by
Steven M. Smith;
Yan Gong;
Stephen T. Turner;
Rhonda M. Cooper-DeHoff;
Amber L. Beitelshees;
Arlene B Chapman;
Eric Boerwinkle;
Kent Bailey;
Julie A. Johnson;
John G. Gums
Background: Thiazides and Β-blockers cause adverse metabolic effects (AMEs), but whether these effects share predictors with blood pressure (BP) response is unknown. We aimed to determine whether AMEs are correlated with BP response in uncomplicated hypertensives.
Methods: In a multicenter, open-label, parallel-group trial, we enrolled 569 persons, aged 17-65, with random assignment to 9 weeks of daily hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by 9 weeks of add-on therapy with the alternate agent. Measurements included home BP, averaged over 1 week, weight and fasting levels of serum glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and uric acid (UA) before and after monotherapy and after add-on therapy.
Results: Increases in UA correlated with reductions in systolic BP (SBP) (r = 0.18; P = 0.003) and diastolic BP (DBP) (r = 0.20; P = 0.001) following HCTZ monotherapy and add-on therapy (r = 0.27 and r = 0.21, respectively; both P< 0.001). After adjustment for age, race, gender, and baseline body mass index (BMI), only the correlation between UA and DBP response became nonsignificant. Reductions in HDL correlated with systolic response following atenolol monotherapy (r = 0.18; P = 0.002) and with systolic and diastolic response following add-on therapy (r = 0.30 and r = 0.24, respectively; both P< 0.0001). These correlations remained significant after covariate adjustment. BP responses were not correlated with changes in glucose, LDL, triglycerides, or weight following either therapy.
Conclusions: BP response correlated with changes in UA following HCTZ therapy and HDL following atenolol therapy. No other significant correlations were observed between BP response and AMEs, suggesting that these effects generally do not share predictors. Patients should be monitored for AMEs, regardless of BP response.
Belatacept is used to prevent allograft rejection but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. In this study, we report control of costimulation-resistant rejection when belatacept was combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin. To assess the means by which the alemtuzumab, belatacept and rapamycin (ABR) regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients and characterized peripheral lymphocyte phenotype and functional responses to donor, third-party and viral antigens using flow cytometry, intracellular cytokine staining and carboxyfluorescein succinimidyl ester-based lymphocyte proliferation. Compared with conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28+ naïve cells, notably diminished in belatacept-resistant CD28- memory subsets and depleted of polyfunctional donor-specific T cells but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development and a reduction in memory subsets - changes not seen in conventionally treated patients. The ABR regimen uniquely altered the immune profile, producing a repertoire enriched for CD28+ T cells, hyporesponsive to donor alloantigen and competent in its protective immune capabilities. The resulting repertoire was permissive for control of rejection with belatacept monotherapy.
To the Editor—In their article, “Inappropriate intravenous antimicrobial starts: An antimicrobial stewardship metric for hemodialysis facilities,” Hahn et al1 describe their application of data reported to CDC’s National Healthcare Safety Network (NHSN) to determine appropriateness of IV antibiotic use in outpatient hemodialysis centers. NHSN’s Dialysis Event (DE) surveillance system was designed to track bloodstream infections (BSIs) and other vascular access infections in hemodialysis outpatients through monitoring of events such as positive blood cultures. The authors examined outpatient IV antimicrobial start (IVAS) events reported to NHSN and considered any IVAS without documentation of coreported positive blood culture, collection of blood sample for culture, or local access site infection to be inappropriate, even when symptoms such as fever, chills, rigors, or drop in blood pressure were present. We applaud these investigators for drawing necessary attention to the issue of antibiotic use in dialysis patients, which is an important area of study with limited data, and for exploring the use of data to inform improvement in practice. However, we have concerns about their approach to the categorization of antibiotic use without incorporation of relevant clinical information or validation of NHSN data for this purpose, and the potential for unintended consequences among patients at high risk for infections and sepsis.
by
Dipak Panigrahy;
Allison Gartung;
Jun Yang;
Haixia Yang;
Molly M. Gilligan;
ML Sulciner;
Swati Bhasin;
Diane R. Bielenberg;
Jaimie Chang;
Birgitta A. Schmidt;
Julia Piwowarski;
Anna Fishbein;
Dulce Soler-Ferran;
Matthew A. Sparks;
Steven J. Staffa;
Bruce D. Hammock;
Mark W. Kieran;
Sui Huang;
Manoj Bhasin;
Charles N. Serhan;
Vikas Sukhatme
Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.
by
Mireille El Ters;
Pengcheng Lu;
Jonathan D. Mahnken;
Jason R. Stubbs;
Shiqin Zhang;
Darren P. Wallace;
Jared J. Grantham;
Arlene Chapman;
Vicente Torres;
Peter C. Harris;
Kyongtae Bae;
Douglas P. Landsittel;
Frederic Rahbari Oskoui;
Michal Mrug;
William M. Bennett;
Alan S. L. Yu
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder.
Methods
We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine.
Results
Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of −1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03).
Conclusion
FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers.
Introduction: Patients with IgA nephropathy (IgAN) and persistent proteinuria are at risk of progression to kidney failure. Atacicept is a novel B-cell–targeted immunomodulator, shown to reduce immunoglobulin levels in patients with autoimmune diseases. Methods: JANUS (NCT02808429) was a phase II study that assessed the safety, pharmacodynamic effects, and efficacy of atacicept in patients with IgAN and proteinuria ≥1 g/d or 0.75 mg/mg on 24-hour UPCR despite maximal standard of care therapy. Results: A total of 16 patients were randomized 1:1:1 to placebo (n = 5), atacicept 25 mg (n = 6), or atacicept 75 mg (n = 5) once weekly using subcutaneous injection. Twelve (75%) completed ≥48 weeks of treatment; 8 (50%) completed 72 weeks of treatment and the 24-week safety follow-up period. Fourteen patients reported treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate in severity. Three patients (placebo n = 1; atacicept 25 mg n = 2) reported serious TEAEs, none of which were treatment related. Dose-dependent reductions in IgA, IgG, IgM, and galactose-deficient (Gd)-IgA1 with atacicept at week 24 were maintained to week 72. Early reduction in proteinuria was observed at week 24 with atacicept. Renal function progressively declined with placebo but remained stable under exposure to atacicept. Conclusion: Atacicept has an acceptable safety profile in patients with IgAN and is effective at reducing the levels of pathogenic factor Gd-IgA1, with potential improvements in proteinuria and renal function.
by
Reem E. Hamoda;
Jennifer C. Gander;
Laura J. McPherson;
Kimberly J. Arriola;
Loren Cobb;
Stephen Pastan;
Laura Plantinga;
Teri Browne;
Erica Hartmann;
Laura Mulloy;
Carlos Zayas;
Jenna Krisher;
Rachel Elizabeth Patzer
Background: The Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT) was an End-Stage Renal Disease (ESRD) Network 6-developed, dialysis facility-level randomized trial testing the effectiveness of a 1-year multicomponent education and quality improvement intervention in increasing referral for kidney transplant evaluation among selected Georgia dialysis facilities. Methods: To assess implementation of the RaDIANT intervention, we conducted a process evaluation at the conclusion of the intervention period (January-December 2014). We administered a 20-item survey to the staff involved with transplant education in 67 dialysis facilities randomized to participate in intervention activities. Survey items assessed facility participation in the intervention (fidelity and reach), helpfulness and willingness to continue intervention activities (sustainability), suggestions for improving intervention components (sustainability), and factors that may have influenced participation and study outcomes (context). We defined high fidelity to the intervention as completing 11 or more activities, and high participation in an activity as having at least 75% participation across intervention facilities. Results: Staff from 65 of the 67 dialysis facilities completed the questionnaire, and more than half (50.8%) reported high adherence (fidelity) to RaDIANT intervention requirements. Nearly two-thirds (63.1%) of facilities reported that RaDIANT intervention activities were helpful or very helpful, with 90.8% of facilities willing to continue at least one intervention component beyond the study period. Intervention components with high participation emphasized staff and patient-level education, including in-service staff orientations, patient and family education programs, and patient educational materials. Suggested improvements for intervention activities emphasized addressing financial barriers to transplantation, with financial education materials perceived as most helpful among RaDIANT educational materials. Variation in facility-level fidelity of the RADIANT intervention did not significantly influence the mean difference in proportion of patients referred pre- (2013) and post-intervention (2014). Conclusions: We found high fidelity to the RaDIANT multicomponent intervention at the majority of intervention facilities, with sustainability of select intervention components at intervention facilities and feasibility for dissemination across ESRD Networks. Future modification of the intervention should emphasize financial education regarding kidney transplantation and amend intervention components that facilities perceive as time-intensive or non-sustainable. Trial registration: Clinicaltrials.gov number NCT02092727. Registered 13 Mar 2014 (retrospectively registered).
In the 1960s, Vallbo and Hagbarth established the microneurography technique in which nerve impulses are recorded directly from a peripheral nerve from conscious humans in real-time (Vallbo, 2018). Microneurography has since had a tremendous impact on the field of integrative neurophysiology, enabling a wide array of studies interrogating the function of sensory afferent nerves, and efferent sympathetic nerves directed to muscle (MSNA) and skin (SSNA). In particular, microneurography of sympathetic nerves has advanced our understanding of the neural control of the circulation in both healthy and diseased populations. It has been used to examine sympathetic nervous system (SNS) regulation by control mechanisms such as baroreflexes, SNS reactivity to stress, the exercise pressor reflex, mechanisms underlying SNS overactivation in chronic disease, prognostic value of MSNA, and sex and race differences in SNS regulation to name a few examples. Importantly, microneurography has added valuable information to clinical trials testing the impact of targeted pharmacologic and nonpharmacologic interventions on SNS function in patient populations.
Variability in transplant rates between different dialysis units has been noted, yet little is known about facility-level factors associated with low standardized transplant ratios (STRs) across the United States End-stage Renal Disease (ESRD) Network regions. We analyzed Centers for Medicare & Medicaid Services Dialysis Facility Report data from 2007 to 2010 to examine facility-level factors associated with low STRs using multivariable mixed models. Among 4098 dialysis facilities treating 305 698 patients, there was wide variability in facility-level STRs across the 18 ESRD Networks. Four-year average STRs ranged from 0.69 (95% confidence interval [CI]: 0.64-0.73) in Network 6 (Southeastern Kidney Council) to 1.61 (95% CI: 1.47-1.76) in Network 1 (New England). Factors significantly associated with a lower STR (p-<-0.0001) included for-profit status, facilities with higher percentage black patients, patients with no health insurance and patients with diabetes. A greater number of facility staff, more transplant centers per 10 000 ESRD patients and a higher percentage of patients who were employed or utilized peritoneal dialysis were associated with higher STRs. The lowest performing dialysis facilities were in the Southeastern United States. Understanding the modifiable facility-level factors associated with low transplant rates may inform interventions to improve access to transplantation. Standardized transplant ratios vary widely among the more than 4,000 dialysis facilities in the United States, and facilities with the lowest rates are located in the Southeast. Also see viewpoint by Patzer and Pastan (page 1499) and counterpoint by Srinivas (page 1506).
Background: The Southeastern United States has the lowest kidney transplant rates in the nation, and racial disparities in kidney transplant access are concentrated in this region. The Southeastern Kidney Transplant Coalition (SEKTC) of Georgia, North Carolina, and South Carolina is an academic and community partnership that was formed with the mission to improve access to kidney transplantation and reduce disparities among African American (AA) end stage renal disease (ESRD) patients in the Southeastern United States.
Methods/Design: We describe the community-based participatory research (CBPR) process utilized in planning the Reducing Disparities In Access to kidNey Transplantation (RaDIANT) Community Study, a trial developed by the SEKTC to reduce health disparities in access to kidney transplantation among AA ESRD patients in Georgia, the state with the lowest kidney transplant rates in the nation. The SEKTC Coalition conducted a needs assessment of the ESRD population in the Southeast and used results to develop a multicomponent, dialysis facility-randomized, quality improvement intervention to improve transplant access among dialysis facilities in GA. A total of 134 dialysis facilities are randomized to receive either: (1) standard of care or "usual" transplant education, or (2) the multicomponent intervention consisting of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients within dialysis facilities. The primary outcome is change in facility-level referral for kidney transplantation from baseline to 12 months; the secondary outcome is reduction in racial disparity in transplant referral.
Discussion: The RaDIANT Community Study aims to improve equity in access to kidney transplantation for ESRD patients in the Southeast.