free 25-OHD and 1,25(OH)2D, calcium, phosphate, parathyroid hormone (PTH), glucose, insulin, aldosterone, and renin. RESULTS: Mean t25-OHD [26.3 ±â€…6.7ng/ml; 65.8 ±â€…16.8nmol/L] were lowest in the GC2 genotype. Mean t1,25(OH)2D [57.6 ±â€…16.5pg/ml; 143.9 ±â€…41.3pmol/L], were lowest in GC1f/1f, GC1f/2, and GC2/2 groups. T25-OHD correlated strongly with calculated free 25-OHD (cf25-OHD) (r = 0.89) and moderately with directly measured free 25-OHD (dmf25-OHD) (r = 0.69). Cf25-OHD correlated with dmf25-OHD (r = 0.69) (P < 0.001 for all). t25-OHD inversely correlated with body mass index (BMI) (r=-0.191; P = 0.006), skin reflectometry, and systolic blood pressure. T25-OHD correlated with fasting insulin and the homeostatic model assessment for insulin resistance (HOMA-IR), however significance for these correlations was not evident after adjustment for BMI. PTH inversely correlated with all measures of 25-OHD, but most strongly with t25-OHD. CONCLUSIONS: Measures of circulating total and free 25-OHD are comparable measures of vitamin D status in heathy children. Correlations are similar with other outcome variables, however t25-OHD remains the strongest correlate of circulating PTH and other variables. These data argue against routine refinement of the t25-OHD measure using currently available assessments of free 25-OHD. CLINICAL TRIAL INFORMATION: Clinicaltrials.gov registration no: NCT01050387 (January 15, 2010).

Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade.

BACKGROUND AND OBJECTIVES: The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m2, and urinary albumin excretion of at least 300 µg/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. RESULTS: The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98). CONCLUSIONS: Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Association between serum 25-hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis.

OBJECTIVE: To identify effects of vitamin D status, as defined by circulating 25-hydroxyvitamin D (25-OHD) levels on the annual frequency of pulmonary exacerbations (Pex) and hospitalizations, on standard measures of pulmonary function, and to identify determinants of 25-OHD levels in pediatric patients with cystic fibrosis (CF). HYPOTHESIS: Higher levels of serum 25-OHD would be associated with fewer Pex and hospitalizations, and improved lung function based on pulmonary function tests (PFTs). STUDY DESIGN: Retrospective chart review of 53 pediatric patients from January 2011 to December 2011. Significant relationships were examined using linear and logistic regression analyses. PATIENT SELECTION: Patients ages 5 through 22 years followed at the CF Care Center and Clinic at Yale-New Haven Hospital, New Haven, CT., who had at least four clinic visits and at least one 25-OHD measurement between January 1, 2011 and December 31, 2011. RESULTS: Serum 25-OHD level and gender were strong independent determinants of the annual number of Pex (P < 0.01, with lower 25-OHD level and female gender associated with Pex). There was a significant influence of gender (P < 0.05) and a near-significant influence of serum 25-OHD (P < 0.08) on hospitalization rate. There was no effect of 25-OHD levels on PFTs. Other candidate factors (age, season, gender, pancreatic sufficiency, or severity of genetic mutation) did not significantly effect 25-OHD level. CONCLUSIONS: The annual number of Pex in pediatric CF patients is significantly associated with 25-OHD levels and gender, raising the consideration that maintaining vitamin D sufficiency may lead to decreased incidence of Pex and hospitalizations requiring antibiotic therapy.

BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial.

BACKGROUND AND OBJECTIVES: Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured. RESULTS: The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events. CONCLUSIONS: In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes.

Modeling the durability of ZOSTAVAX® vaccine efficacy in people ≥60 years of age.

Since 2006, the vaccine, ZOSTAVAX(®), has been licensed to prevent herpes zoster. Only limited clinical follow-up data are available to evaluate duration of protection, an important consideration when developing HZ vaccination policy recommendations. Four Poisson regression models were developed based on an integrated analysis of data from the Shingles Prevention Study and its Short Term Persistence extension to estimate the effects of years-since-vaccination and chronological-age on vaccine efficacy among people ≥60 years old. The models included number of HZ cases parsed into categories by chronological-age and time-since-vaccination as the dependent variable with different explanatory variables in each model. In all models, the interaction between vaccine-group and chronological-age was statistically significant indicating that vaccine efficacy decreases with the expected effects of advancing age but the interaction between vaccine-group and time-since-vaccination was not statistically significant indicating that much of the reduction in vaccine efficacy over time-since-vaccination can be explained by increasing age.

Conventional Therapy in Adults With X-Linked Hypophosphatemia: Effects on Enthesopathy and Dental Disease.

CONTEXT: Treatment of X-linked hypophosphatemia (XLH) with active vitamin D metabolites and phosphate can partially correct skeletal deformities. It is unclear whether therapy influences the occurrence of two major long-term morbidities in XLH: enthesopathy and dental disease. OBJECTIVE: The objective of the study was to investigate the relationship between treatment and enthesopathy and dental disease in adult XLH patients. DESIGN: The study was designed as observational and cross-sectional. SETTING: The study was conducted at an academic medical center's hospital research unit. PARTICIPANTS: Fifty-two XLH patients aged 18 years or older at the time of the study participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The number of enthesopathy sites identified by radiographic skeletal survey and dental disease severity (more than five or five or fewer dental abscesses), identified historically, were measured. METHODS: Associations between proportion of adult life and total life with treatment and number of enthesopathy sites were assessed using multiple linear regression, whereas associations between these exposure variables and dental disease severity were assessed using multiple logistic regression. All models were adjusted for confounding factors. RESULTS: Neither proportion of adult nor total life with treatment was a significant predictor of extent of enthesopathy. In contrast, both of these treatment variables were significant predictors of dental disease severity (multivariate-adjusted global P = .0080 and P = .0010, respectively). Participants treated 0% of adulthood were more likely to have severe dental disease than those treated 100% of adulthood (adjusted odds ratio 25 [95% confidence interval 1.2-520]). As the proportion of adult life with treatment increased, the odds of having severe dental disease decreased (multivariate-adjusted P for trend = .015). CONCLUSIONS: Treatment in adulthood may not promote or prevent enthesopathy; however, it may be associated with a lower risk of experiencing severe dental disease.

Effect of paricalcitol on circulating parathyroid hormone in X-linked hypophosphatemia: a randomized, double-blind, placebo-controlled study.

CONTEXT: Hyperparathyroidism occurs frequently in X-linked hypophosphatemia (XLH) and may exacerbate phosphaturia, potentially affecting skeletal abnormalities. OBJECTIVE: The objective of the study was to suppress elevated PTH levels in XLH patients. DESIGN: This was a prospective, randomized, placebo-controlled, double-blind, 1-year trial of paricalcitol, with outcomes measured at entry and 1 year later. SETTING: PATIENTS were recruited from the investigators' clinics or referred from throughout the United States. Data were collected in an in-patient hospital research unit. PATIENTS: Subjects with a clinical diagnosis of XLH and hyperparathyroidism were offered participation and were eligible if they were 9 years old or older and not pregnant, and their serum calcium level was less than 10.7 mg/dL, their 25-hydroxyvitamin D level was 20 ng/mL or greater, and their creatinine level was 1.5 mg/dL or less. INTERVENTION: The intervention for this study was the use of paricalcitol or placebo for 1 year. MAIN OUTCOME MEASURES: Determined prior to trial onset was the change in PTH area under the curve. Secondary outcomes included renal phosphate threshold per glomerular filtration rate, serum phosphorus, serum alkaline phosphatase activity, and (99m)Tc-methylenediphosphonate bone scans. RESULTS: PTH area under the curve decreased 17% with paricalcitol, differing (P = .007) from the 20% increase with placebo. The renal phosphate threshold per glomerular filtration rate increased 17% with paricalcitol and decreased 21% with placebo (P = .05). Serum phosphorus increased 12% with paricalcitol but did not differ from placebo. Paricalcitol decreased alkaline phosphatase activity in adults by 21% (no change with placebo, P = .04). Bone scans improved in 6 of 17 paricalcitol subjects, whereas no placebo-treated subject improved. Hypercalciuria developed in six paricalcitol subjects and persisted from baseline in one placebo subject. CONCLUSIONS: Suppression of PTH may be a useful strategy for skeletal improvement in XLH patients with hyperparathyroidism, and paricalcitol appears to be an effective adjunct to standard therapy in this setting. Although paricalcitol was well tolerated, urinary calcium and serum calcium and creatinine should be monitored closely with its use.

Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy.

Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy.

Piecewise analysis of patient survival after onset of AKI.

BACKGROUND AND OBJECTIVES: AKI affects approximately 2%-7% of hospitalized patients and >35% of critically ill patients. Survival after AKI may be described as having an acute phase (including an initial hyperacute component) followed by a convalescent phase, which may itself have early and late components. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study was used to model mortality risk among patients with dialysis-requiring AKI. This study assumed that the mortality hazard can be described by a piecewise log-linear function with change points. Using an average likelihood method, the authors tested for the number of change points in a piecewise log-linear hazard model. The maximum likelihood approach to locate the change point(s) was then adopted, and associated parameters and standard errors were estimated. RESULTS: There were 1124 ATN participants with follow-up to 1 year. The mortality hazard of AKI decreased over time with inflections in the rate of decrease at days 4, 42, and 148, with the sharpest change at day 42. The daily rate of decline in the log of the hazard for death was 0.220 over the first 4 days, 0.046 between day 4 and day 42, 0.017 between day 42 and day 148, and 0.003 between day 148 and day 365. CONCLUSIONS: There appear to be two major phases of mortality risk after AKI: an early phase extending over the first 6 weeks and a late phase from 6 weeks to 1 year. Within the first 42 days, this can be further divided into hyperacute (days 1-4) and acute (days 4-42) phases. After 42 days, there appear to be early (days 42-148) and late (after day 148) convalescent phases. These findings may help to inform the design of AKI clinical trials and assist critical care physicians in prognostic stratification.

Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers.

Circulating 25-hydroxyvitamin D (25-OHD) levels vary among human populations. Only limited information regarding determinants of these measures is available for infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25-OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25-OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self-reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25-OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self-reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25-OHD. GC SNPs were associated with both circulating DBP and 25-OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25-OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25-OHD. Moreover, the effect of GC SNPs on 25-OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD. However, the GC genotype also affects circulating 25-OHD independently of its effect on circulating DBP. These findings provide data that may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds.