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The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619., Competing Interests: Declaration of Competing Interest L.M. Dember receives compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases, consulting fees from AstraZeneca, Cara Therapeutics, and Merck, and compensation for serving on Data and Safety Monitoring Boards for the National Institute of Diabetes and Digestive and Kidney Diseases, CSL Behring, and Vertex Pharmaceuticals. D.M. Charytan reports consulting fees from Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Allena Pharmaceuticals (DSMB), Fresenius, Gilead, Novo Nordisk, GSK, Medtronic, Merck, Amgen, CSL Behring, Zogenix, and Renalytix; research funding from Medtronic, clinical trial support from Gilead, NovoNordisk, Amgen, and Boehringer Ingelheim; royalties from UpToDate.com for authorship or editorial activities; and expert witness fees related to proton pump inhibitors. D. Esserman serves on data monitoring boards for Ablative Solutions and PhaseBio. M. Jhamb reports research funding from Bayer LLC, Dialysis Clinic Inc. and Pfizer, and advisory board fees from Xcenda LLC, Boehringer Ingelheim, Lilly, and CKD Networks of Excellence. S. Joffe reports compensation for service on a Data and Safety Monitoring Board for CSL Behring. K.L. Johansen reports consultancy for GlaxoSmithKline, Akebia, and Vifor; advisory or leadership role for GSK; and role as an Associate Editor of Journal of the American Society of Nephrology. S. Kalim reports receiving speaking fees and consulting fees from Fresenius Kabi. P.L. Kimmel reports compensation from Elsevier for his roles as Co-Editor of Chronic Renal Disease, and Co-Editor of Psychosocial Aspects of Chronic Kidney Disease. E.J. Krebs receives research funding from the US Department of Veterans Affairs (VA), National Institutes of Health (NIH), and the Patient Centered Outcomes Research Institute (PCORI), has received support (paid to her institution) from Origin Editorial for serving as Associate Editor for PCORI research reports, travel expense reimbursement from the American College of Physicians, and has provided unpaid expert service as a member of the Foundation for Opioid Response Efforts Scientific Advisory Council, temporary member (ad hoc) for the Food and Drug Administration (FDA) Drug Safety and Risk Management Advisory Committee, panel member for FDA Public Workshop on Reconsidering Mandatory Opioid Prescriber Education, member of Society of General Internal Medicine (SGIM) program and award committees, and chair or member of data safety monitoring boards for VA, NIH, and PCORI studies. R. Mehrotra serves as the Editor-in-Chief of the Clinical Journal of the American Society of Nephrology. J.L. Steel reports compensation for serving on a Data and Safety Monitoring Board for the National Institute of Diabetes and Digestive and Kidney Diseases and for her role as an editor for the Journal of Gastrointestinal Cancers, and royalties from Springer. L. Bernardo, K.L. Cavanaugh, S.T. Crowley, D. Cukor A.Z. Doorenbos, D.A. Edwards, M.J. Fischer, N. Kuzla, P. Mishra, B. Pellegrino, D.M. White, and J.G. Yabes have no disclosures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Kidney health advocacy organizations and leaders in the nephrology community have repeatedly emphasized the need to increase home dialysis utilization in the United States. Limited awareness and understanding of options for the management of kidney failure among patients living with advanced CKD is a significant barrier to increasing the selection and use of home dialysis. Studies have shown that providing targeted comprehensive patient education before the onset of kidney failure can improve patients' awareness of kidney disease and substantially increase the informed utilization of home dialysis. Unfortunately, in the absence of validated evidence-based education protocols, outcomes associated with home dialysis use vary widely among published studies, potentially affecting the routine implementation and reporting of these services among patients with advanced CKD. This review provides pragmatic guidance on establishing effective patient-centered education programs to empower patients to make informed decisions about their KRT and, in turn, increase home dialysis use., (Copyright © 2023 by the American Society of Nephrology.)

Background: Home dialysis utilization is lower among veterans than in the general US population. Several sociodemographic factors and comorbidities contribute to peritoneal dialysis (PD) underutilization. In 2019, the Veterans Health Administration (VHA) Kidney Disease Program Office convened a PD workgroup to address this concern., Observations: The PD workgroup was explicitly concerned by the limited availability of PD within the VHA, which frequently requires veterans to transition kidney disease care from US Department of Veterans Affairs medical centers (VAMCs) to non-VHA facilities when they progress from chronic kidney disease to end-stage kidney disease, causing fragmentation of care. Since the administrative requirements and infrastructure of VAMCs vary, the workgroup focused its deliberations on synthesizing a standard process for evaluating the feasibility and establishing a new PD program within any individual VAMC. A 3-phased approach was envisioned, beginning with ascertainment of prerequisites, leading to an examination of the clinical and financial feasibility through the process of data gathering and synthesis, culminating in a business plan that translates the previous 2 steps into an administrative document necessary for obtaining VHA approvals., Conclusions: VAMCs can use the guide presented here to improve therapeutic options for veterans with kidney failure by establishing a new or restructured PD program., (Copyright © 2023 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Objectives: Serum creatinine-based estimated glomerular filtration rate equations and muscle mass are powerful markers of health and mortality risk. However, the serum creatinine-to-cystatin-C ratio may be a better indicator of health status. The objective of this study was to describe the relationship between creatinine-to-cystatin-C ratio and all-cause mortality when stratifying patients as per race and as per chronic kidney disease status., Methods: This was a retrospective cohort study examining black and nonblack US veterans between October 2004 and September 2019, with baseline cystatin C and creatinine data from those not on dialysis during the study period. Veterans were divided into four creatinine-to-cystatin-C ratio groups: <0.75, 0.75-<1.00, 1.0-<1.25, and ≥1.25. The primary outcome of interest was all-cause mortality subsequent to the cystatin C laboratory measure., Results: Among 22,316 US veterans, the mean (± standard deviation) age of the cohort was 67 ± 14 years, 5% were female, 82% were nonblack, and 18% were black. The proportion of black veterans increased across creatinine-to-cystatin-C ratio groups. In the fully adjusted model, compared with the reference (creatinine-to-cystatin-C ratio: 1.00-<1.25), a creatinine-to-cystatin-C ratio <0.75 had the highest mortality risk among both black and nonblack veterans (nonblack: hazard ratio [HR] [95% confidence interval {CI}]: 3.01 [2.78-3.26] and black: 4.17 [3.31-5.24]). A creatinine-to-cystatin-ratio ≥1.25 was associated with lower death risk than the referent in both groups (nonblack: HR [95% CI]: 0.89 [0.80-0.99] and black: HR [95% CI]: 0.55 [0.45-0.69]). However, there was a significant difference in the effect by race (Wald's P-value: <0.01)., Conclusions: Higher creatinine-to-cystatin-C ratios indicate better health status and are strongly associated with lower mortality risk regardless of the kidney function level, and the relation was similar for both black and nonblack veterans, but with different strengths of effect across racial groups. Thereby, use of a fixed race coefficient in estimating kidney function may be biased., (Published by Elsevier Inc.)

Background: Patient awareness of chronic kidney disease (CKD) is low in part due to suboptimal testing for CKD among those at risk and lack of discussions about kidney disease between patients and clinicians. To bridge these gaps, the National Kidney Foundation developed the Kidney Score Platform, which is a web-based series of tools that includes resources for health care professionals as well as an interactive, dynamic patient-facing component that includes a brief questionnaire about risk factors for kidney disease, individualized assessment of risk for developing CKD, and self-management tools to manage one's kidney disease., Objective: The aim of this study is to perform usability testing of the patient component of the Kidney Score platform among veterans with and at risk for kidney disease and among clinicians working as primary care providers in Veterans Affairs administration., Methods: Think-aloud exercises were conducted, during which participants (veterans and clinicians) engaged with the platform while verbalizing their thoughts and making their perceptions, reasonings, and decision points explicit. A usability facilitator observed participants' behaviors and probed selectively to clarify their comprehension of the tool's instructions, content, and overall functionality. Thematic analysis on the audio-recording transcripts was performed, focusing on positive attributes, negative comments, and areas that required facilitator involvement., Results: Veterans (N=18) were 78% (14/18) male with a mean age of 58.1 years. Two-thirds (12/18) were of non-White race/ethnicity, 28% (5/18) had laboratory evidence of CKD without a formal diagnosis, and 50% (9/18) carried a diagnosis of hypertension or diabetes. Clinicians (N=19) were 29% (5/17) male, 30% (5/17) of non-White race/ethnicity, and had a mean of 17 (range 4-32) years of experience. Veterans and clinicians easily navigated the online tool and appreciated the personalized results page as well as the inclusion of infographics to deliver key educational messages. Three major themes related to content and communication about risk for CKD emerged from the think-aloud exercises: (1) tension between lay and medical terminology when discussing kidney disease and diagnostic tests, (2) importance of linking general information to concrete self-management actions, and (3) usefulness of the tool as an adjunct to the office visit to prepare for patient-clinician communication. Importantly, these themes were consistent among interviews involving both veterans and clinicians., Conclusions: Veterans and clinicians both thought that the Kidney Score Platform would successfully promote communication and discussion about kidney disease in primary care settings. Tension between using medical terminology that is used regularly by clinicians versus lay terminology to promote CKD awareness was a key challenge, and knowledge of this can inform the development of future CKD educational materials., (©Delphine S Tuot, Susan T Crowley, Lois A Katz, Joseph Leung, Delly K Alcantara-Cadillo, Christopher Ruser, Elizabeth Talbot-Montgomery, Joseph A Vassalotti. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.09.2022.)

Importance: Since 2014, when Congress passed the Veterans Access Choice and Accountability (Choice) Act (replaced in 2018 with the more comprehensive Maintaining Internal Systems and Strengthening Integrated Outside Networks [MISSION] Act), the Department of Veterans Affairs (VA) has been paying for US veterans to receive increasing amounts of care in the private sector (non-VA care or VA community care). However, little is known about the implications of these legislative changes for the VA system., Objective: To describe the implications for the VA system of recent increases in VA-financed non-VA care., Design, Setting, and Participants: This qualitative study was a thematic analysis of documentation in the electronic health records (EHRs) of a random sample of US veterans with advanced kidney disease between June 6, 2019, and February 5, 2021., Exposures: Mentions of community care in participant EHRs., Main Outcomes and Measures: Dominant themes pertaining to VA-financed non-VA care., Results: Among 1000 study participants, the mean (SD) age was 73.8 (11.4) years, and 957 participants (95.7%) were male. Three interrelated themes pertaining to VA-financed non-VA care emerged from qualitative analysis of documentation in cohort member EHRs: (1) VA as mothership, which describes extensive care coordination by VA staff members and clinicians to facilitate care outside the VA and the tendency of veterans and their non-VA clinicians to rely on the VA to fill gaps in this care; (2) hidden work of veterans, which describes the efforts of veterans and their family members to navigate the referral process, and to serve as intermediaries between VA and non-VA clinicians; and (3) strain on the VA system, which describes a challenging referral process and the ways in which cross-system care has stretched the traditional roles of VA staff and clinicians and interfered with VA care processes., Conclusions and Relevance: The findings of this qualitative study describing VA-financed non-VA care for veterans with advanced kidney disease spotlight the substantial challenges of cross-system use and the strain placed on the VA system, VA staff and clinicians, and veterans and their families in recent years. These difficult-to-measure consequences of cross-system care should be considered when budgeting, evaluating, and planning the provision of VA-financed non-VA care in the private sector.

Background: Transitioning to maintenance hemodialysis (HD) is a vulnerable period for persons with end-stage renal disease (ESRD), punctuated by high rates of depression, hospitalizations and death. Screening for depression during this time may help to improve patient outcomes but formal inquiry has yet to be conducted. Among a national Veteran cohort, we examined whether depression screening in the year prior to HD initiation led to improved outcomes in the year thereafter., Methods: Associations between pre-ESRD depression screening and post-ESRD outcomes were examined with Cox proportional hazards models (mortality) and Poisson regression models (hospitalization). Hierarchal adjustment models accounted for sociodemographic, clinical, pre-ESRD care and dialysis characteristics., Results: The final analytic cohort of the study was 30 013 Veterans of whom 64% underwent pre-ESRD depression screening. During the 12 months post-transition, the crude all-cause mortality rate was 0.32 person-year for those screened and 0.35 person-year for those not screened, while the median (interquartile range) hospitalizations were 2 (2, 2) per year for both groups. In fully adjusted models, pre-ESRD depression screening was associated with a lower risk of mortality [hazard ratio (95% confidence interval): 0.94 (0.90-0.99)] and hospitalization [incidence rate ratio (95% confidence interval): 0.97 (0.9-0.99)]., Conclusion: Depression screening among adults prior to maintenance HD transition may be associated with better outcomes during the following year., (Published by Oxford University Press on behalf of ERA-EDTA 2021.)

Competing Interests: P.H. Pun reports personal fees from AstraZeneca, Fresenius Medical Care, Janssen Pharmaceuticals, and Relypsa, outside the submitted work. The remaining author has nothing to disclose.

Background: Patient awareness, clinician detection, and management of chronic kidney disease remain suboptimal, despite clinical practice guidelines and diverse education programs., Objective: This protocol describes a study to develop and investigate the impact of the National Kidney Foundation Kidney Score Platform on chronic kidney disease awareness, communication, and management, by leveraging the Behavior Change Wheel, an implementation science framework that helps identify behavioral intervention targets and functions that address barriers to behavior change., Methods: We interviewed 20 patients with chronic kidney disease and 11 clinicians to identify patient and clinician behaviors suitable for intervention and barriers to behavior change (eg, limited awareness of chronic kidney disease clinical practice guidelines within primary care settings, limited data analytics to highlight chronic kidney disease care gaps, asymptomatic nature of chronic kidney disease in conjunction with patient reliance on primary care clinicians to determine risk and order kidney testing). Leveraging the Behavior Change Wheel, the Kidney Score Platform was developed with a patient-facing online Risk Calculator and a clinician-facing Clinical Practice Toolkit. The Risk Calculator utilizes risk predictive analytics to provide interactive health information tailored to an individual's chronic kidney disease risk and health status. The Clinical Practice Toolkit assists clinicians in discussing chronic kidney disease with individuals at risk for and with kidney disease and in managing their patient population with chronic kidney disease. The Kidney Score Platform will be tested in 2 Veterans Affairs primary health care settings using a pre-post study design. Outcomes will include changes in patient self-efficacy for chronic kidney disease management (primary outcome), quality of communication with clinicians about chronic kidney disease, and practitioners' knowledge of chronic kidney disease guidelines. Process outcomes will identify usability and adoption of different elements of the Kidney Score Platform using qualitative and quantitative methods., Results: As of September 2020, usability studies are underway with veterans and clinicians to refine the patient-facing components of the Kidney Score Platform before study initiation. Results and subsequent changes to the Kidney Score Platform will be published at a later date. The study is expected to be completed by December 2021., Conclusions: Results of this study will be used to inform integration of the Kidney Score Platform within primary care settings so that it can serve as a central component of the National Kidney Foundation public awareness campaign to educate, engage, and empower individuals at risk for and living with chronic kidney disease., International Registered Report Identifier (irrid): PRR1-10.2196/22024., (©Delphine S Tuot, Susan T Crowley, Lois A Katz, Joseph Leung, Delly K Alcantara-Cadillo, Christopher Ruser, Elizabeth Talbot-Montgomery, Joseph A Vassalotti. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 19.10.2020.)

Chronic kidney disease (CKD) affects >10% of the adult population. Each year, approximately 120,000 Americans develop end-stage kidney disease and initiate dialysis, which is costly and associated with functional impairments, worse health-related quality of life, and high early-mortality rates, exceeding 20% in the first year. Recent declarations by the World Kidney Day and the U.S. Government Executive Order seek to implement strategies that reduce the burden of kidney failure by slowing CKD progression and controlling uremia without dialysis. Pragmatic dietary interventions may have a role in improving CKD outcomes and preventing or delaying dialysis initiation. Evidence suggests that a patient-centered plant-dominant low-protein diet (PLADO) of 0.6–0.8 g/kg/day composed of >50% plant-based sources, administered by dietitians trained in non-dialysis CKD care, is promising and consistent with the precision nutrition. The scientific premise of the PLADO stems from the observations that high protein diets with high meat intake not only result in higher cardiovascular disease risk but also higher CKD incidence and faster CKD progression due to increased intraglomerular pressure and glomerular hyperfiltration. Meat intake increases production of nitrogenous end-products, worsens uremia, and may increase the risk of constipation with resulting hyperkalemia from the typical low fiber intake. A plant-dominant, fiber-rich, low-protein diet may lead to favorable alterations in the gut microbiome, which can modulate uremic toxin generation and slow CKD progression, along with reducing cardiovascular risk. PLADO is a heart-healthy, safe, flexible, and feasible diet that could be the centerpiece of a conservative and preservative CKD-management strategy that challenges the prevailing dialysis-centered paradigm., Competing Interests: K. Kalantar-Zadeh has received honoraria and/or support from Abbott, Abbvie, ACI Clinical (Cara Therapeutics), Akebia, Alexion, Amgen, Ardelyx, ASN (American Society of Nephrology), Astra-Zeneca, Aveo, BBraun, Chugai, Cytokinetics, Daiichi, DaVita, Fresenius, Genentech, Haymarket Media, Hofstra Medical School, IFKF (International Federation of Kidney Foundations), ISH (International Society of Hemodialysis), International Society of Renal Nutrition & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, Kabi, Keryx, Kissei, Novartis, OPKO, NIH (National Institutes of Health), NKF (National Kidney Foundations), Pfizer, Regulus, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, Shire, VA (Veterans’ Affairs), Vifor, UpToDate, ZS-Pharma. No relevant sources of conflict of interest have been declared by other authors.

Background: Adults with end-stage renal disease (ESRD) requiring chronic dialysis continue to suffer from poor health outcomes and represent a population rightfully targeted for quality improvement. Electronic dashboards are increasingly used in healthcare to facilitate quality measurement and improvement. However, detailed descriptions of the creation of healthcare dashboards are uncommonly available and formal inquiry into perceptions, satisfaction, and utility by clinical users has been rarely conducted, particularly in the context of dialysis care. Therefore, we characterized the development, implementation and user experience with Veterans Health Administration (VHA) dialysis dashboard., Methods: A clinical-quality dialysis dashboard was implemented, which displays clinical performance measures (CPMs) for Veterans with ESRD receiving chronic hemodialysis at all VHA facilities. Data on user experience and perceptions were collected via an e-mail questionnaire to dialysis medical directors and nurse managers at these facilities., Results: Since 2016 the dialysis dashboard reports monthly on CPMs for approximately 3000 Veterans receiving chronic hemodialysis across 70 VHA dialysis facilities. Of 141 dialysis medical directors and nurse managers, 61 completed the questionnaire. Sixty-six percent of respondents did not find the dashboard difficult to access, 64% agreed that it is easy to use, 59% agreed that its layout is good, and the majority agreed that presentation of data is clear (54%), accurate (56%), and up-to-date (54%). Forty-eight percent of respondents indicated that it helped them improve patient care while 12% did not. Respondents indicated that they used the dialysis dashboard for clinical reporting (71%), quality assessment/performance improvement (QAPI) (62%), and decision-making (23%)., Conclusions: Most users of the VHA dialysis dashboard found it accurate, up-to-date, easy to use, and helpful in improving patient care. It meets diverse user needs, including administrative reporting, clinical benchmarking and decision-making, and quality assurance and performance improvement (QAPI) activities. Moreover, the VHA dialysis dashboard affords national-, regional- and facility-level assessments of quality of care, guides and motivates best clinical practices, targets QAPI efforts, and informs and promotes population health management improvement efforts for Veterans receiving chronic hemodialysis.

Spinal cord injury (SCI) is a debilitating condition that can cause impaired motor function or full paralysis. In the days to weeks following the initial mechanical injury to the spinal cord, inflammation and apoptosis can cause additional damage to the injured tissues. This secondary injury impairs recovery. Brain-derived neurotrophic factor is a secreted protein that has been shown to improve a variety of neurological conditions, including SCI, by promoting neuron survival and synaptic plasticity. This study treated a mouse model of contusion SCI using a single dose of brain-derived neurotrophic factor (BDNF) mRNA nanomicelles prepared with polyethylene glycol polyamino acid block copolymer directly injected into the injured tissue. BDNF levels in the injured spinal cord tissue were approximately doubled by mRNA treatment. Motor function was monitored using the Basso Mouse Scale and Noldus CatWalk Automated Gait Analysis System for 6 weeks post-injury. BDNF-treated mice showed improved motor function recovery, demonstrating the feasibility of mRNA delivery to treat SCI., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Intervertebral disk (IVD) degeneration is often associated with severity of lower back pain. IVD core is an avascular, highly hydrated tissue composed of type II collagen, glycosaminoglycans, and proteoglycans. The disk degeneration is not only a destruction of IVD structure but also is related to a disorder of the turnover of the disk matrix, leading the jelly-like IVD core to be replaced by fibrous components. Here we present a disease-modifying strategy for IVD degenerative diseases by direct regulation of the cells in the IVD using mRNA medicine, to alter the misbalanced homeostasis during disk degeneration. When mRNA encoding a cartilage-anabolic transcription factor, runt-related transcription factor-1, was administered to a rat model of coccygeal disk degeneration using a polyplex nanomicelle composed of polyethylene glycol-polyamino acid block copolymers and mRNA, the disk height was maintained to a significantly higher extent (≈81%) compared to saline control (69%), with prevention of fibrosis in the disk tissue. In addition, the use of nanomicelles effectively prevented inflammation, which was observed by injection of naked mRNA into the disk. This proof-of-concept study revealed that mRNA medicine has a potential for treating IVD degenerative diseases by introducing a cartilage-anabolic factor into the host cells, proposing a new therapeutic strategy using mRNA medicine., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Outcomes of veterans with ESRD may differ depending on where they receive dialysis and who finances this care, but little is known about variation in outcomes across different dialysis settings and financial arrangements., Methods: We examined survival among 27,241 Veterans Affairs (VA)-enrolled veterans who initiated chronic dialysis in 2008-2011 at ( 1 ) VA-based units, ( 2 ) community-based clinics through the Veterans Affairs Purchased Care program (VA-PC), ( 3 ) community-based clinics under Medicare, or ( 4 ) more than one of these settings ("dual" care). Using a Cox proportional hazards model, we compared all-cause mortality across dialysis settings during the 2-year period after dialysis initiation, adjusting for demographic and clinical characteristics., Results: Overall, 4% of patients received dialysis in VA, 11% under VA-PC, 67% under Medicare, and 18% in dual settings (nearly half receiving dual VA and VA-PC dialysis). Crude 2-year mortality was 25% for veterans receiving dialysis in the VA, 30% under VA-PC, 42% under Medicare, and 23% in dual settings. After adjustment, dialysis patients in VA or in dual settings had significantly lower 2-year mortality than those under Medicare; mortality did not differ in VA-PC and Medicare dialysis settings., Conclusions: Mortality rates were highest for veterans receiving dialysis in Medicare or VA-PC settings and lowest for veterans receiving dialysis in the VA or dual settings. These findings inform institutional decisions about provision of dialysis for veterans. Further research identifying processes associated with improved survival for patients receiving VA-based dialysis may be useful in establishing best practices for outsourced veteran care., (Copyright © 2019 by the American Society of Nephrology.)

The metabolic instability of mRNA currently limits its utility for gene therapy. Compared to plasmid DNA, mRNA is significantly more susceptible to digestion by RNase in the circulation following systemic dosing. To increase mRNA metabolic stability, we hybridized a complementary reverse mRNA with forward mRNA to generate double-stranded mRNA (dsmRNA). RNase A digestion of dsmRNA established a 3000-fold improved metabolic stability compared to single-stranded mRNA (ssmRNA). Formulation of a dsmRNA polyplex using a PEG-peptide further improved the stability by 3000-fold. Hydrodynamic dosing and quantitative bioluminescence imaging of luciferase expression in the liver of mice established the potent transfection efficiency of dsmRNA and dsmRNA polyplexes. However, hybridization of the reverse mRNA against the 5' and 3' UTR of forward mRNA resulted in UTR denaturation and a tenfold loss in expression. Repeat dosing of dsmRNA polyplexes produced an equivalent transient expression, suggesting the lack of an immune response in mice. Co-administration of excess uncapped dsmRNA with a dsmRNA polyplex failed to knock down expression, suggesting that dsmRNA is not a Dicer substrate. Maximal circulatory stability was achieved using a fully complementary dsmRNA polyplex. The results established dsmRNA as a novel metabolically stable and transfection-competent form of mRNA.

Just as the "New Deal" aimed to elevate the "forgotten man" of the Great Depression through governmental relief and reform, so does the Department of Veterans Affairs (VA) health care system aim to improve the health of veterans with the invisible illness of chronic kidney disease through a concerted series of health care delivery reforms. Augmenting its primary care platform with advances in informatics and health service delivery initiatives targeting kidney disease, the VA is changing how nephrology care is provided to veterans with the goal of optimized population kidney health. As the largest provider of kidney health services in the country, the VA offers an instructive case study of the value of comprehensive health care coverage for people with chronic kidney disease. Recent reports of kidney health outcomes among veterans support the benefit of the VA's integrated health care delivery system. Suggestions to optimize veterans' kidney health further may be equally applicable to other health systems caring for people afflicted with kidney disease., (Published by Elsevier Inc.)

Background and Objectives: The highly specialized and technologically focused approach to care inherent to many health systems can adversely affect patients' emotional experiences of illness, while also obscuring these effects from the clinician's view. We describe what we learned from patients with advanced kidney disease about the emotional impact of illness and care., Design, Setting, Participants, & Measurements: As part of an ongoing study on advance care planning, we conducted semistructured interviews at the VA Puget Sound Healthcare System in Seattle, Washington, with 27 patients with advanced kidney disease between April of 2014 and May of 2016. Of these, ten (37%) were receiving center hemodialysis, five (19%) were receiving peritoneal dialysis, and 12 (44%) had an eGFR≤20 ml/min per 1.73 m 2 and had not started dialysis. Interviews were audiotaped, transcribed, and analyzed inductively using grounded theory methods., Results: We here describe three emergent themes related to patients' emotional experiences of care and illness: ( 1 ) emotional impact of interactions with individual providers: when providers seemed to lack insight into the patient's experience of illness and treatment, this could engender a sense of mistrust, abandonment, isolation, and/or alienation; ( 2 ) emotional impact of encounters with the health care system: just as they could be affected emotionally by interactions with individual providers, patients could also be affected by how care was organized, which could similarly lead to feelings of mistrust, abandonment, isolation, and/or alienation; and ( 3 ) emotional impact of meaning-making: patients struggled to make sense of their illness experience, worked to apportion blame, and were often quick to blame themselves and to assume that their illness could have been prevented., Conclusions: Interactions with individual providers and with the wider health system coupled with patients' own struggles to make meaning of their illness can take a large emotional toll. A deeper appreciation of patients' emotional experiences may offer important opportunities to improve care., (Copyright © 2018 by the American Society of Nephrology.)

Objective: Measuring motor function in mice is important for studying models of spinal cord injury (SCI) or other diseases. Several methods exist based on visual observation of mice moving in an open field. Though these methods require very little equipment, observers must be trained, and the possibility of human error or subjectivity cannot be eliminated. The Noldus CatWalk XT Automated Gait Analysis system assesses mouse motor function by taking high-resolution videos of the mice, with specialized software to measure several aspects of the animal's gait. This instrument reduces the possibility of human error, but it is not always clear what data is important for assessing motor function. This study used data collected during mouse SCI experiments to create a simple mathematical model that combines the data collected by the CatWalk system into a single score, the Combined CatWalk Index or CCI., Results: The CCI system produces similar results to the Basso Mouse Scale or the CatWalk's Step Sequence Regularity Index. However, the CCI has a significantly smaller coefficient of variation than either other method. Additionally, CCI scoring shows slightly better correlation with impact force. The CCI system is likely to be a useful tool for SCI research.

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study ( n =190 cases of incident DKD and 190 matched controls) and a prospective cohort study ( n =1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome., (Copyright © 2017 by the American Society of Nephrology.)

Each year approximately 13,000 Veterans transition to maintenance dialysis, mostly in the traditional form of thrice-weekly hemodialysis from the start. Among >6000 dialysis units nationwide, there are currently approximately 70 Veterans Affairs (VA) dialysis centers. Given this number of VA dialysis centers and their limited capacity, only 10% of all incident dialysis Veterans initiate treatment in a VA center. Evidence suggests that, among Veterans, the receipt of care within the VA system is associated with favorable outcomes, potentially because of the enhanced access to healthcare resources. Data from the United States Renal Data System Special Study Center "Transition-of-Care-in-CKD" suggest that Veterans who receive dialysis in a VA unit exhibit greater survival compared with the non-VA centers. Substantial financial expenditures arise from the high volume of outsourced care and higher dialysis reimbursement paid by the VA than by Medicare to outsourced providers. Given the exceedingly high mortality and abrupt decline in residual kidney function (RKF) in the first dialysis year, it is possible that incremental transition to dialysis through an initial twice-weekly hemodialysis regimen might preserve RKF, prolong vascular access longevity, improve patients' quality of life, and be a more patient-centered approach, more consistent with "personalized" dialysis. Broad implementation of incremental dialysis might also result in more Veterans receiving care within a VA dialysis unit. Controlled trials are needed to examine the safety and efficacy of incremental hemodialysis in Veterans and other populations; the administrative and health care as well as provider structure within the VA system would facilitate the performance of such trials., (© 2017 Wiley Periodicals, Inc.)

The Veterans Affairs (VA) is the largest integrated health care system in the United States and is responsible for the care of a population with a disproportionately high rate of CKD. As such, ensuring access to kidney health services is a VA imperative. One facet of the VA's strategy to reduce CKD is to leverage the use of teletechnology to expand the VA's outreach to Veterans with kidney disease. A wide array of teletechnology services have been deployed to both pull in Veterans and push out kidney health services to Veterans in their preferred health care venue. Teletechnology, thus, expands Veteran choice, facilitates their access to care, and furthers the goal of delivering patient-centered kidney specialty care. The VA has demonstrated the feasibility of virtual delivery of kidney specialty care services and education via synchronous and asynchronous approaches. The challenges ahead include determining the relative health care value of kidney telehealth services, identifying Veterans most likely to benefit from specific technologies and optimizing the adoption of effective kidney telehealth services by both providers and patients alike to ensure optimal and timely kidney health care delivery., (Published by Elsevier Inc.)

Nonviral gene delivery to the liver has been under evolution for nearly 30years. Early demonstrations established relatively simple nonviral vectors could mediate gene expression in HepG2 cells which understandably led to speculation that these same vectors would be immediately successful at transfecting primary hepatocytes in vivo. However, it was soon recognized that the properties of a nonviral vector resulting in efficient transfection in vitro were uncorrelated with those needed to achieve efficient nonviral transfection in vivo. The discovery of major barriers to liver gene transfer has set the field on a course to design biocompatible vectors that demonstrate increased DNA stability in the circulation with correlating expression in liver. The improved understanding of what limits nonviral vector gene transfer efficiency in vivo has resulted in more sophisticated, low molecular weight vectors that allow systematic optimization of nanoparticle size, charge and ligand presentation. While the field has evolved DNA nanoparticles that are stable in the circulation, target hepatocytes, and deliver DNA to the cytosol, breaching the nucleus remains the last major barrier to a fully successful nonviral gene transfer system for the liver. The lessons learned along the way are fundamentally important to the design of all systemically delivered nanoparticle nonviral gene delivery systems., (Copyright © 2015 Elsevier B.V. All rights reserved.)

PEGylated polylysine peptides of the general structure PEG30 kDa-Cys-Trp-LysN (N = 10 to 30) were used to form fully condensed plasmid DNA (pGL3) polyplexes at a ratio of 1 nmol of peptide per μg of DNA (ranging from N:P 3:1 to 10:1 depending on Lys repeat). Co-administration of 5 to 80 nmols of excess PEG-peptide with fully formed polyplexes inhibited the liver uptake of (125)I-pGL3-polyplexes. The percent inhibition was dependent on the PEG-peptide dose and was saturable, consistent with inhibition of scavenger receptors. The scavenger receptor inhibition potency of PEG-peptides was dependent on the length of the Lys repeat, which increased 10-fold when comparing PEG30 kDa-Cys-Trp-Lys10 (IC50 of 20.2 μM) with PEG30 kDa-Cys-Trp-Lys25 (IC50 of 2.1 μM). We hypothesize that PEG-peptides inhibit scavenger receptors by spontaneously forming small 40 to 60 nm albumin nanoparticles that bind to and saturate the receptor. Scavenger receptor inhibition delayed the metabolism of pGL3-polyplexes, resulting in efficient gene expression in liver hepatocytes following delayed hydrodynamic dosing. PEG-peptides represent a new class of scavenger inhibitors that will likely have broad utility in blocking unwanted liver uptake and metabolism of a variety of nanoparticles.

The expression efficiency in liver following hydrodynamic delivery of in vitro transcribed mRNA was improved 2000-fold using a codon-optimized mRNA luciferase construct with flanking 3' and 5' human β-globin untranslated regions (UTR mRNA) over an unoptimized mRNA without β-globin UTRs. Nanoparticle UTR mRNA polyplexes were formed using a novel polyacridine polyethylene glycol (PEG) peptide, resulting in an additional 15-fold increase in expression efficiency in the liver. The combined increase in expression for UTR mRNA PEG-peptide polyplexes was 3500-fold over mRNA lacking UTRs and PEG-peptide. The expression efficiency of UTR mRNA polyplex was 10-fold greater than the expression from an equivalent 1 μg dose of pGL3. Maximal expression was maintained from 4 to 24 h. Serum incubation established the unique ability of the polyacridine PEG-peptide to protect UTR mRNA polyplexes from RNase metabolism by binding to double-stranded regions. UTR mRNA PEG-peptide polyplexes are efficient nonviral vectors that circumvent the need for a nuclear uptake, representing an advancement toward the development of a targeted gene delivery system to transfect liver hepatocytes.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu., (Copyright © 2015 Leung et al.)

The miniaturization of gene transfer assays to either 384- or 1536-well plates greatly economizes the expense and allows much higher throughput when transfecting immortalized and primary cells compared with more conventional 96-well assays. To validate the approach, luciferase and green fluorescent protein (GFP) reporter gene transfer assays were developed to determine the influence of cell seeding number, transfection reagent to DNA ratios, transfection time, DNA dose, and luciferin dose on linearity and sensitivity. HepG2, CHO, and NIH 3T3 cells were transfected with polyethylenimine (PEI)-DNA in both 384- and 1536-well plates. The results established optimal transfection parameters in 384-well plates in a total assay volume of 35μl and in 1536-well plates in a total assay volume of 8μl. A luciferase assay performed in 384-well plates produced a Z' score of 0.53, making it acceptable for high-throughput screening. Primary hepatocytes were harvested from mouse liver and transfected with PEI DNA and calcium phosphate DNA nanoparticles in 384-well plates. Optimal transfection of primary hepatocytes was achieved on as few as 250cellsperwell in 384-well plates, with CaPO4 proving to be 10-fold more potent than PEI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Two uptake mechanisms were identified for PEGylated DNA polyplex biodistribution to the liver. At a low polyplex dose, a rapid-uptake mechanism dominates, resulting in 60% capture by liver in 5 min, due to a saturable receptor-mediated process. Rapid-uptake led to the fast metabolism of polyplexes by liver (t1/2 = 2.1 h), correlating with a 1-μg pGL3 polyplex dose losing full transfection competency after 4 h in the liver. Dose escalation of either polyplex or poly(ethylene glycol) (PEG) peptide led to the saturation of rapid-uptake and revealed a delayed-uptake mechanism for polyplexes by liver. Delayed-uptake was characterized by the slower liver accumulation of 40% of the polyplex dose over 40 min, followed by slow metabolism (t1/2 = 15 h) and an extended time (12 h) for a 1-μg pGL3 polyplex dose, remaining fully transfection competent in the liver. The delayed-uptake mechanism is consistent with polyplexes crossing liver fenestrated endothelial cells to reach steady state in the space of Disse. The results describe how to control polyplex biodistribution to liver to avoid rapid-uptake and metabolism, in favor of delayed-uptake, to preserve polyplex transfection competency in the liver for up to 12 h.

The first governmental agency to provide maintenance hemodialysis to patients with end-stage renal disease (ESRD) was the Veterans Administration (VA; now the US Department of Veterans Affairs). Many historical VA policies and programs set the stage for the later care of both veteran and civilian patients with ESRD. More recent VA initiatives that target restructuring of care models based on quality management, system-wide payment policies to promote cost-effective dialysis, and innovation grants aim to improve contemporary care. The VA currently supports an expanded and diversified nationwide treatment program for patients with ESRD using an integrated patient-centered care paradigm. This narrative review of ESRD care by the VA explores not only the medical advances, but also the historical, socioeconomic, ethical, and political forces related to the care of veterans with ESRD., (Published by Elsevier Inc.)

Background: American College of Rheumatology guidelines recommend that patients taking glucocorticoids also take calcium and vitamin D supplements, regardless of the dose or intended duration of glucocorticoid use, to decrease their risk of glucocorticoid-induced osteopenia or osteoporosis (GIOP)., Objective: To increase the number of prescriptions made for calcium and vitamin D in patients who receive a prescription for glucocorticoids using an automated, computerized order set., Design: Pre-post test design., Patients: A total of 1,041 outpatients receiving care at a single VA medical center. INTERVENTION/MAIN MEASURES: We developed an automated order set in which calcium and vitamin D were automatically co-ordered with glucocorticoid prescriptions of at least 2-week duration. We tested the impact of the order set by comparing the number of calcium and vitamin D prescriptions in patients taking glucocorticoids during a 12-month period before (T1) and after (T2) implementation. The automated order set could be modified by the treating physician, and it was not generated for patients with hypercalcemia., Key Results: A total of 535 patients during T1 and 506 patients during T2 had a glucocorticoid prescription of at least 2-week duration. The percent of co-prescriptions for calcium increased from 37 to 49% and vitamin D from 38 to 53% (both p < 0.0001) after the new automated order set was implemented., Conclusions: Implementation of an automatic prescription for calcium and vitamin D supplementation modestly increases the number of patients on glucocorticoids who are prescribed calcium and vitamin D supplementation.

Background: The Hamiltonian Path Problem asks whether there is a route in a directed graph from a beginning node to an ending node, visiting each node exactly once. The Hamiltonian Path Problem is NP complete, achieving surprising computational complexity with modest increases in size. This challenge has inspired researchers to broaden the definition of a computer. DNA computers have been developed that solve NP complete problems. Bacterial computers can be programmed by constructing genetic circuits to execute an algorithm that is responsive to the environment and whose result can be observed. Each bacterium can examine a solution to a mathematical problem and billions of them can explore billions of possible solutions. Bacterial computers can be automated, made responsive to selection, and reproduce themselves so that more processing capacity is applied to problems over time., Results: We programmed bacteria with a genetic circuit that enables them to evaluate all possible paths in a directed graph in order to find a Hamiltonian path. We encoded a three node directed graph as DNA segments that were autonomously shuffled randomly inside bacteria by a Hin/hixC recombination system we previously adapted from Salmonella typhimurium for use in Escherichia coli. We represented nodes in the graph as linked halves of two different genes encoding red or green fluorescent proteins. Bacterial populations displayed phenotypes that reflected random ordering of edges in the graph. Individual bacterial clones that found a Hamiltonian path reported their success by fluorescing both red and green, resulting in yellow colonies. We used DNA sequencing to verify that the yellow phenotype resulted from genotypes that represented Hamiltonian path solutions, demonstrating that our bacterial computer functioned as expected., Conclusion: We successfully designed, constructed, and tested a bacterial computer capable of finding a Hamiltonian path in a three node directed graph. This proof-of-concept experiment demonstrates that bacterial computing is a new way to address NP-complete problems using the inherent advantages of genetic systems. The results of our experiments also validate synthetic biology as a valuable approach to biological engineering. We designed and constructed basic parts, devices, and systems using synthetic biology principles of standardization and abstraction.

Acute kidney injury (AKI) is common among critically ill patients and results in increased mortality in this population. This review focuses on the diagnosis and management of AKI. The authors first explore new aspects of diagnosis, including new criteria that take into account even modest changes in renal function, and the development of novel biomarkers to allow earlier identification and better differential diagnosis of AKI. The authors also explore the available data on choice of dialysis modality and dialysis dose for the treatment of AKI, as well as the breakthrough development of the bioartificial kidney. Last, the authors review co-interventions that may have relevance to prognosis of AKI, such as intensive insulin therapy and the use of erythropoietin.

Determination of the optimal dose of renal replacement therapy in critically ill patients with acute kidney injury has been controversial. Questions have recently been raised regarding the design and execution of the US Department of Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) Study, which demonstrated no improvement in 60-day all-cause mortality with more intensive management of renal replacement therapy. In the present article we present our rationale for these aspects of the design and conduct of the study, including our use of both intermittent and continuous modalities of renal support, our approach to initiation of study therapy and the volume management during study therapy. In addition, the article presents data on hypotension during therapy and recovery of kidney function in the perspective of other studies of renal support in acute kidney injury. Finally, we address the implications of the ATN Study results for clinical practice from the perspective of the study investigators.

Background: The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial., Methods: We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour., Results: Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups., Conclusions: Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.), (2008 Massachusetts Medical Society)

Background and Objectives: Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies., Design, Setting, Participants, & Measurements: Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable., Results: 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%., Conclusions: The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Although the National Kidney Foundation (NKF) has published clinical practice guidelines for the management of risk factors for cardiovascular disease, these guidelines have not been tested rigorously for their effectiveness. We conducted an observational study among patients with end-stage kidney disease to examine the prognostic impact of threshold levels recommended by the NKF for blood pressure, hemoglobin, calcium-phosphate product, parathyroid hormone, low-density lipoprotein, and glycosylated hemoglobin. The study population (N = 197) was assembled from a previously completed randomized trial examining arteriovenous graft thrombosis. Cox proportional hazard analysis was used to calculate hazard ratios for the association of levels outside guideline recommended targets and death, adjusting for age, comorbidity, race, and albumin. The proportion of patients outside guideline targets ranged from 33% to 81%, and the impact of levels outside guideline targets on mortality varied substantially. Elevated calcium-phosphate product and glycosylated hemoglobin had harmful effects, with adjusted hazard ratios of 1.58 (95% CI 1.00-2.50; p = 0.050) and 2.21 (95% CI 0.99-4.97; p = 0.054), respectively. Nontarget levels for blood pressure, hemoglobin, and parathyroid hormone had little effect, with adjusted hazard ratios of 1.15 (95% CI 0.74-1.78; p = 0.542), 1.04 (95% CI 0.65-1.68; p = 0.866), and 0.90 (95% CI 0.50-1.61; p = 0.722), respectively. Elevated low-density lipoprotein had a paradoxically beneficial effect, with an adjusted hazard ratio of 0.48 (95% CI 0.23-1.00; p = 0.049). These results suggest that the prognostic impact of current threshold levels recommended by select NKF guidelines on mortality is variable. Accordingly, the development and implementation of clinical practice guidelines should be accompanied by corresponding efforts to confirm their impact on patient outcomes. Such efforts are essential for the improvement of guidelines and to inform health policy optimally.

Current literature suggests that side holes may be detrimental to dialysis catheter performance. Today, these catheters are primarily available with side holes. The purpose of this study was to compare flow rates, infection rate, and survival of side hole vs. non side hole hemodialysis catheters. Over a 16-month period patients were arbitrarily assigned to either a 14.5 F MAHURKAR MAXID cuffed dual lumen tunneled catheter with side holes or a 14.5 F MAHURKAR MAXID cuffed dual lumen tunneled catheter without side holes ("non side hole catheters"). We performed a retrospective analysis of catheter flow rates, patency, catheter survival, and catheter-related infections. Information was gathered for the life of the catheter or up to 28 weeks. A total of 54 patients were enrolled in the study. Thirty-seven of 54 (68%) patients received a catheter with side holes for a total of 3,930 catheter days and 17/54 (32%) received a similar catheter without side holes for a total of 2,188 catheter days. Catheter infection necessitating removal of the catheter occurred in 10/37 catheters with side holes and 1/17 without side holes. Infection rates per 1,000 catheter days were 2.545 with side holes and 0.254 without side holes (p<0.001). Slightly improved catheter survival (p<0.05) was recorded with the non side hole catheters. No insertion complication (e.g., air embolization, bleeding, or kinking) occurred with either catheter. One catheter without side holes had to be repositioned 5 days after insertion because of poor flows. No significant difference was recorded in mean blood flow rates between the catheters. Results indicate reduced catheter infection rate in hemodialysis patients with the use of non side hole dual lumen tunneled cuffed catheters.

Objective: It is uncertain which blood pressure values (pre- or post-haemodialysis) best represent the average daily blood pressure in haemodialysis patients. The purpose of this study was to verify the power of peridialysis blood pressure to predict interdialytic blood pressure, and to ascertain the influence of blood pressure fluctuations during dialysis on this predictive ability., Methods and Results: We performed ambulatory blood pressure monitoring during the interdialytic period on 60 stable haemodialysis patients (mean age 53 +/- 16 years, 33 male) between two mid-week haemodialysis sessions. Pre- and post-haemodialysis blood pressures were 154/82 and 142/77 mmHg, respectively, and 44-h interdialytic blood pressure was 136/77 mmHg. Overall, post-haemodialysis blood pressure values correlated with interdialytic ambulatory blood pressure marginally better than did pre-haemodialysis values (r = 0.52 versus 0.61 for pre- and post-dialysis systolic pressure, respectively; r = 0.67 versus 0.72 for pre- and post-dialysis diastolic pressure, respectively). The average of the pre- and post-haemodialysis values showed a slightly better correlation with interdialytic blood pressure (r = 0.65 and 0.75 for systolic and diastolic pressure, respectively). When we stratified patients according to systolic blood pressure behaviour during dialysis, pre-dialysis blood pressure was the stronger predictor of interdialytic blood pressure in the quartile with greatest intradialytic blood pressure fall (r = 0.67 versus 0.44 for pre- and post-dialysis systolic blood pressure, respectively), whereas post-dialysis values were substantially better in the group with a rise in systolic pressure during dialysis (r = 0.26 versus 0.59 for pre- and post-dialysis systolic blood pressure, respectively)., Conclusions: These data demonstrate that peridialysis blood pressure values are of limited accuracy in predicting interdialytic blood pressure, post-dialysis values are minimally better predictors than pre-dialysis blood pressures, and the average of pre- and post-haemodialysis values is marginally better than both. In addition, blood pressure fluctuations during dialysis have a sizable impact on this predictive ability. Clinical decisions related to blood pressure management and research design in haemodialysis hypertension should take these factors into account.

Aim: Human immunodeficiency virus-associated nephropathy (HIVAN) is projected to be a leading cause of end-stage renal disease (ESRD) in young African American men in the new millennium. Little is known about the early natural history of the disease, including the prevalence of asymptomatic nephropathy. The primary aim of this study was to define the prevalence of persistent asymptomatic proteinuria in a contemporary, ambulatory human immunodeficiency virus- (HIV) infected population. The secondary aim was to correlate the presence of persistent proteinuria with measures of HIV disease., Methods: Using a readily available screening tool, the urine dipstick, we determined the prevalence of persistent asymptomatic proteinuria in the outpatient VA Connecticut (VA CT) Healthcare System West Haven HIV Clinic population. We compared the presence of persistent proteinuria with measures of HIV viral disease., Results: The prevalence of persistent asymptomatic proteinuria was 14% (7 of 49 patients). The presence of persistent proteinuria was not correlated with viral load., Conclusions: A significant prevalence of occult renal disease exists in the asymptomatic HIV-seropositive outpatient population and is not correlated with viral load.

Ambulatory blood pressure monitoring (ABPM) has been increasingly used in hemodialysis (HD) practice and research; however, no study has evaluated the reproducibility of ABPM in this population. To address this question, we performed 48-hour interdialytic ABPM on 21 HD patients (mean age, 53 +/- 16 years; 7 women) on two different occasions 68 +/- 34 days (range, 30 to 154 days) apart. To qualify for the protocol, patients had to be at the same dry weight and on the same vasoactive drug regimen at both monitoring periods. BP was analyzed according to three different methods: isolated pre-HD and post-HD values, average pre-HD and post-HD values for the five HD sessions surrounding each monitoring period, and 48-hour interdialytic ABPM. Reproducibility was determined by analysis of the SD of the differences (SDD) between the two monitoring periods and the coefficient of variation of each method of BP determination. Our results show better reproducibility of ABPM (SDD, 10.6/6.6 mm Hg; coefficient of variation, 7.5%/8.1%) compared with isolated pre-HD BP (SDD, 24.4/11.3 mm Hg; coefficient of variation, 16.7%/14.1%) or post-HD BP (SDD, 16.8/14.5 mm Hg; coefficient of variation, 11.7%/17.8%), and averaged pre-HD BP (SDD, 14.7/7.2 mm Hg; coefficient of variation, 10.1%/9.1%) or post-HD BP (SDD, 12.4/8.7 mm Hg; coefficient of variation, 8.9%/11.1%). The reproducibility of the decrease in BP during sleep was poor, with up to 43% of the subjects changing dipping category within or between interdialytic periods. We conclude that ABPM is the most accurate method to study BP in HD patients over time. However, variability is significant, and there is poor reproducibility of the nocturnal decline in BP.

Background: Background Ambulatory blood pressure monitoring (ABPM) has been used increasingly in assessing dialysis patients. However, devices have not been validated formally for this population. Formal device validation is important in order to guarantee adequate performance for populations with special characteristics, such as patients undergoing hemodialysis., Objective: To achieve formal validation of the SpaceLabs 90207 ambulatory blood pressure device (SLD) using a modified British Hypertension Society protocol., Methods: Eighty-five hemodialysis patients were studied, generating 255 readings. Readings were obtained with patients supine (in a dialysis chair) over 5-10 min during hemodialysis. Simultaneous, same-arm readings were obtained through the use of a T connector to a calibrated mercury manometer. The mean differences between readings obtained by observers and those obtained by the device were calculated. Limits of agreement between observers and SLD were determined and plotted according to the method of Bland and Altman. For grading of performance, we determined the number of readings for which the readings obtained by the device were within 5, 10, and 15mmHg of manometer readings. Final gradings were ascribed according to British Hypertension Society criteria., Results: The mean blood pressure (+/-SD) was 141/76+/-31/15mmHg (observers) and 141/77+/-27/15mmHg (SLD), and the mean (+/-SD) difference between observers and device (observer-device) was -0.5+/-7.5mmHg for systolic blood pressure (SBP) and -0.2+/-5.2mmHg for diastolic blood pressure (DBP). The device was less accurate in extreme ranges of SBP. In fact, there was a positive correlation between average [(observer+device)/2] and difference (observer-device) for SBP (r =0. 54, P <0.0001), showing that underestimation in higher ranges, and overestimation in lower ranges of blood pressure occurred for SBP. For SBP, 53% of readings were within 5mmHg of those obtained by the observers, 85% were within 10mmHg, and 97% within 15mmHg. For DBP, 78% were within 5mmHg, 96% within 10mmHg, and 98% within 15mmHg. These observations conferred on the device grade C for SBP and grade B for DBP. The type of vascular access and the presence of non-functioning arteriovenous grafts and fistulas in the ipsilateral arm did not alter these results significantly., Conclusions: These data validate the use of this device for hemodialysis patients. However, caution should be exercised in the evaluation of upper and lower ranges of SBP.

The differentiation between atheroembolic disease (AED) and allergic interstitial nephritis (AIN) may pose a clinical challenge. Gallium scans have been proposed to identify AIN with good discriminating ability. We report herein a case of atheroembolic disease presenting as acute renal failure with persistent delayed uptake of gallium-67 by nuclear imaging. The distinction between AED and AIN could be made only with a renal biopsy, which confirmed the correct diagnosis. This case report and the presented review of the literature suggest that gallium scans are nonspecific and should not supplant renal biopsy for definitive histological diagnosis.

Angioplasty of the internal mammary artery (IMA) bypass graft has been shown to be a safe and effective revascularization procedure. However, angiographic and long term clinical outcomes in the high-risk group of patients presenting with rest angina has not been well documented. We report the results of IMA angioplasty in 20 patients with rest angina out of 614 (3.2%) who received a left IMA graft at our institution between April 1987 and September 1994. All patients were admitted with rest angina, 12 patients demonstrated persistent ischemia despite medical therapy, two patients were in heart failure, and one patient was in cardiogenic shock. Balloon angioplasty was successful in 15 of 20 patients (75%). Failed angioplasty was associated with either severe IMA tortuousity (three patients) or inability to cross the anastomotic stenosis with the guide wire (two patients). Each of these five patients required angioplasty of either the native left anterior descending artery or other saphenous vein grafts for clinical stabilization. No patient suffered a major complication (myocardial infarction, emergent coronary bypass surgery, death). Clinical follow-up was obtained in all 20 patients (6 months, 7 years, mean 27 months). Twelve patients (60%) were asymptomatic or had stable angina at follow-up, and 8 returned with anginal symptoms. Four patients required repeat angioplasty for disease in other vessels, two were treated medically for angina, one underwent repeat CABG, and cardiac transplantation was performed in one patient for refractory heart failure. Angiographic follow up was obtained in 10/15 (66%) successful angioplasty patients, and only one patient demonstrated restenosis at the treated site (10%). During follow up one patient developed an IMA stenosis at a previous dissection site in the body of the graft that was treated with angioplasty. These results suggest that IMA angioplasty in patients with rest angina is associated with excellent long term patency and clinical efficacy, as well as low procedural risk.

Local release of mitogenic and chemotactic signals during angioplasty-induced vascular injury may initiate restenosis. We investigated whether mechanical injury to vascular smooth muscle cells (VSMC) results in the release of biologically active peptide growth factors. Monolayers of bovine SMC cultures were mechanically injured by cell scraping. Conditioned medium (CM) from control and injured SMC cultures was collected, and the mitogenic activity was measured by [3H]thymidine incorporation in recipient SMC cultures. Mitogenic activity from injured CM was detected within 15 min after injury. When the CM from injured cells was removed 15 min after injury and replaced with serum-free media, there was no detectable mitogenic activity in the replacement CM assessed 1-6 days postinjury. Suramin, a nonspecific peptide growth factor antagonist, significantly inhibited the mitogenic activity of injured CM. Basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF A chain), and epidermal growth factor (EGF) were detected in CM from injured cells by immunoblot analysis. The mitogenic activity of injured CM was significantly inhibited with neutralizing antibodies to bFGF (34%), PDGF-AA (32%), PDGF-BB (25%), and EGF (25%). A neutralizing antibody to transforming growth factor (TGF)-beta had no effect. In conclusion, bFGF, PDGF, and EGF are immediately released from mechanically injured VSMC. VSMC likely contain preformed, biologically active growth factors that are efficiently released from the cell cytoplasm following mechanical injury. Conditioned medium from injured VSMC is highly mitogenic, and this activity is probably due to multiple growth factors interacting synergistically.