Laminin-521: a novel target for pathogenic autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.

Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is an autoimmune disease characterized by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase (MPO), an autoantigen responsible for AAV, increases with age, anti-MPO autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. METHODS: Young (8 weeks) and aged (either 15 or 22 months) mice were immunized with whole proteins or peptides from ovalbumin, as a model foreign antigen, or MPO protein or peptides. Mice were subjected to a model of active anti-MPO glomerulonephritis. Cellular and humoral immune responses, and tissue inflammation were assessed. RESULTS: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to MPO and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen-specific production of the pro-inflammatory cytokines IFN-γ and IL-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell-mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. CONCLUSION: Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of AAV in older people.

Recurrent membranous nephropathy after transplantation: donor antigen and HLA converge in defining risk.

Membranous nephropathy, like many forms of glomerulonephritis, is an HLA-associated autoimmune disease that can recur in the transplanted kidney. In this issue of Kidney International, Berchtold and colleagues publish an intriguing and important paper on risk factors for recurrent post-transplant membranous nephropathy due to autoimmunity to PLA2R1. They found that the genetics of both the autoantigen and donor HLA are important determinants of the risk of recurrent disease in the graft.

Tertiary lymphoid tissue in kidneys: understanding local immunity and inflammation.

Tertiary lymphoid tissues are peripheral foci of immune activity that develop in kidneys and other peripheral organs in the context of chronic inflammation. In this issue of Kidney International, Sato and colleagues present a detailed characterization of tertiary lymphoid tissues in mouse and human kidneys in the context of acute kidney injury, chronic pyelonephritis, aging, and chronic kidney disease, showing the importance of nontraditional roles of B cells in the inflamed kidney microenvironment.

Bronchopulmonary pharmacokinetics of (R)-salbutamol and (S)-salbutamol enantiomers in pulmonary epithelial lining fluid and lung tissue of horses.

AIMS: Salbutamol is usually administered as a racemic mixture but little is known about the enantioselectivity of salbutamol pharmacokinetics in the lung. This study was designed to investigate enantiomer concentrations in lung tissue after inhaled dosing. METHODS: Horses (n = 12) received racemic salbutamol 1000 µg via inhalation. Enantioselective ultra performance liquid chromatography-tandem mass spectrometry was used to determine salbutamol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples. RESULTS: Mean ± 95% confidence interval (CI) yield of PELF was 57 ± 10 mg. Initial mean ± 95%CI (R)- and (S)-salbutamol PELF concentrations were 389 ± 189 ng g-1 and 378 ± 177 ng g-1 respectively, and both reduced approximately 50% by 15 min. Mean ± 95%CI central lung levels of drug were higher than peripheral lung tissue for both (R)-salbutamol (875 ± 945 vs. 49.5 ± 12 ng g-1 ) and (S)-salbutamol (877 ± 955 vs. 50.9 ± 12 ng g-1 ) respectively. There was no evidence of enantioselectivity in PELF or central lung but minor (~2%) enantioselectivity was observed in the peripheral lung. Enantioselectivity was clearly evident in plasma with (S):(R) ratio of 1.25 and 1.14 for both area under the concentration-time curve (0-25 min) and Cmax respectively. CONCLUSIONS: PELF sampling in horses offers sufficient yield allowing direct detection of drug and, combined with tissue sampling, is a valuable model to investigate bronchopulmonary pharmacokinetics. Salbutamol did not demonstrate enantioselectivity in PELF or central lung tissue uptake following acute dosing, however, enantioselective plasma concentrations were demonstrated, with minor enantioselectivity in the peripheral lung.

Exposure-based Interventions for the management of individuals with high levels of needle fear across the lifespan: a clinical practice guideline and call for further research.

Needle fear typically begins in childhood and represents an important health-related issue across the lifespan. Individuals who are highly fearful of needles frequently avoid health care. Although guidance exists for managing needle pain and fear during procedures, the most highly fearful may refuse or abstain from such procedures. The purpose of a clinical practice guideline (CPG) is to provide actionable instruction on the management of a particular health concern; this guidance emerges from a systematic process. Using evidence from a rigorous systematic review interpreted by an expert panel, this CPG provides recommendations on exposure-based interventions for high levels of needle fear in children and adults. The AGREE-II, GRADE, and Cochrane methodologies were used. Exposure-based interventions were included. The included evidence was very low quality on average. Strong recommendations include the following. In vivo (live/in person) exposure-based therapy is recommended (vs. no treatment) for children seven years and older and adults with high levels of needle fear. Non-in vivo (imaginal, computer-based) exposure (vs. no treatment) is recommended for individuals (over seven years of age) who are unwilling to undergo in vivo exposure. Although there were no included trials which examined children < 7 years, exposure-based interventions are discussed as good clinical practice. Implementation considerations are discussed and clinical tools are provided. Utilization of these recommended practices may lead to improved health outcomes due to better health care compliance. Research on the understanding and treatment of high levels of needle fear is urgently needed; specific recommendations are provided.

Galactose therapy reduces proteinuria in patients with recurrent focal segmental glomerulosclerosis after kidney transplantation.

Primary focal segmental glomerulosclerosis is an important cause of end-stage kidney disease with a high rate of recurrent disease after kidney transplantation. Current therapy achieves remission in only half of patients. Recent interest has focused on the potential role of galactose in binding and inactivating the putative circulating permeability factor, supported by in vitro and clinical case report studies. Orally active and without major adverse effects, galactose has a favourable treatment profile compared with current immunosuppressive treatment options. We describe our experience using galactose therapy in two patients with recurrent focal segmental glomerulosclerosis after renal transplantation. Galactose was associated with symptomatic improvement and stabilization of graft function in one case; the other case was complicated by concurrent malignancy. In both cases, we observed a marked reduction in proteinuria with galactose treatment.

Evaluation of the Family Integrated Care model of neonatal intensive care: a cluster randomized controlled trial in Canada and Australia.

BACKGROUND: Admission to the neonatal intensive care unit (NICU) may disrupt parent-infant interaction with adverse consequences for infants and their families. Several family-centered care programs promote parent-infant interaction in the NICU; however, all of these retain the premise that health-care professionals should provide most of the infant's care. Parents play a mainly supportive role in the NICU and continue to feel anxious and unprepared to care for their infant after discharge. In the Family Integrated Care (FICare) model, parents provide all except the most advanced medical care for their infants with support from the medical team. Our hypothesis is that infants whose families complete the FICare program will have greater weight gain and better clinical and parental outcomes compared with infants provided with standard NICU care. METHODS/DESIGN: FICare is being evaluated in a cluster randomized controlled trial among infants born at ≤ 33 weeks' gestation admitted to 19 Canadian, 6 Australian, and 1 New Zealand tertiary-level NICU. Trial enrollment began in April, 2013, with a target sample size of 675 infants in each arm, to be completed by August, 2015. Participating sites were stratified by country, and by NICU size within Canada, for randomization to either the FICare intervention or control arm. In intervention sites, parents are taught how to provide most of their infant's care and supported by nursing staff, veteran parents, a program coordinator, and education sessions. In control sites standard NICU care is provided. The primary outcome is infants' weight gain at 21 days after enrollment, which will be compared between the FICare and control groups using Student's t-test adjusted for site-level clustering, and multi-level hierarchical models accounting for both clustering and potential confounders. Similar analyses will examine secondary outcomes including breastfeeding, clinical outcomes, safety, parental stress and anxiety, and resource use. The trial was designed, is being conducted, and will be reported according to the CONSORT 2010 guidelines for cluster randomized controlled trials. DISCUSSION: By evaluating the impact of integrating parents into the care of their infant in the NICU, this trial may transform the delivery of neonatal care. TRIAL REGISTRATION: NCT01852695 , registered December 19, 2012.

Improvements in staff quality of work life and family satisfaction following the move to single-family room NICU design.

OBJECTIVE: The purpose of this study was to determine whether there were differences in staff quality of work life and parent satisfaction when a neonatal intensive care unit moved from an open-bay design to a single-room model of care. DESIGN: This descriptive study measured staff quality of work life and family satisfaction before and at 2 time periods after the relocation of a perinatal centre and the introduction of single-family room care. Differences in work life quality and satisfaction were determined using 2-sample t-tests. RESULT: There were improvements in staff quality of work life and family satisfaction at both time periods following the move. CONCLUSION: Lessons learned may be of value to other units considering such a move. A neonatal intensive care unit designed to contribute to parental and staff well-being is a model to be considered for future neonatal designs.

A pilot cohort analytic study of Family Integrated Care in a Canadian neonatal intensive care unit.

BACKGROUND: We have developed a Family Integrated Care (FIC) model for use in a neonatal intensive care unit (NICU) where parents provide most of the care for their infant, while nurses teach and counsel parents. The objective of this pilot prospective cohort analytic study was to explore the feasibility, safety, and potential outcomes of implementing this model in a Canadian NICU. METHODS: Infants born ≤ 35 weeks gestation, receiving continuous positive airway pressure or less respiratory support, with a primary caregiver willing and able to spend ≥ 8 hours a day with their infant were eligible. Families attended daily education sessions and were mentored at the bedside by nurses. The primary outcome was weight gain, as measured by change in z-score for weight 21 days after enrolment. For each enrolled infant, we identified two matched controls from the previous year's clinical database. Differences in weight gain between the two groups were analyzed using a linear mixed effects multivariable regression model. We also measured parental stress levels using the Parental Stress Survey: NICU, and interviewed parents and nurses regarding their experiences with FIC. RESULTS: This study included 42 mothers and their infants. Of the enrolled infants, matched control data were available for 31 who completed the study. The rate of change in weight gain was significantly higher in FIC infants compared with control infants (p < 0.05). There was also a significant increase in the incidence of breastfeeding at discharge (82.1 vs. 45.5%, p < 0.05). The mean Parental Stress Survey: NICU score for FIC mothers was 3.06 ± 0.12 at enrolment, which decreased significantly to 2.30 ± 0.13 at discharge (p < 0.05). Feedback from the parents and nurses indicated that FIC was feasible and appropriately implemented. CONCLUSIONS: This study suggests that the FIC model is feasible and safe in a Canadian healthcare setting and results in improved weight gain among preterm infants. In addition, this innovation has the potential to improve other short and long-term infant and family outcomes. A multi-centre randomized controlled trial is needed to further evaluate the efficacy of FIC in the Canadian context.

Implementing family-integrated care in the NICU: engaging veteran parents in program design and delivery.

The purpose of this article is to describe and evaluate how "veteran" parents were engaged as experts in the design and implementation of a family-integrated care program in a Canadian neonatal intensive care unit (NICU). Three parents of preterm infants previously discharged from the NICU participated in the design and implementation of a family-integrated care pilot program. The steering committee for the program included 5 staff members (a physician, a NICU nurse, a parent education nurse, a lactation consultant, and a social worker) and the parent volunteers. This article includes a total of 42 mothers of infants born at 35-week gestation or less were enrolled in the pilot program. A detailed description and qualitative evaluation of the engagement of veteran parents in the design and implementation of the family-integrated care program. The effectiveness of engaging veteran parents in developing this model of care was evaluated by written feedback from the veteran parents and the other steering committee members. In addition, a structured interview at discharge with the 42 mothers enrolled in the pilot study was used to assess their experiences of the peer-to-peer support provided by veteran parents. Veteran NICU parents brought a wealth of wisdom and expertise developed through personal experience to the design and implementation of the family-integrated care program. The veteran parents played a significant role in both the initial development of the program and in the provision of peer-to-peer support during program implementation. Engagement of parents with prior experience of the NICU care environment is a critical step in the design and implementation of a program of family-integrated care.

Implementation of a Meds to Beds Medication Use Program and Parent Experience at the Time of Transition From a Neonatal Intensive Care Unit to Home.

OBJECTIVE: This study aims to describe the overall experience of the neonatal intensive care unit (NICU) parent at time of transition home related to discharge medication use, following implementation of a Meds to Beds program. METHODS: A descriptive, qualitative study was used to explore parent experiences around medication use during transition home. Eleven parents whose infants required medications at the time of transition home from the NICU participated in a semi-structured telephone interview post-discharge. The data were coded and analyzed for themes. RESULTS: Major themes nested within the key stages of medication use in preparation for transition home from the NICU were identified: in-hospital preparation (practice early and often, Meds to Beds, and relationship with clinical pharmacist), transition home (schedule and routine, strategies for medication administration) and post-discharge (refills and long-term medication management). Strategies based on parent experiences to improve the process and ameliorate anxiety are presented. CONCLUSIONS: Parents expressed how effective the Meds to Beds program was on the transition home by increasing parental confidence and knowledge around medications and reducing stress around the acquisition of medications for home. They also reported comfort in having a relationship with the NICU clinical pharmacist, providing a tailored approach to coordinating care both in hospital and during the transition home. Regardless of implementation of a Meds to Beds program, great opportunities remain to refine the transition home. Implementing the suggested improvement strategies could provide significant positive effects with respect to patient care and parental stress during the transition home.

Glomerular Disease Education Experience across Nephrology Fellowship Programs: An International Survey.

Introduction: Glomerulonephritis (GN) education is an important, albeit a challenging, component of nephrology fellowship training. We hypothesized that trainee experience varies widely across programs, leading to differences in self-reported competency levels in the diagnosis and management of glomerular diseases. Methods: The Glomerular Disease Study & Trial Consortium (GlomCon) conducted an anonymous online survey to determine the educational experience of nephrology trainees. We used multiple-choice questions to obtain data about (a) curriculum-based education, (b) dedicated specialty clinic, and (c) exposure to pathology. We leveraged a visual analog scale of 1-100 (with a higher number indicating a higher comfort level) to assess self-reported levels of clinical competency. The survey was disseminated via email to the subscribing members of GlomCon and through Twitter. Results: In total, there were 109 respondents to our survey, and 56% were from training programs in the USA. Exposure to a specialized GN clinic was reported by 45%, while 77% reported the presence of an onsite nephropathologist at their training program. Self-reported competency scores were 59 ± 25 and 52 ± 25 for diagnosis and treatment of glomerular diseases, respectively. Days spent in a GN clinic per year, years of fellowship, and dedicated nephropathology didactics were associated with higher diagnosis and treatment competency scores. Conclusion: Trainees report a wide variation in glomerular disease education across fellowship programs. A lack of nephropathology exposure and a dedicated GN curriculum was associated with lower scores in self-reported clinical competency in caring for patients with glomerular disease.

Coached, Coordinated, Enhanced Neonatal Transition (CCENT): protocol for a multicentre pragmatic randomised controlled trial of transition-to-home support for parents of high-risk infants.

INTRODUCTION: Having an infant admitted to the neonatal intensive care unit (NICU) is associated with increased parental stress, anxiety and depression. Enhanced support for parents may decrease parental stress and improve subsequent parent and child outcomes. The Coached, Coordinated, Enhanced Neonatal Transition (CCENT) programme is a novel bundled intervention of psychosocial support delivered by a nurse navigator that includes Acceptance and Commitment Therapy-based coaching, care coordination and anticipatory education for parents of high-risk infants in the NICU through the first year at home. The primary objective is to evaluate the impact of the intervention on parent stress at 12 months. METHODS AND ANALYSIS: This is a multicentre pragmatic randomised controlled superiority trial with 1:1 allocation to the CCENT model versus control (standard neonatal follow-up). Parents of high-risk infants (n=236) will be recruited from seven NICUs across three Canadian provinces. Intervention participants are assigned a nurse navigator who will provide the intervention for 12 months. Outcomes are measured at baseline, 6 weeks, 4, 12 and 18 months. The primary outcome measure is the total score of the Parenting Stress Index Fourth Edition Short Form at 12 months. Secondary outcomes include parental mental health, empowerment and health-related quality of life for calculation of quality-adjusted life years (QALYs). A cost-effectiveness analysis will examine the incremental cost of CCENT versus usual care per QALY gained. Qualitative interviews will explore parent and healthcare provider experiences with the intervention. ETHICS AND DISSEMINATION: Research ethics approval was obtained from Clinical Trials Ontario, Children's Hospital of Eastern Ontario Research Ethics Board (REB), The Hospital for Sick Children REB, UBC Children's and Women's REB and McGill University Health Centre REB. Results will be shared with Canadian level III NICUs, neonatal follow-up programmes and academic forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03350243).

Towards an architecture of flexibility.

OBJECTIVE: Our objective was to explore the case for adoption of flexibility as a core value in the design process for Neonatal Intensive Care Units (NICUs). METHODS: Guidelines for NICU design and care of NICU patients and families were examined to identify opportunities for building flexibility into NICU design to optimize function and experience. RESULTS: Benefits of building flexibility into NICU design included the ability for units to adapt quickly and economically to unpredictable events and demographic changes. Further, by centering family presence as a design necessity, NICUs may better protect families from experiencing additional harm due to separation and interruption of restorative activities. We were able to highlight several examples of current NICUs, which have successfully adopted flexible design and operational models to provide optimal levels of clinical and family-centered care. CONCLUSION: By intentionally incorporating flexibility into the design of an NICU, infants, families, and healthcare providers can be provided with an environment that can adapt to shifting needs to optimally support unit function and clinical outcomes.

Integrating Parents in Neonatal and Pediatric Research.

BACKGROUND: Parents and their infants are the beneficiaries of neonatal and pediatric research, but in the past they have been excluded from most stages of research projects. As a result, many projects may fail to produce the most worthwhile information for parents and families. Lately, veteran resource parents and patients have been increasingly integrated in research initiatives. METHODS: Benchmarking of neonatal and pediatric research initiatives where resource parents and/or ex neonatal patients have helped to optimize pediatric research. We review ways in which resource parents/patients can be involved in research, with examples and practical ideas of how to proceed. RESULTS: Resource parents/patients can be collaborators in research and be integrated in many steps: prioritizing research projects, designing trials, determining the outcomes of interest, ethics review, developing and improving consent procedures, collection and interpretation of data, participation in data safety monitoring committees, publication of results, and presentation to peer groups. Some of the strategies for integration of stakeholders in clinical research are more complex, may involve risk and require more training than others. CONCLUSION: We suggest that groups wanting to involve parents in their research endeavors start with simpler tasks that entail less risk and develop teams of resource parents who have differing interests and abilities. Quality control of programs is essential, such as frequently giving and obtaining feedback from resource parents/patients and researchers. In the future, integration of resource parents/patients into every step of clinical research will be essential to ensure that parent and family important outcomes are examined.

Does It Matter if This Baby Is 22 or 23 Weeks?

A 530-g girl born at 22 weeks and 6 days' gestation (determined by an ultrasound at 11 weeks) was admitted to the NICU. Her mother had received prenatal steroids. At 12 hours of age, she was stable on low ventilator settings. Her blood pressure was fine. Her urine output was good. After counseling, her parents voiced understanding of the risks and wanted all available life-supporting measures. Many nurses were distressed that doctors were trying to save a "22-weeker." In the past, 4 infants born at 22 weeks' gestation had been admitted to that NICU, and all had died. The attending physician on call had to deal with many sick infants and the nurses' moral distress.

PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.