Francis Perry Wilson

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

IMPORTANCE Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD). OBJECTIVE To quantify the association between PPI use and incident CKD in a population-based cohort. DESIGN, SETTING, AND PARTICIPANTS In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System. EXPOSURES Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator. MAIN OUTCOMES AND MEASURES Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort. RESULTS Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21). CONCLUSIONS AND RELEVANCE Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Association between e-alert implementation for detection of acute kidney injury and outcomes: a systematic review

Background. Electronic alerts (e‐alerts) for acute kidney injury (AKI) in hospitalized patients are increasingly being implemented; however, their impact on outcomes remains uncertain. Methods. We performed a systematic review. Electronic databases and grey literature were searched for original studies published between 1990 and 2016. Randomized, quasi‐randomized, observational and before‐and‐after studies that included hospitalized patients, implemented e‐alerts for AKI and described their impact on one of care processes, patient‐centred outcomes or resource utilization measures were included. Results. Our search yielded six studies (n = 10 165 patients). E‐alerts were generally automated, triggered through electronic health records and not linked to clinical decision support. In pooled analysis, e‐alerts did not improve mortality [odds ratio (OR) 1.05; 95% confidence intervals (CI), 0.84‐1.31; n = 3 studies; n = 3425 patients; I2 = 0%] or reduce renal replacement therapy (RRT) use (OR 1.20; 95% CI, 0.91‐1.57; n = 2 studies; n = 3236 patients; I2 = 0%). Isolated studies reported improvements in selected care processes. Pooled analysis found no significant differences in prescribed fluid therapy. Conclusions. In the available studies, e‐alerts for AKI do not improve survival or reduce RRT utilization. The impact of e‐alerts on processes of care was variable. Additional research is needed to understand those aspects of e‐alerts that are most likely to improve care processes and outcomes.

Clinical Implications of Cluster Analysis-Based Classification of Acute Decompensated Heart Failure and Correlation with Bedside Hemodynamic Profiles

Background Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies. Objective To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside. Methods We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data. Results We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1–3 had 45–70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not. Conclusions By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous considerations of etiology, comorbid conditions, and biomarker levels, may be superior to bedside classifications.

Impact of e-alert for detection of acute kidney injury on processes of care and outcomes: protocol for a systematic review and meta-analysis

Introduction Acute kidney injury (AKI) is a common complication in hospitalised patients. It imposes significant risk for major morbidity and mortality. Moreover, patients suffering an episode of AKI consume considerable health resources. Recently, a number of studies have evaluated the implementation of automated electronic alerts (e-alerts) configured from electronic medical records (EMR) and clinical information systems (CIS) to warn healthcare providers of early or impending AKI in hospitalised patients. The impact of e-alerts on care processes, patient outcomes and health resource use, however, remains uncertain. Methods and analysis We will perform a systematic review to describe and appraise e-alerts for AKI, and evaluate their impact on processes of care, clinical outcomes and health services use. In consultation with a research librarian, a search strategy will be developed and electronic databases (ie, MEDLINE, EMBASE, CINAHL, Cochrane Library and Inspec via Engineering Village) searched. Selected grey literature sources will also be searched. Search themes will focus on e-alerts and AKI. Citation screening, selection, quality assessment and data abstraction will be performed in duplicate. The primary analysis will be narrative; however, where feasible, pooled analysis will be performed. Each e-alert will be described according to trigger, type of alert, target recipient and degree of intrusiveness. Pooled effect estimates will be described, where applicable. Ethics and dissemination Our systematic review will synthesise the literature on the value of e-alerts to detect AKI, and their impact on processes, patient-centred outcomes and resource use, and also identify key knowledge gaps and barriers to implementation. This is a fundamental step in a broader research programme aimed to understand the ideal structure of e-alerts, target population and methods for implementation, to derive benefit. Research ethics approval is not required for this review. Systematic review registration number CRD42016033033.

Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

Pharmacologic Treatment of Common Symptoms in Dialysis Patients: A Narrative Review.

End‐stage renal disease (ESRD) patients receiving hemodialysis experience a heavy burden of disease‐related symptoms, which lead to reduced quality of life. This review focuses on aspects of ESRD‐related pharmacokinetics and on efficacy of drugs for treatment of somatic symptoms. Fatigue, pruritus, insomnia, and cramps are the most common symptoms in ESRD, and studies suggest that they are often undertreated. However, few evidence‐based guidelines exist to guide therapy in patients received dialysis. In the context of this review, we examine the role of l‐Carnitine in the treatment of fatigue and cramps; human growth hormone analog Norditropin and anabolic steroid Nandrolone for the treatment of fatigue; Gabapentin and other agents for the management of pruritis; Vitamin and creatine supplementation in the management of dialysis‐associated cramps, and somnambulates in the treatment of dialysis‐related insomnia. Treatment decisions should be made in consultation with patients with a full accounting of the potential risks and benefits of these therapies.

ASSOCIATION OF ALTERNATIVE APPROACHES TO NORMALIZING PERITONEAL DIALYSIS CLEARANCE WITH MORTALITY AND TECHNIQUE FAILURE: A RETROSPECTIVE ANALYSIS USING THE UNITED STATES RENAL DATA SYSTEM-DIALYSIS MORBIDITY AND MORTALITY STUDY, WAVE 2.

♦ Background: Total body water (V) is an imprecise metric for normalization of dialytic urea clearance (Kt). This poses a risk of early mortality/technique failure (TF). We examined differences in the distribution of peritoneal Kt/V when V was calculated with actual weight (AW), ideal weight (IW), and adjusted weight (ADW). We also examined the associations of these Kt/V measurements, Kt/body surface area (BSA), and non-normalized Kt with mortality and TF. ♦ Methods: This is a retrospective cohort study of 534 incident peritoneal dialysis (PD) patients from the Dialysis Morbidity and Mortality Study Wave 2 linked with United States Renal Data System through 2010. Using Cox-proportional hazard models, we examined the relationship of several normalization strategies for peritoneal urea clearance, including Kt/VAW, Kt/VIW, Kt/VADW, Kt/BSA, and non-normalized Kt, with the outcomes of mortality and TF. Harrells c-statistics were used to assess the relative predictive ability of clearance metrics for mortality and TF. The distributions of Kt/VAW, KT/VIW, and KT/VADW were compared within and between body mass index (BMI) strata. ♦ Results: Median patient age: 59 (54% male; 72% white; 91% continuous ambulatory PD [CAPD]). Median 24-hour urine volume: 700 mL; median estimated glomerular filtration rate (eGFR) at initiation: 7.15 mL/min/1.73 m2. Technique failure and transplant-censored mortality at 5 years: 37%. Death and transplant-censored TF at 5 years: 60%. There were no significant differences in initial eGFR and 24-hour urine volume across BMI strata. There were statistically significant differences in each Kt/V calculation within the underweight, overweight, and obese strata. After adjustment, there were no significant differences in the hazard ratios (HRs) for TF/mortality for each clearance calculation. Harrells c-statistics for mortality for each clearance calculation were 0.78, and for TF, 0.60 – 0.61. ♦ Conclusions: Peritoneal urea clearances are sensitive to subtle changes in the estimation of V. However, there were no detectable significant associations of Kt/VAW, Kt/VIW, Kt/VADW, Kt/BSA, or Kt with TF or mortality.

Evaluating biomarkers for prognostic enrichment of clinical trials

Background/Aims: A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment. Methods: We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria. Items (1)–(3) are amenable to quantitative analysis. We developed the Biomarker Prognostic Enrichment Tool for evaluating biomarkers for prognostic enrichment at varying levels of screening stringency. Results: We demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics using Biomarker Prognostic Enrichment Tool. Biomarker Prognostic Enrichment Tool is available as a webtool at http://prognosticenrichment.com and as a package for the R statistical computing platform. Conclusion: In some clinical settings, even biomarkers with modest prognostic performance can be useful for prognostic enrichment. In addition to the quantitative analysis provided by Biomarker Prognostic Enrichment Tool, investigators must consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria.