Background/Objective
Vitamin D has anti-inflammatory and immune-regulating properties. We aimed to determine if high-dose cholecalciferol supplementation for 1 yr in subjects with early CKD improved circulating markers of inflammation and immunity.
Subjects/Methods
In this double-blind, randomized, placebo-controlled trial, 46 subjects with early CKD (Stage 2–3) were supplemented with oral cholecalciferol (50 000 IU weekly for 12 weeks followed by 50 000 IU every other wk for 40 wks) or a matching placebo for 1 yr. Serum tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein-10, and neutrophil gelatinase-associated lipocalin were measured at baseline, 12 wks, and 1 yr. Serum cathelicidin (LL-37) was measured at baseline and 12 wks. An in vitro experiment was performed to investigate the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on MCP-1 secretion in THP-1 monocytes activated with lipopolysaccharide (LPS) and Pseudomonas aeruginosa.
Results
By 12 wks, serum MCP-1 decreased in the cholecalciferol group (66.2 ± 2.5 to 60.8 ± 2.6 pg/mL, group-by-time interaction P = 0.02) but was not different from baseline at 1 yr. Other markers of inflammation and immunity did not change. In vitro, LPS- and Pseudomonas-activated monocytes treated with1,25(OH)2D3 had significantly less MCP-1 secretion compared to untreated cells.
Conclusions
High-dose cholecalciferol decreased serum MCP-1 concentrations by 12 wks in patients with early CKD, although the decrease was not maintained for the remainder of the year. In vitro results confirm an MCP-1-lowering effect of vitamin D. Future studies should determine if vitamin D-mediated reductions in MCP-1 concentrations reflect improved clinical outcomes.
Background
Early detection of chronic kidney disease (CKD) is sub-optimal among the general population and among high risk patients. The prevalence and impact of major CKD risk factors, diabetes (DM) and hypertension (HTN), on CKD documentation among managed care populations have not been previously reported. We examined this issue in a Kaiser Permanente Georgia (KPG) CKD cohort.
Methods
KPG enrollees were included in the CKD cohort if they had eGFRs between 60 and 365 days apart that were <90 ml/min during 1999-2006. The current analysis is restricted to participants with eGFR 10-59 ml/min/1.73 m2. CKD documentation was defined as a presenting diagnosis of CKD by a primary care physician or nephrologist using ICD-9 event codes. The association between CKD documentation and DM and HTN were assessed with multivariate logistic regression models.
Results
Of the 50,438 subjects within the overall KPG CKD cohort, 20% (N = 10,266) were eligible for inclusion in the current analysis. Overall, CKD diagnosis documentation was low; only 14.4% of subjects had an event-based CKD diagnosis at baseline. Gender and types 2 diabetes interacted on CKD documentation. The prevalence of CKD documentation increased with the presence of hypertension and/or type 2 diabetes, but type 2 diabetes had a lower effect on CKD documentation. In multivariate analysis, significant predictors of CKD documentation were eGFR, hypertension, type 2 diabetes, congestive heart failure, peripheral artery disease, statin use, age and gender. CKD documentation was lower among women than similarly affected men.
Conclusion
Among patients with an eGFR 10-59, documentation of CKD diagnosis by primary and subspecialty providers is low within a managed care patient cohort. Gender disparities in CKD documentation observed in the general population were also present among KPG CKD enrollees.
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.
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.
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.
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Elevated Resting Blood Pressure (ERBP) in the prehypertensive range is associated with increased risk of hypertension and cardiovascular disease, the mechanisms of which remain unclear. Prior studies have suggested that ERBP may be associated with overactivation and dysregulation of the sympathetic nervous system (SNS). We hypothesized that compared to normotensives (≤120/80 mmHg), ERBP (120/80-139/89 mmHg) has higher SNS activity, impaired arterial baroreflex sensitivity (BRS), and increased vascular inflammation. Twenty-nine participants were studied: 16 otherwise healthy individuals with ERBP (blood pressure (BP) 130 ± 2/85 ± 2 mmHg) and 13 matched normotensive controls (mean BP 114 ± 2/73 ± 2 mmHg). We measured muscle sympathetic nerve activity (MSNA), beat-to-beat BP, and continuous electrocardiogram at rest and during arterial BRS testing via the modified Oxford technique. Blood was analyzed for the following biomarkers of vascular inflammation: lipoprotein-associated phospholipase A2 (Lp-PLA2), E-selectin, and intercellular adhesion molecule 1 (ICAM-1). Resting MSNA burst frequency (22 ± 2 vs. 16 ± 2 bursts/min, P = 0.036) and burst incidence (36 ± 3 vs. 25 ± 3 bursts/100 heart beats, P = 0.025) were higher in ERBP compared to controls. Cardiovagal BRS was blunted in ERBP compared to controls (13 ± 2 vs. 20 ± 3 msec/mmHg, P = 0.032), while there was no difference in sympathetic BRS between groups. Lp-PLA2 (169 ± 8 vs. 142 ± 9 nmol/min/mL, P = 0.020) and E-selectin (6.89 ± 0.6 vs. 4.45 ± 0.51 ng/mL, P = 0.004) were higher in ERBP versus controls. E-selectin (r = 0.501, P = 0.011) and ICAM-1 (r = 0.481, P = 0.015) were positively correlated with MSNA, while E-selectin was negatively correlated with cardiovagal BRS (r = -0.427, P = 0.030). These findings demonstrate that individuals with ERBP have SNS overactivity and impaired arterial BRS that are linked to biomarkers of vascular inflammation.
Background: Vitamin D deficiency is highly prevalent among hemodialysis patients, but little data exist in support of an optimal repletion regimen.
Objective: The objective was to ascertain the efficacy of weekly very-high-dose cholecalciferol (vitamin D3) in correcting vitamin D insufficiency and deficiency in patients with stage 5D chronic kidney disease.
Design: We conducted a prospective, double-blind, randomized controlled pilot study that compared placebo with very high doses of oral cholecalciferol for 3 wk (200,000 IU/wk) in hemodialysis patients. We examined the rate of correction of vitamin D insufficiency or deficiency and the effect of treatment on markers of mineral metabolism and routine laboratory variables.
Results: Twenty-seven subjects received placebo, and 25 received cholecalciferol. The majority (94%) of subjects had serum 25-hydroxyvitamin D [25(OH)D] concentrations <30 ng/mL. Study groups were similar with respect to baseline clinical characteristics, with the exception of hemoglobin concentrations, which were lower in the cholecalciferol-treated group (P < 0.04). At follow-up, 90.5% of subjects treated with cholecalciferol achieved serum 25(OH)D concentrations ≥30 ng/mL in contrast to 13.6% of the placebo group. There were no significant changes in serum calcium, phosphate, or intact parathyroid hormone during the study.
Conclusion: Short-term, high-dose oral cholecalciferol treatment of vitamin D deficiency in hemodialysis patients appears to be effective and with no evidence of toxic effects. This trial was registered at clinicaltrials.gov as NCT00912782.
Background:
End stage renal disease (ESRD) is characterized by autonomic dysfunction. During orthostatic stress, sympathetic (SNS) activity increases and parasympathetic (PNS) activity decreases to maintain arterial blood pressure (BP). We hypothesized that ESRD patients have impaired ability to adjust cardiac SNS and PNS activity during orthostasis, which could contribute to increased blood pressure variability, orthostatic intolerance and falls.
Methods:
We measured beat-to-beat BP and Electrocardiography at baseline and during increasing lower body negative pressure (LBNP) in 20 ESRD patients and 18 matched controls (CON). Heart rate variability was quantified as total power (TP) and standard deviation of the N-N interval, reflecting both SNS and PNS; high frequency (HF), root mean square of successive differences of neighboring N-N intervals (RMSSD), and percent of consecutive N-N intervals differing >50 milliseconds (pNN50), reflecting cardiac PNS activity; and low frequency (LF) and LF/HF, reflecting sympoathovagal balance. BP variability was quantified as the standard deviation in systolic (SDSAP) and diastolic (SDDAP) BP.
Results:
Baseline HF, RMSSD, and pNN50 were significantly lower in ESRD (P < 0.05). While CON had a significant decrease in HF (P = 0.015), RMSSD (P = 0.003), and pNN50 (P = 0.005) during LBNP, there was no change in heart rate variability in ESRD. There was no significant difference in BP response, but ESRD had a significantly blunted heart rate response during graded LBNP compared to controls (P < 0.001). There was no significant difference in SDSAP or SDDAP during LBNP between groups (P > 0.05).
Conclusions:
These data suggest that ESRD patients have impaired autonomic adjustments to orthostatic stress.
by
April L. Kelley;
Etienne Karita;
Patrick S Sullivan;
Francois Katangulia;
Elwyn Chomba;
Michel Carael;
Joseph Telfair;
Steve M. Dunham;
Cheswa M. Vwalika;
Michele G. Kautzman;
Susan M Wall;
Susan A Allen
Background
Most incident HIV infections in sub-Saharan Africa occur between cohabiting, discordant, heterosexual couples. Though couples' voluntary HIV counseling and testing (CVCT) is an effective, well-studied intervention in Africa, <1% of couples have been jointly tested.
Methods
We conducted cross-sectional household surveys in Kigali, Rwanda (n = 600) and Lusaka, Zambia (n = 603) to ascertain knowledge, perceptions, and barriers to use of CVCT.
Results
Compared to Lusaka, Kigali respondents were significantly more aware of HIV testing sites (79% vs. 56%); had greater knowledge of HIV serodiscordance between couples (83% vs. 43%); believed CVCT is good (96% vs. 72%); and were willing to test jointly (91% vs. 47%). Stigma, fear of partner reaction, and distance/cost/logistics were CVCT barriers.
Conclusions
Though most respondents had positive attitudes toward CVCT, the majority were unaware that serodiscordance between cohabiting couples is possible. Future messages should target gaps in knowledge about serodiscordance, provide logistical information about CVCT services, and aim to reduce stigma and fear.
Objective: This report describes three patients with Ebola virus disease who were treated in the United States and developed for severe critical illness and multiple organ failure secondary to Ebola virus infection. The patients received mechanical ventilation, renal replacement therapy, invasive monitoring, vasopressor support, and investigational therapies for Ebola virus disease.
Data Sources: Patient medical records from three tertiary care centers (Emory University Hospital, University of Nebraska Medical Center, and Texas Health Presbyterian Dallas Hospital).
Study Selection: Not applicable.
Data Extraction: Not applicable.
Data Synthesis: Not applicable.
Conclusion: In the severe form, patients with Ebola virus disease may require life-sustaining therapy, including mechanical ventilation and renal replacement therapy. In conjunction with other reported cases, this series suggests that respiratory and renal failure may occur in severe Ebola virus disease, especially in patients burdened with high viral loads. Ebola virus disease complicated by multiple organ failure can be survivable with the application of advanced life support measures. This collective, multicenter experience is presented with the hope that it may inform future treatment of patients with Ebola virus disease requiring critical care treatment.