Sex as a biological variable in acute kidney injury.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the preclinical and clinical studies investigating sex as a biological variable, as well as the impact of gender, on the development of and progression of acute kidney injury (AKI). RECENT FINDINGS: Despite a matched degree of ischemia-reperfusion AKI based on measured glomerular filtration rates, male and female mice demonstrated important sex biases in cardiorenal outcomes (1). Although the 2012 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for AKI reported that female sex is associated with increased rates of hospital acquired AKI, subsequent meta-analyses do not show increased risk of AKI in women. Recent large scale, multicenter epidemiologic studies suggest males have higher rates of hospital acquired AKI. However, women have been consistently shown to have worse renal outcomes after AKI. There may be also be gender-based differences in presentation to care and management. SUMMARY: Sex is an important biological variable in animal models of acute kidney injury. The impact of sex on AKI likely varies based on the etiology of AKI. Preclinical studies demonstrate the nuances of sex chromosomes, sex hormones and epigenetic factors on AKI, however these have not been well studied in humans. Gender may also impact processes of care, treatment and clinical outcomes related to AKI. The scientific rigor and reproducibility of translational studies benefit from the consideration of sex and gender.

Knowledge and Practice of Incremental Hemodialysis: A Survey of Canadian Nephrologists.

BACKGROUND: Incremental hemodialysis, a strategy to individualize dialysis prescription based on residual kidney function, may be associated with enhanced quality of life and decreased health care costs compared with conventional hemodialysis. OBJECTIVE: We surveyed practicing Canadian nephrologists to assess knowledge, perceptions, and practice pattern on the use of incremental hemodialysis. DESIGN/SETTING: We distributed a cross-sectional, web-based survey. We asked about incremental hemodialysis prescribing practices, including frequency of prescription, clinical factors used to determine suitability for treatment, and barriers to implementation. The survey was conducted from September 21 to October 30, 2020. PARTICIPANTS: We distributed the survey to practicing Canadian nephrologists identified from a private membership list of the Canadian Society of Nephrology (CSN), as well as to nephrologists named on a publicly available national list of practicing Canadian nephrologists created from provincial College of Physician registries. These were samples of convenience. METHODS: We conducted descriptive analysis of categorical data including frequencies for nominal variables and measures of central tendency (mean) and dispersion (standard deviation) for ordinal variables. We used chi-square analysis to identify association between participant and practice characteristics and their opinions and attitudes toward incremental dialysis. We used simple thematic analysis on free-text responses on questions regarding the prescription of incremental hemodialysis, focusing on age and baseline management of cardiac and noncardiac comorbidities. RESULTS: The response rate was 35% (243/691). Most (138/211, 65%) of the participants prescribed incremental hemodialysis using an individualized approach at the nephrologist's discretion. Most participants (200/203, 98%) did not report any policy for implementation. Residual urine output was identified as the most important factor for eligibility (112/172, 65%), followed by electrolyte stability (76/172, 44%) and patient goals of care (69/117, 40%). Most participants agreed that dialysis prescriptions should take residual kidney function into consideration; however, 74% of the participants disagreed with a statement that there was strong evidence supporting incremental hemodialysis. Barriers identified included patient safety, patient acceptance of dose escalation, and logistics of scheduling. Despite these barriers, 82% of participants felt that that incremental hemodialysis is feasible with their current resources and 78% agreed that with specific criteria, it is a safe option. LIMITATIONS: The generalizability of our study is limited by its response rate of 35%; however, this is comparable with typical response rates seen in electronic surveys. Most participants practice in an academic setting, which may have introduced bias to the results. CONCLUSIONS: Despite the perception of limited evidence and a lack of guidance on implementation, incremental hemodialysis is frequently practiced by Canadian nephrologists. Barriers to implementation were identified, highlighting the need for research to guide practice.

CONTEXTE: L'hémodialyse incrémentale est une stratégie tenant compte de la fonction rénale résiduelle pour individualiser la prescription de dialyse. Comparée à l'hémodialyse conventionnelle, cette modalité pourrait être associée à une amélioration de la qualité de vie des patients et à une réduction des coûts de santé. OBJECTIF: Nous avons interrogé des néphrologues canadiens en exercice afin d'évaluer leurs connaissances, leurs perceptions et leurs habitudes de pratique relativement à l'hémodialyse incrémentale. CONCEPTION DE L'ÉTUDE: Une enquête transversale en ligne a été distribuée. Les questions portaient sur les pratiques de prescription de l'hémodialyse incrémentale, notamment sur la fréquence de prescription, les facteurs cliniques utilisés pour déterminer l'adéquation du traitement, et les obstacles à la mise en œuvre. Le sondage a été réalisé entre le 21 septembre et le 30 octobre 2020. PARTICIPANTS: Nous avons distribué le sondage aux néphrologues canadiens en exercice figurant sur une liste privée des membres de la Société canadienne de néphrologie (SCN), ainsi qu'aux néphrologues figurant sur une liste nationale publique des néphrologues canadiens en exercice, créée à partir des registres des Collèges des médecins provinciaux. Il s'agit d'échantillons de commodité. MÉTHODOLOGIE: Nous avons procédé à une analyse descriptive des données catégoriques, notamment des fréquences pour les variables nominales et des mesures de tendance centrale (moyenne) et de dispersion (écart-type) pour les variables ordinales. Nous avons utilisé l'analyse du chi-carré pour établir l'association des caractéristiques des répondants et de leurs pratiques avec leurs opinions et comportements à l'égard de la dialyse incrémentale. Nous avons procédé à une analyse thématique simple des réponses en texte libre aux questions portant sur la prescription de l'hémodialyse incrémentale, en se concentrant sur l'âge et la prise en charge initiale des comorbidités cardiaques et non cardiaques. RÉSULTATS: Le taux de réponse était de 35 % (243/691). Une majorité de répondants (138/211 [65 %]) prescrivaient l'hémodialyse incrémentale selon une approche individualisée à la discrétion du néphrologue. La quasi-totalité des répondants (200/203 [98 %]) n'a pas fait état d'une politique de mise en œuvre. La diurèse résiduelle a été désignée comme le principal facteur d'admissibilité (112/172 [65 %]), suivie de la stabilité électrolytique (76/172 [44 %]) et des objectifs de soins du patient (69/117 [40 %]). La plupart des répondants ont convenu que la prescription de dialyse devrait tenir compte de la fonction rénale résiduelle; 74 % d'entre eux se sont toutefois dits en désaccord avec une affirmation selon laquelle il existe de solides preuves appuyant l'hémodialyse incrémentale. La sécurité du patient, l'acceptation par le patient d'une augmentation de la dose et la logistique de la planification figurent parmi les obstacles à la mise en œuvre mentionnés par les répondants. Malgré ces obstacles, 82 % des répondants étaient d'avis que l'hémodialyse incrémentale est possible avec les ressources actuelles, et 78 % étaient d'accord pour dire qu'avec des critères précis, cette modalité est une option sûre. LIMITES: La généralisabilité de notre étude est limitée par son faible taux de réponse (35 %), bien que celui-ci soit comparable à ceux qu'on observe généralement pour les enquêtes électroniques. La plupart des répondants exerçaient dans un cadre académique, ce qui peut avoir introduit un biais dans les résultats. CONCLUSION: L'hémodialyse incrémentale est fréquemment prescrite par les néphrologues canadiens, malgré une perception de preuves limitées et un manque d'orientation pour sa mise en œuvre. Les répondants ont mentionné quelques obstacles à sa mise en œuvre, soulignant ainsi la nécessité de mener des recherches afin de mieux orienter la pratique.

Finding the Needle in the Hay Stack: Population-based Study of Prediagnostic Symptomatic Interval in Children With CNS Tumors.

Central nervous system (CNS) tumors in children are a devastating diagnosis and delay in diagnosis is well documented in the literature. The aim of this study was to document and characterize time to diagnosis of CNS tumors among children 0 to 17 years of age in a pediatric center. A retrospective chart review was conducted of medical records of children with CNS tumors from 2000 to 2016 in British Columbia, Canada and 148 reports were available for review. Average age at diagnosis was 87.8 months (SD=59.7; median=72). One third (30%) were diagnosed after a single visit to a health care provider and 11 (7.7%) after more than 4 visits. Median time to diagnosis (prediagnostic symptomatic interval [PSI]) was 62 days (average 197±341 d; range, 0 to 2047 d). Longest period was time from first symptom to first health care provider visit (PSI1, median 37 d). Tumors in the posterior fossa and symptoms of ataxia or paresis were associated with a significantly shorter PSI. CNS tumors in children continue to pose a diagnostic challenge with variability in time to diagnosis. Our population-based study suggests variability in time to diagnosis with a need for education of families to identify symptoms associated with CNS tumors.

Management of asymptomatic bacteriuria in children.

Question I am aware of how common pediatric urinary tract infection (UTI) is, and of the potential long-term sequelae if left untreated. Therefore, in our practice we treat every child who presents with symptomatic UTI with antibiotics. However, should the same practice be applied to children with bacteriuria that is asymptomatic?Answer Historically, asymptomatic bacteriuria (ABU) was treated with antibiotics in all populations, including in children. However, more recent evidence has shown no benefit and often harm associated with the use of antibiotics to treat pediatric ABU. Some studies suggest that owing to the different microbiology associated with ABU it should not be considered in the spectrum of UTI. These children should not be treated with antibiotics unless they have received a renal transplant or have undergone invasive urologic procedures.

Prise en charge de la bactériurie asymptomatique chez l'enfant.

Question Je connais la fréquence des infections des voies urinaires (IVU) chez les enfants, de même que leurs séquelles potentielles si elles ne sont pas traitées. Par conséquent, dans notre clinique, nous traitons par antibiothérapie tous les enfants souffrant d'IVU symptomatiques. Par ailleurs, devrions-nous en faire autant chez les enfants qui ont une bactériurie asymptomatique?Réponse La bactériurie asymptomatique (BUA) était habituellement traitée avec des antibiotiques dans toutes les populations, y compris les enfants. Par ailleurs, selon les données probantes plus récentes, l'antibiothérapie ne s'est pas révélée bénéfique et entraîne même souvent des préjudices dans le traitement de la BUA chez l'enfant. Certaines études font valoir qu'en raison de la microbiologie différente en cause dans la BUA, celle-ci ne devrait pas être considérée comme appartenant au spectre des IVU. Ces enfants ne devraient pas recevoir d'antibiothérapie à moins d'avoir subi une greffe de rein ou des interventions urologiques invasives.

Multidisciplinary Cleft Palate Program at BC Children's Hospital: Are We Meeting the Standards of Care?

OBJECTIVE: To characterize current Cleft Palate Program (CPP) practices and evaluate the timeliness of appointments with respect to patient age and diagnosis based on American Cleft Palate-Craniofacial Association (ACPA) population guidelines and CPP patient-specific recommendations. DESIGN: A retrospective review of CPP patient appointments from November 6, 2012, to March 31, 2015, was done. Data were analyzed using descriptive and inferential statistics. SETTING: The study was conducted using data from the CPP at BC Children's Hospital. PATIENTS: A total of 1214 appointments were considered in the analysis, including syndromic and nonsyndromic patients of 0 to 27 years of age. MAIN OUTCOME MEASURES: Percentage of patients meeting follow-up targets by ACPA standards and CPP team recommendations. RESULTS: Our results showed patients 5 years and younger or nonsyndromic were more likely to be seen on time (P < .001). No relationship between the timeliness of an appointment and specific patient diagnoses or distance to clinic was found. With the exception of nursing (97% of appointments were on time), all disciplines had less than 45% of appointments on time with 51% of appointments meeting ACPA guidelines for timeliness and 32% of all appointments meeting CPP recommendations. CONCLUSION: Timely care for the cleft/craniofacial patient populations represents a challenge for the CPP. Although half of patients may meet the general ACPA guidelines, only 32% of patients are meeting the CPP patient-specific recommendations. To provide better patient care, future adjustments are needed, which may include improved resource allotment and program support.

OBJECTIF: Caractériser les pratiques du programme sur la fente labiopalatine (PFL) et évaluer la rapidité des rendez-vous compte tenu de l'âge du patient et du diagnostic en fonction des lignes directrices en population de l'American Cleft Palate-Craniofacial Association (ACPA) et des recommandations aux patients du PFL. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des rendez-vous des patients du PFL entre le 6 novembre 2012 et le 31 mars 2015. Ils ont analysé les données au moyen de statistiques descriptives et inférentielles. LIEU: L'étude a été réalisée à l'aide des données du PFL du BC Children's Hospital. PATIENTS: Les chercheurs ont évalué 1 214 rendez-vous dans l'analyse, incluant les patients syndromiques et non syndromiques de 0 à 27 ans. PRINCIPALES MESURES: Pourcentage de patients qui respectaient les cibles de suivi fixées par les normes de l'ACPA et les recommandations du PFL. RÉSULTATS: Les résultats ont démontré que les patients de cinq ans et moins et les patients non syndromiques étaient plus susceptibles d'être vus dans les délais fixés (P < .001). Il n'y avait pas de lien entre le moment d'un rendez-vous et le diagnostic exact du patient ou la distance de la clinique. À l'exception des soins infirmiers (où 97 % des rendez-vous avaient lieu dans les délais fixés), toutes les disciplines tenaient moins de 45 % de leurs rendez-vous dans les délais fixés. Ainsi, 51% de ces rendez-vous respectaient les lignes directrices de l'ACPA en matière de rapidité et 32 % de tous les rendez-vous, les recommandations du PFL. CONCLUSIONS: Au sein du PFL, il était difficile d'offrir des soins rapides à la population de patients ayant une fente labiopalatine ou craniofaciale. Même si la moitié des patients peut respecter les directives générales de l'ACPA, seulement 32 % d'entre eux respectent les recommandations du PFL. Pour mieux soigner les patients, il faudra apporter des correctifs, qui pourraient inclure une meilleure répartition des ressources et un meilleur soutien du programme.

Hyaluronan-binding by CD44 reduces the memory potential of activated murine CD8 T cells.

Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44-/- and CD44+/+ OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria-OVA, there was a slight increase in the percentage of CD44+/+ cells at the effector site. However, CD44+/+ cells were out-competed by CD44-/- cells after the contraction phase in the lymphoid tissues, and the CD44-/- cells preferentially formed more memory cells. The hyaluronan-binding CD44+/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44+/+ and CD44-/- OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.

Native Folding of a Recombinant gpE1/gpE2 Heterodimer Vaccine Antigen from a Precursor Protein Fused with Fc IgG.

A recombinant strain HCV1 (hepatitis C virus [HCV] genotype 1a) gpE1/gpE2 (E1E2) vaccine candidate was previously shown by our group to protect chimpanzees and generate broad cross-neutralizing antibodies in animals and humans. In addition, recent independent studies have highlighted the importance of conserved neutralizing epitopes in HCV vaccine development that map to antigenic clusters in E2 or the E1E2 heterodimer. E1E2 can be purified using Galanthis nivalis lectin agarose (GNA), but this technique is suboptimal for global production. Our goal was to investigate a high-affinity and scalable method for isolating E1E2. We generated an Fc tag-derived (Fc-d) E1E2 that was selectively captured by protein G Sepharose, with the tag being removed subsequently using PreScission protease. Surprisingly, despite the presence of the large Fc tag, Fc-d E1E2 formed heterodimers similar to those formed by GNA-purified wild-type (WT) E1E2 and exhibited nearly identical binding profiles to HCV monoclonal antibodies that target conserved neutralizing epitopes in E2 (HC33.4, HC84.26, and AR3B) and the E1E2 heterodimer (AR4A and AR5A). Antisera from immunized mice showed that Fc-d E1E2 elicited anti-E2 antibody titers and neutralization of HCV pseudotype viruses similar to those with WT E1E2. Competition enzyme-linked immunosorbent assays (ELISAs) showed that antisera from immunized mice inhibited monoclonal antibody binding to neutralizing epitopes. Antisera from Fc-d E1E2-immunized mice exhibited stronger competition for AR3B and AR5A than the WT, whereas the levels of competition for HC84.26 and AR4A were similar. We anticipate that Fc-d E1E2 will provide a scalable purification and manufacturing process using protein A/G-based chromatography. IMPORTANCE: A prophylactic HCV vaccine is still needed to control this global disease despite the availability of direct-acting antivirals. Previously, we demonstrated that a recombinant envelope glycoprotein (E1E2) vaccine (genotype 1a) elicited cross-neutralizing antibodies from human volunteers. A challenge for isolating the E1E2 antigen is the reliance on GNA, which is unsuitable for large scale-up and global vaccine delivery. We have generated a novel Fc domain-tagged E1E2 antigen that forms functional heterodimers similar to those with native E1E2. Affinity purification and removal of the Fc tag from E1E2 resulted in an antigen with a nearly identical profile of cross-neutralizing epitopes. This antigen elicited anti-HCV antibodies that targeted conserved neutralizing epitopes of E1E2. Owing to the high selectivity and cost-effective binding capacity of affinity resins for capture of the Fc-tagged rE1E2, we anticipate that our method will provide a means for large-scale production of this HCV vaccine candidate.