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Aberrant transforming growth factor beta (TGFβ) signaling during embryogenesis is implicated in severe congenital abnormalities, including kidney malformations. However, the molecular mechanisms that underlie congenital kidney malformations related to TGFβ signaling remain poorly understood. Here, we review current understanding of the lineage-specific roles of TGFβ signaling during kidney development and how dysregulation of TGFβ signaling contributes to the pathogenesis of kidney malformation.

One hundred years have passed since the discovery of insulin—an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.

BACKGROUND AND OBJECTIVES Children with isolated unilateral multicystic dysplastic kidney (MCDK) or congenital solitary kidney (CSK) undergo serial renal ultrasonography with variable frequency until they are transitioned to adult care. A growing body of literature suggests the value of frequent ultrasonography in this population is limited, providing no benefit to overall outcomes. Despite emerging evidence, ultrasound remains overused, resulting in avoidable health care expenditures and unnecessary use of resources. With our initiative, we aimed to improve quality of care by reducing avoidable ultrasounds in these children. METHODS This was a single-center, prospective, interrupted time series of children RESULTS The algorithm resulted in a 47% reduction (P < .001) in the proportion of avoidable ultrasounds ordered in children with MCDK and CSK. This reduction was sustainable over a 6-month period and would result in at least $46 000 annual savings. CONCLUSIONS Introduction of a clinical decision-making algorithm was associated with a reduction in avoidable ultrasound testing. Improving adherence across providers may allow for an even more pronounced reduction.

Traditionally, peer review was a closed process conducted only by individuals working in the research field. To establish a more integrated and patient-centered approach, one of Canada's largest kidney research networks (Can-SOLVE CKD) has created a Research Operations Committee (ROC) that includes patients as key members. The ROC represents one way for achieving meaningful patient-oriented research (POR).Can-SOLVE CKD, a network created as part of the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR).The ROC consists of patients, physicians, scientists, Indigenous partners, experts in research methodology, and a member of Can-SOLVE CKD's operational team. On an annual basis, Can-SOLVE CKD's research teams provide the ROC with a review package, which incorporates information from patient engagement check-in calls and surveys, the project's knowledge translation plan and products, and a progress report written by the project team. The ROC evaluates the review package and provides feedback and recommendations accordingly.The transparent nature of the process, regular feedback and review, along with an overt accountability and scoring system, has been embraced by both patients and researchers. As a result of the ROC process, the number of patient leads for each project has grown over a 3-year period and more researchers have received POR and cultural sensitivity training.While anecdotal evidence suggests this approach is beneficial for achieving POR, formal mechanisms of evaluation are currently lacking.This ROC framework ensures patients are active contributors throughout the research process and could be adopted by other organizations to achieve a more patient-centered approach to research.L’évaluation par les pairs consiste habituellement en un processus fermé et mené uniquement par des personnes travaillant dans le domaine de la recherche. Pour développer une approche plus intégrée et davantage axée sur les patients, un des plus importants réseaux canadiens de recherche sur les maladies rénales (Can-SOLVE CKD) a créé un comité de gestion de la recherche (CGR) où les patients sont des membres à part entière. Une approche qui vise la conduite d’activités de recherches significatives et davantage orientées vers le patient.Can-SOLVE CKD, un réseau créé dans le cadre de la Stratégie de recherche axée sur le patient (SRAP) des Instituts de recherche en santé du Canada (IRSC).Le CGR rassemble des patients, des médecins, des chercheurs, des partenaires autochtones, des experts en méthodologie de recherche et un membre de l’équipe d’intervention de Can-SOLVE CKD. Une fois par année, l’équipe de recherche de Can-SOLVE CKD fournit au CGR un dossier d’examen. Ce dossier contient les informations recueillies lors d’appels ou de sondages vérifiant l’engagement des patients, le plan d’application des connaissances du projet et ses résultats, de même qu’un rapport périodique rédigé par l’équipe responsable du projet. Le CGR évalue ce dossier et émet ses commentaires et recommandations.La transparence du processus, la rétroaction et la révision sur une base régulière, de même que les systèmes de responsabilité et de notation ouverts ont été adoptés tant par les patients que par les chercheurs. Grâce à ce processus, le nombre de patients candidats pour chaque projet a augmenté sur une période de trois ans, et davantage de chercheurs ont reçu une formation sur les réalités culturelles et la pratique d’activités de recherche axées sur le patient.Bien que des preuves anecdotiques suggèrent que cette approche soit bénéfique à la conduite de recherches axées sur le patient, des mécanismes formels pour son évaluation manquent toujours.Le cadre proposé par le CGR assure une contribution active des patients tout au long du processus de recherche. Ce program pourrait être adopté par d’autres organizations et permettre la réalisation d’activités de recherche davantage axées sur le patient.

COVID‐19 has halted research around the globe and forced researchers out of their labs. Non‐emergency medical appointments were cancelled. Ongoing clinical trials were challenged to create new modes of operation while public pressure mounted to find therapeutic options against COVID‐19. Yet, the inability to conduct research during COVID‐19 was overcome with cooperation, resource sharing, and compassion, which provides important lessons on how to improve health related research as we enter a new normal.

CONTEXT MD/PhD programmes provide structured paths for physician-scientist training. However, considerable proportions of graduates of these programmes do not pursue careers in research consistent with their training. OBJECTIVES We sought to identify factors associated with sustained involvement in research after completion of all postgraduate training. METHODS Anonymised data from a national survey of Canadian MD/PhD programme graduates who had completed all physician-scientist training (n = 70) were analysed. Multivariable logistic regression was used to measure the associations between characteristics of graduates and five indicators of sustained research involvement following postgraduate training: (i) protected research time in the current appointment; (ii) percentage of time dedicated to research; (iii) planned future involvement in research; (iv) role as a principal investigator on a recent funded project, and (v) receipt of funding from a federal granting agency since graduation. RESULTS The majority of graduates were significantly involved in research on the basis of at least one outcome. Completion of a research fellowship, number of first-authored or co-authored manuscripts published during MD/PhD training, and duration of MD/PhD training were positively associated with continued research involvement. Completion of a Masters degree prior to MD/PhD training, female gender, debt greater than CAD$50 000 at completion of training, and pursuit of a clinical specialty other than internal medicine, paediatrics, neurology, pathology and the surgical specialties were negatively associated with sustained research involvement. CONCLUSIONS Most MD/PhD programme graduates remain significantly involved in research, but this involvement often does not correspond to traditional physician-scientist roles, in which a majority of time is dedicated to research. To minimise loss of investment in physician-scientist training, MD/PhD programmes should prioritise research productivity during training and the pursuit of additional research training during residency, and policymakers should establish stable sources of funding to reduce debt among graduates. Our data suggest further study is warranted to identify interventions to reduce attrition among female MD/PhD programme graduates.

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm–derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm–derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

Background Combined MD/PhD programs provide a structured path for physician-scientist training, but assessment of their success within Canada is limited by a lack of quantitative data. We collected outcomes data for graduates of Canadian MD/PhD programs. Methods We developed and implemented a Web-based survey consisting of 41 questions designed to collect outcomes data for Canadian MD/PhD program alumni from 8 Canadian universities who had graduated before September 2015. Respondents were categorized into 2 groups according to whether they had or had not completed all training. Results Of the 186 eligible alumni of MD/PhD programs, 139 (74.7%) completed the survey. A total of 136/138 respondents (98.6%) had completed or were currently completing residency training, and 66/80 (82%) had completed at least 1 postgraduate fellowship. Most (58 [83%]) of the 70 respondents who had completed all training were appointed as faculty at academic institutions, and 37 (53%) had been principal investigators on at least 1 recent funded project. Among the 58 respondents appointed at academic institutions, 44/57 (77%) dedicated at least 20% of their time to research, and 25/57 (44%) dedicated at least 50% to research. During their combined degree, 102/136 respondents (75.0%) published 3 or more first-author papers, and 133/136 (97.8%) matched with their first choice of specialty. The median length of physician-scientist training was 13.5 years. Most respondents graduated with debt despite having been supported by Canadian Institutes of Health Research MD/PhD studentships. Interpretation Most Canadian MD/PhD program alumni pursued careers consistent with their physician-scientist training, which indicates that these programs are meeting their primary objective. Nevertheless, our findings highlight that a minority of these positions are research intensive; this finding warrants further study. Our data provide a baseline for future monitoring of the output of Canadian MD/PhD programs.

Objective This study compared the efficacy of two psychological interventions, a coping and communication-enhancing intervention (CCI) and supportive counseling (SC), in reducing depressive symptoms, cancer-specific distress, fear of recurrence, and emotional well-being of women diagnosed with gynecological cancer. Demographic, medical, and psychological moderators of intervention effects were evaluated. Methods Three hundred fifty-two women with gynecological cancer were randomly assigned to eight sessions of CCI, eight sessions of SC, or usual care (UC). Participants completed measures of distress and wellbeing at six time points over an 18month period of time. Results CCI had a beneficial impact on depressive symptoms and cancer specific distress over the first six months as compared with UC and SC and had a beneficial impact on emotional well-being. The greater coping skill development in CCI has made it a more effective intervention than traditional SC across a broader range of key psychological outcomes. Declines among women in the SC condition were not significantly different from UC. Conclusions The CCI intervention had significant effect on patients' depression, cancer-specific distress, and emotional well-being during a time when the majority of newly diagnosed patients experience elevated levels of distress. Ameliorating such distress post-diagnosis merits its incorporation into clinical care. A brief 8-session structured intervention can be readily applied to this distressed population in need. Brief supportive counseling did not evidence treatment effects, suggesting that more structured approaches are crucial to truly deliver benefits.

Biomedical scientists aim to contribute to further understanding of disease pathogenesis and to develop new diagnostic and therapeutic tools that relieve disease burden. Yet the majority of biomedical scientists do not develop their academic career or professional identity as "translational scientists," and are not actively involved in the continuum from scientific concept to development of new strategies that change medical practice. The collaborative nature of translational medicine and the lengthy process of bringing innovative findings from bench to bedside conflict with established pathways of building a career in academia. This collaborative approach also poses a problem for evaluating individual contributions and progress. The traditional evaluation of scientific success measured by the impact and number of publications and grants scientists achieve is inadequate when the product is a team effort that may take decades to complete. Further, where scientists are trained to be independent thinkers and to establish unique scientific niches, translational medicine depends on combining individual insights and strengths for the greater good. Training programs that are specifically geared to prepare scientists for a career in translational medicine are not widespread. In addition, the legal, regulatory, scientific and clinical infrastructure and support required for translational research is often underdeveloped in academic institutions and funding organizations, further discouraging the development and success of translational scientists in the academic setting. In this perspective we discuss challenges and potential solutions that could allow for physicians, physician scientists and basic scientists to develop a professional identity and a fruitful career in translational medicine.

There is increasing evidence that unconscious bias can affect realworld decision-making processes in publication just as in many other fields.1 In response, the editorial board of Pediatric Research is working to investigate and reduce the bias in the publication acceptance rates in order to preserve the integrity of the peer review process and publication. As news items have suggested that gender bias is a major problem in academia,2 we reviewed papers submitted between 1 November 2017 and 9 August 2018 to Pediatric Research. Encouragingly, we found that the acceptance rates of manuscripts were not significantly different between corresponding authors who were male or female. However, we incidentally uncovered a higher rejection rate in the manuscripts where the corresponding author had a name that could not be identified as either male or female and did not have a picture on their website so that we could identify their gender.3 It is important to point out that we do not know the reason for this, but its identification is the first step to further exploration, including assessing whether unconscious bias may play a role […]

Aberrant hedgehog (Hh) signaling during embryogenesis results in various severe congenital abnormalities, including renal malformations. The molecular mechanisms that underlie congenital renal malformations remain poorly understood. Here, we review the current understanding of the lineage-specific roles of Hh signaling during renal morphogenesis and how aberrant Hh signaling during embryonic kidney development contributes to renal malformation.

Women scientists are less likely to obtain Assistant Professorship and achieve promotion, and obtain less grant funding than men. Scientist/clinician-scientist training programs which provide salary awards as well as training and mentorship are a potential intervention to improve outcomes among women scientists. We hypothesized whether a programmatic approach to scientist/clinician-scientist training is associated with improved outcomes for women scientists in Canada when compared with salary awards alone. Trainees within the Kidney Research Scientist Core Education and National Training Program (KRESCENT), Canadian Child Health Clinician Scientist Program (CCHCSP), and the Canadian Institutes of Health Research (CIHR) salary award programs were evaluated.To examine whether the structured KRESCENT training program with salary support improves academic success for women scientists relative to salary awards alone.Retrospective cohort study.Canadian national research scientist and clinician-scientist training programs and salary awards.KRESCENT cohort (n = 59, 2005-2017), CCHCSP cohort (n = 58, 2002-2015), and CIHR (n = 571, 2005-2015) Salary Awardees for postdoctoral fellows (PDF) and new investigators (NI).National operating grant funding success, achieving an academic position as an Assistant Professor for PDF, or achieving promotion to Associate Professor for NI.The gender distribution of each cohort was determined using first name and NamepediA and was examined for PDF and NI, followed by a description of trainee outcomes by gender and training level.KRESCENT and CIHR PDF were balanced (12/27, 44% men and 55/116, 47% women) while CCHCSP had a higher proportion of women (13/20, 65%). KRESCENT and CCHCSP NI retained women scientists (19/32, 59% and 22/38, 58% women), whereas CIHR NI had fewer women (165/455, 36% women vs 290/455, 64% men,KRESCENT and CCHCSP training program cohort size and heterogeneity; assigning gender by first name may result in misclassification; lack of data on the respective applicant pools; and inability to examine intersectionality with gender, ethnicity, and sexual orientation.Overall trainee performance across programs is remarkable by community standards regardless of gender. KRESCENT and CCHCSP training programs demonstrated balanced success in their PDF and NI, whereas the CIHR awardees had reduced representation of women scientists from PDF to NI. This exploratory study highlights the utility of programmatic training approaches like the KRESCENT program as potential tools to support and retain women scientists in the academic pipeline during the challenging PDF to NI transition period.Les chercheuses sont moins susceptibles que les hommes d’obtenir une promotion ou un poste de professeur adjoint, en plus d’obtenir moins de subventions. Des programmes de formation pour les chercheurs et chercheurs cliniciens offrant des bourses salariales ainsi que de la formation et du mentorat pourraient s’avérer pertinents pour améliorer la situation des femmes en sciences. Nous avons émis l’hypothèse qu’une approche programmatique de la formation des chercheurs et chercheurs cliniciens pourrait améliorer les résultats pour les chercheuses canadiennes comparativement aux bourses salariales seules. Pour ce faire, les stagiaires du Programme national de formation scientifique et d’encadrement des chercheurs spécialisés dans le domaine rénal (KRESCENT), du Programme canadien des cliniciens-chercheurs en santé de l’enfant (PCCCSE) et des programmes de bourses salariales des Instituts de recherche en santé du Canada (IRSC) ont été évalués.Vérifier si le programme de formation structuré KRESCENT avec soutien salarial favorise le succès académique des scientifiques féminines par rapport aux bourses salariales uniquement.Étude de cohorte rétrospective.Programmes nationaux de formation et de bourses salariales pour les chercheurs et les chercheurs cliniciens du Canada.La cohorte KRESCENT (n = 59; 2005-2017), la cohorte PCCCSE (n = 58; 2002-2015) et les récipiendaires d’une bourse salariale des IRSC (n = 571; 2005-2015) destinées aux boursiers postdoctoraux (BPD) et aux nouveaux chercheurs (NC).Le succès du financement des subventions de fonctionnement nationales, l’obtention d’un poste de professeur adjoint à l’université pour les BPD ou l’obtention d’une promotion au poste de professeur agrégé pour les NC.La répartition des genres dans chaque cohorte a été déterminée à l’aide du prénom et de Namepedia, et a été examinée en fonction du statut (BPD ou NC). Les résultats des stagiaires ont été décrits selon le genre et le niveau de formation.Dans le cas des BPD, les cohortes KRESCENT et IRSC étaient plutôt équilibrées (44 % d’hommes [12/27] pour KRESCENT et 47 % [55/116] de femmes pour IRSC). Les femmes BPD étaient plus nombreuses dans la cohorte PCCCSE (13/20 [65 %]). Du côté des NC, les femmes étaient majoritaires dans les cohortes KRESCENT et PCCCSE (respectivement 59 % [19/32] et 58 % [22/38] de femmes) et les hommes étaient plus nombreux dans la cohorte IRSC (64 % d’hommes [290/455]; 36 % de femmes [165/455] [p = 0,01]). Nous avons observé un taux élevé de réussite des subventions de fonctionnement chez les NC (91 à 95 %) dans toutes les cohortes, sans égard au genre. Une forte proportion de BPD du PCCCSE avaient obtenu un poste de professeur adjoint (18/20 [90 %]); ceci pourrait s’expliquer en partie par le plus long suivi (9,3 ± 3 ans) comparativement aux BPD du KRESCENT (7/27 [26 %]; 0,88 ± 4,5 ans). Ces données n’étaient pas disponibles pour les BPD des IRSC. On a vu une augmentation des promotions à des postes de professeurs agrégés pour les nouvelles chercheuses de la cohorte KRESCENT (p = 0,02, pour 0,25 ± 3,2 ans de suivi). Les NC du PCCCSE présentaient un taux élevé de promotions (37/38 [97 %]; 6,9 ± 3,6 ans de suivi), indépendamment du genre. Une tendance globale pour un plus grand nombre d’hommes poursuivant des recherches biomédicales a été observée.Parmi les limites, on compte la taille et l’hétérogénéité des cohortes KRESCENT et PCCCSE; de possibles erreurs de classification dues à l’attribution du genre par le prénom; le manque de données sur les bassins respectifs de candidats; l’incapacité d’examiner l’intersectionnalité avec le genre, l’origine ethnique et l’orientation sexuelle.Le rendement global des stagiaires dans l’ensemble des programmes est remarquable, quel que soit leur genre, par rapport aux normes communautaires. Les programmes de formation de KRESCENT et PCCCSE ont démontré un succès équilibré chez leurs BPD et NC, tandis que les récipiendaires d’une bourse des IRSC ont montré une plus faible représentation de chercheuses tant chez les BPD et les NC. Cette étude exploratoire met en lumière la pertinence d’approches de formation programmatique comme le KRESCENT pour soutenir et retenir les scientifiques féminines dans le domaine académique pendant la difficile période de transition entre le statut de boursière postdoctorale et celui de nouvelle chercheuse.

Cerebellar granule cell (GC) development relies on precise regulation of sonic hedgehog (Shh)-Gli signalling activity, failure of which is associated with motor disorders and medulloblastoma. Mutations in the pathway regulator suppressor of fused (Sufu), which modulates Gli activators and repressors, are linked to cerebellar dysfunction and tumourigenesis. The mechanism by which Sufu calibrates Shh signalling in GCs is unknown. Math1-Cre-mediated deletion of Sufu in mouse GC progenitors (GCPs) demonstrated that Sufu restricts GCP proliferation and promotes cell cycle exit, by promoting expression of Gli3R and suppressing Gli2 levels. Sufu is also required to promote a high threshold of pathway activity in GCPs. Remarkably, central cerebellar lobules are more deleteriously impacted by Sufu deletion, but are less sensitive to downstream genetic manipulations to reduce Gli2 expression or overexpress a Gli3R mimic, compared with anterior lobules. Transcriptome sequencing uncovered new Sufu targets, especially Fgf8, which is upregulated in Sufu-mutant GCPs. We demonstrate that Fgf8 is necessary and sufficient to drive Sufu-mutant GCP proliferation. This study reveals new insights into the spatial and temporal regulation of cerebellar Shh-Gli signalling, while uncovering new targets, such as Fgf8.

Normal kidney function depends on the proper development of the nephron, the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of Hedgehog intracellular effector Smoothened (Smo-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-Hedgehog-Smo signaling acts through GLI3 repressor. Whole kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFβ2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFβ2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal Hedgehog-TGFβ2 signaling axis acts to control nephrogenesis.

Far too much biomedical research is wasted and ends in the so called "Valley of Death": the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine. Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed. Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently. Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities.

Integrin-linked kinase (ILK) is an intracellular scaffold protein with critical cell-specific functions in the embryonic and mature mammalian kidney. Previously, we demonstrated a requirement for Ilk during ureteric branching and cell cycle regulation in collecting duct cells in vivo. Although in vitro data indicate that ILK controls p38 mitogen-activated protein kinase (p38MAPK) activity, the contribution of ILK-p38MAPK signaling to branching morphogenesis in vivo is not defined. Here, we identified genes that are regulated by Ilk in ureteric cells using a whole-genome expression analysis of whole-kidney mRNA in mice with Ilk deficiency in the ureteric cell lineage. Six genes with expression in ureteric tip cells, including Wnt11, were downregulated, whereas the expression of dual-specificity phosphatase 8 (DUSP8) was upregulated. Phosphorylation of p38MAPK was decreased in kidney tissue with Ilk deficiency, but no significant decrease in the phosphorylation of other intracellular effectors previously shown to control renal morphogenesis was observed. Pharmacologic inhibition of p38MAPK activity in murine inner medullary collecting duct 3 (mIMCD3) cells decreased expression of Wnt11, Krt23, and Slo4c1. DUSP8 overexpression in mIMCD3 cells significantly inhibited p38MAPK activation and the expression of Wnt11 and Slo4c1. Adenovirus-mediated overexpression of DUSP8 in cultured embryonic murine kidneys decreased ureteric branching and p38MAPK activation. Together, these data demonstrate that Ilk controls branching morphogenesis by regulating the expression of DUSP8, which inhibits p38MAPK activity and decreases branching morphogenesis.

The human kidney is composed of an arborized network of collecting ducts, calyces and urinary pelvis that facilitate urine excretion and regulate urine composition. The renal collecting system is formed in utero, completed by the 34th week of gestation in humans, and dictates final nephron complement. The renal collecting system arises from the ureteric bud, a derivative of the intermediate-mesoderm derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The ureteric bud subsequently undergoes a series of iterative branching and remodeling events in a process called renal branching morphogenesis. Altered signaling that disrupts patterning of the nephric duct, ureteric induction, or renal branching morphogenesis leads to varied malformations of the renal collecting system collectively known as congenital anomalies of the kidney and urinary tract (CAKUT) and is the most frequently detected congenital renal aberration in infants. Here, we describe critical morphogenetic and cellular events that govern nephric duct specification, ureteric bud induction, renal branching morphogenesis, and cessation of renal branching morphogenesis. We also highlight salient molecular signaling pathways that govern these processes, and the investigative techniques used to interrogate them.

The renal stroma is defined as a heterogeneous population of cells that serve both as a supportive framework and as a source of specialized cells in the renal capsule, glomerulus, vasculature, and interstitium. In this chapter, we review published evidence defining what, where, and why stromal cells are important. We describe the functions of the renal stroma andhow stromal derivatives are crucial for normal kidney function. Next, we review the specification of stromal cells from the Osr1+ intermediate mesoderm and T+ presomitic mesoderm during embryogenesis and stromal cell differentiation. We focus on stromal signaling mechanisms that act in both a cell and non-cell autonomous manner in communication with the nephron progenitor and ureteric lineages. To conclude, stromal cells and the contribution of stromal cells to renal fibrosis and chronic kidney disease are described.

The human kidney is composed of an arborized network of collecting ducts that converge at the urinary calyces and pelvis to facilitate urine excretion. The renal collecting system arises from the ureteric bud (UB), a derivative of the intermediate mesoderm–derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The UB subsequently undergoes a series of iterative branching and remodeling events in a process termed renal branching morphogenesis. Formation of the renal collecting system is completed by the 34th week of gestation in humans. Perturbations in patterning of the nephric duct, ureteric induction, or renal branching morphogenesis leads to a spectrum of malformations collectively termed congenital anomalies of the kidney and urinary tract. In this chapter, we describe critical morphogenetic and cellular events that govern nephric duct specification, UB induction, renal branching morphogenesis, and cessation of renal branching morphogenesis.

Schimke immuno-osseous dysplasia (SIOD) is a pleiotropic disorder caused by mutations in the SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like-1 ( SMARCAL1) gene, with multiple clinical features, notably end-stage renal disease. Here we characterize the renal pathology in SIOD patients. Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS). Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman’s capsule. To better understand the role of SMARCAL1 in the pathogenesis of FSGS, we defined SMARCAL1 expression in the developing and mature kidney. In the developing fetal kidney, SMARCAL1 is expressed in the ureteric epithelium, stroma, metanephric mesenchyme, and in all stages of the developing nephron, including the maturing glomerulus. In postnatal kidneys, SMARCAL1 expression is localized to epithelial tubules of the nephron, collecting ducts, and glomerulus (podocytes and endothelial cells). Interestingly, not all cells within the same lineage expressed SMARCAL1. In renal biopsies from SIOD patients, TUNEL analysis detected marked increases in DNA fragmentation. Our results highlight the cells that may contribute to the renal pathogenesis in SIOD. Further, we suggest that disruptions in genomic integrity during fetal kidney development contribute to the pathogenesis of FSGS in SIOD patients.

Renal dysplasia, a developmental disorder characterized by defective ureteric branching morphogenesis and nephrogenesis, ranks as one of the major causes of renal failure among the pediatric population. Herein, we demonstrate that the levels of activated β-catenin are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. By using a conditional mouse model of mesenchymal β-catenin overexpression, we identify two novel signaling pathways mediated by β-catenin in the development of renal dysplasia. First, the overexpression of β-catenin within the metanephric mesenchyme leads to ectopic and disorganized branching morphogenesis caused by β-catenin directly binding Tcf/lef consensus binding sites in the Gdnf promoter and up-regulating Gdnf transcription. Second, β-catenin overexpression in the metanephric mesenchyme leads to elevated levels of transcriptionally active β-catenin in the ureteric epithelium. Interestingly, this increase of β-catenin–mediated transcription results from a novel Ret/β-catenin signaling pathway. Consistent with these findings, analysis of human dysplastic renal tissue demonstrates that undifferentiated mesenchymal cells expressing high levels of β-catenin also express increased GDNF. Furthermore, dysplastic ureteric tubules that were surrounded by high levels of GDNF also exhibited increased levels of activated β-catenin. Together, these data support a model in which the elevation of β-catenin in the metanephric mesenchyme results in cell-autonomous and non–cell-autonomous events that lead to the genesis of renal dysplasia.

The kidney is a model developmental paradigm of vertebrate organogenesis. As in many other organs, kidney development involves reciprocal inductive tissue interactions between multiple cell lineages. The most well defined of these interactions occurs between the ureteric bud and the nephrogenic mesenchyme. A population of mesenchymal cells distinct from nephrogenic precursors and termed stromal cells, have been relatively understudied. Yet existing knowledge indicates that stromal cells are critical regulators in the normal and diseased kidney. This commentary reviews current knowledge regarding the origin and functional roles of the stromal cell population during kidney development. Gaps in our current understanding of renal stromal cells and future directions needed to advance this expanding field of study are highlighted.

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD +‐dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age‐related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1 Y/Y) mice had lower GFRs and fewer glomeruli than their wild‐type (Sirt1 +/+) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1 Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1 Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.

Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease.

Renal primary cilia are microscopic sensory organelles found on the apical surface of epithelial cells of the nephron and collecting duct. They are based upon a microtubular cytoskeleton, bounded by a specialized membrane, and contain an array of proteins that facilitate their assembly, maintenance and function. Cilium-based signalling is important for the control of epithelial differentiation and has been implicated in the pathogenesis of various cystic kidney diseases and in renal repair. As such, visualizing renal primary cilia and understanding their composition has become an essential component of many studies of inherited kidney disease and mechanisms of epithelial regeneration. Primary cilia were initially identified in the kidney using electron microscopy and this remains a useful technique for the high resolution examination of these organelles. New reagents and techniques now also allow the structure and composition of primary cilia to be analysed in detail using fluorescence microscopy. Primary cilia can be imaged in situ in sections of kidney, and many renal-derived cell lines produce primary cilia in culture providing a simplified and accessible system in which to investigate these organelles. Here we outline microscopy-based techniques commonly used for studying renal primary cilia.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of all birth defects As a group, they are the cause of most cases of end-stage renal disease (ESRD) in children. Additionally, they are the most frequent malformations detected by prenatal ultrasound. CAKUT occur in association with nonrenal malformations in about 30 % of cases. In the majority of patients, CAKUT are sporadic; however, mutations in several renal development genes have been identified as etiologic factors. The widespread use and increased sensitivity of fetal ultrasound in identifying CAKUT has led to the frequent diagnosis of these anomalies in utero. It is important to diagnose and initiate therapy in affected patients to minimize renal damage and prevent or delay the onset ESRD. In this chapter, I will present an overview of issues related to the etiology, pathobiology, diagnosis, and clinical management of CAKUT, which will serve as a foundation for more detailed presentation in subsequent chapters.

Congenital hydronephrosis, defined as congenital dilatation of one or more components of the renal collecting system, is detected in 1-2% of all pregnancies. The majority of antenatally detected hydronephrosis is non-obstructive and either resolves or stabilizes. Management of persistently severe cases may include surgical intervention, the only available treatment. Recent data demonstrate that hedgehog signaling plays a critical role in regulating the structure and function of the collecting system in a manner dependent on the formation of GLI3 repressor. Here, we review the pathobiology and clinical management of non-obstructive hydronephrosis and describe how inhibitors of GLI3 repressor formation may serve as novel therapies for this disorder.

Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development increased β-catenin levels and caused renal aplasia or severe hypodysplasia. Analysis of gene expression in the dysplastic tissue identified downregulation of genes required for ureteric branching and upregulation of Tgfβ2 and Dkk1. Treatment of wild-type kidney explants with TGFβ2 or DKK1 generated morphogenetic phenotypes strikingly similar to those observed in mutant kidney tissue. Stabilization of β-catenin after the onset of kidney development also caused dysplasia and upregulation of Tgfβ2 and Dkk1 in the epithelium. Together, these results demonstrate that elevation of β-catenin levels during kidney development causes dysplasia.

Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation–3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.

This article serves to describe the Can-SOLVE CKD network, a program of research projects and infrastructure that has excited patients and given them hope that we can truly transform the care they receive.Chronic kidney disease (CKD) is a complex disorder that affects more than 4 million Canadians and costs the Canadian health care system more than $40 billion per year. The evidence base for guiding care in CKD is small, and even in areas where evidence exists, uptake of evidence into clinical practice has been slow. Compounding these complexities are the variations in outcomes for patients with CKD and difficulties predicting who is most likely to develop complications over time. Clearly these gaps in our knowledge and understanding of CKD need to be filled, but the current state of CKD research is not where it needs to be. A culture of clinical trials and inquiry into the disease is lacking, and much of the existing evidence base addresses the concerns of the researchers but not necessarily those of the patients.The Canadian Institutes of Health Research (CIHR) has launched the national Strategy for Patient-Oriented Research (SPOR), a coalition of federal, provincial, and territorial partners dedicated to integrating research into care. Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) is one of five pan-Canadian chronic kidney disease networks supported through the SPOR. The vision of Can-SOLVE CKD is that by 2020 every Canadian with or at high risk for CKD will receive the best recommended care, experience optimal outcomes, and have the opportunity to participate in studies with novel therapies, regardless of age, sex, gender, location, or ethnicity.The overarching objective of Can-SOLVE CKD is to accelerate the translation of knowledge about CKD into clinical research and practice. By focusing on the patient's voice and implementing relevant findings in real time, Can-SOLVE CKD will transform the care that CKD patients receive, and will improve kidney health for future generations.Le présent article décrit le réseau Can-SOLVE CKD, un réseau basé sur un programme de projets et d’infrastructures de recherche qui ont soulevé l’enthousiasme des patients et qui nourrissent leur espoir de voir une réelle réforme des soins qu’ils reçoivent.L’insuffisance rénale chronique (IRC) est un trouble complexe qui affecte plus de quatre millions de Canadiens et qui engendre au système de santé canadien des coûts annuels de l’ordre de 40 milliards de dollars. Les données probantes sous-tendant les soins en IRC sont rares, et dans les branches où ces données existent, leur intégration à la pratique clinique se montre insuffisante. Ces problèmes sont aggravés d’abord par la grande variabilité du pronostic de la maladie, puis par la difficulté de prévoir quels patients seront les plus susceptibles de développer des complications. Ces lacunes de connaissances et de compréhension de l’IRC doivent manifestement être comblées; cependant, force est de constater que la recherche actuelle sur l’IRC est inadéquate. Outre l’absence d’une culture médicale qui encourage les essais cliniques, les données recueillies rejoignent les préoccupations des chercheurs sans nécessairement refléter celles des patients.Lancée par l’Institut de recherche en santé du Canada (IRSC), la Stratégie de recherche axée sur le patient (SRAP) consiste en une coalition de partenaires fédéraux, provinciaux et territoriaux visant l’intégration des résultats de la recherche dans les soins prodigués aux patients. Le réseau Can-SOLVE CKD (Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease) est l’un des cinq réseaux de recherche pancanadiens sur les maladies chroniques soutenus par la SRAP. L’objectif du réseau Can-SOLVE CKD est tripartite : on souhaite que, d’ici 2020, tous les Canadiens atteints d’IRC (ou à haut risque de développer la maladie) 1- reçoivent les meilleurs soins; 2- obtiennent des résultats de santé optimaux; 3- aient l’occasion de participer à des études cliniques pertinentes (et ce, sans égard à leur âge, leur sexe, leur ethnicité ou leur lieu de résidence).L’objectif principal du réseau Can-SOLVE CKD est d’accélérer l’application des connaissances sur l’IRC, tant en recherche qu’en pratique clinique. En s’intéressant aux préoccupations des patients et en appliquant en temps réel les résultats pertinents de la recherche, Can-SOLVE CKD transformera la façon dont seront soignés les patients atteints d’IRC et améliorera la santé rénale globale des générations futures.

Branching morphogenesis, defined as the growth and branching of epithelial tubules, is a fundamental developmental process involved in the formation of a variety of mammalian tissues, including the kidney. Defective renal branching may result in a number of clinically relevant abnormalities, including renal agenesis, renal dysplasia, multiplex kidneys, and hypertension. In this review we describe the morphological events that generate the characteristic tree-like structure of the mammalian collecting system. We also highlight new knowledge related to both established and novel signaling systems that are important for stimulating and inhibiting branching morphogenesis.

Abnormalities of kidney and urinary tract development are the most common cause of end-stage kidney failure in childhood in the United States. Over the past 20 years, the advent of mutant and transgenic mice and the manipulation of gene expression in other animal models has resulted in major advances in identification of the cellular and molecular mechanisms that direct kidney morphogenesis, providing insights into the pathophysiology of renal and urologic anomalies. This review focuses on the molecular mechanisms that define kidney progenitor cell populations, induce nephron formation within the metanephric mesenchyme, initiate and organize ureteric bud branching, and participate in terminal differentiation of the nephron. Highlighted are common signaling pathways that function at multiple stages during kidney development, including signaling via Wnts, bone morphogenic proteins, fibroblast growth factor, sonic hedgehog, RET/glial cell-derived neurotrophic factor, and notch pathways. Also emphasized are the roles of transcription factors Odd1, Eya1, Pax2, Lim1, and WT-1 in directing renal development. Areas requiring future investigation include the factors that modulate signaling pathways to provide temporal and site-specific effects. The evolution of our understanding of the cellular and molecular mechanisms of kidney development may provide methods for improved diagnosis of renal anomalies and, hopefully, targets for intervention for this common cause of childhood end-stage kidney disease.

The mammalian kidney consists of highly specialised cells that function in an integrated manner to maintain homeostasis of body fluids, electrolytes and nutrients. Formation of multicellular structures and differentiation of kidney cells are tightly regulated processes that begin during the fifth week and end by approximately 34 weeks of human gestation. This review focuses on the morphological, cellular and molecular steps required for kidney formation. Although some of this information is derived from studies of the human kidney, much has arisen from the study of genetic models of mammalian kidney morphogenesis. These models reveal mechanisms by which cell lineages are established in the embryonic kidney and the genetic pathways that are involved in their establishment and maintenance.

Mutations in the human NIMA (Never in Mitosis gene A)-related kinase 8 (Nek8) are associated with a rare form of the juvenile renal cystic disease, nephronophthisis type 9, and mutations in murine Nek8 cause renal cysts in jck mice. Cystogenesis involves dysfunctional ciliary signaling, and we have previously reported that Nek8 localizes to the primary cilium in mouse kidney epithelial cells. We now report that in developing mouse kidney, Nek8 is detected in the cilia of a subset of ureteric-bud-derived tubules at embryonic day (E)15.5. An increasing proportion of ureteric-bud-derived tubules express ciliary Nek8 until E18.5. Postnatal day 1 and 7 Nek8 is observed with equal frequency in both ureteric-bud and non-ureteric-bud-derived tubules. To investigate the cell biological consequences of kinase-deficient and jck mutant forms of Nek8, we transiently expressed green fluorescent protein (GFP)-tagged constructs in vitro. Mutations in the kinase and C-terminal domains of Nek8 adversely affected ciliary targeting but did not affect ciliogenesis or ciliary length. Consistent with these in vitro observations, kidneys from homozygous jck mice revealed reduced ciliary expression of Nek8 compared with kidneys from heterozygous (unaffected) mice. These data indicate that the ciliary localization of Nek8 in a subset of ureteric-bud-derived kidney tubules is essential for maintaining the integrity of those tubules in the mammalian kidney.

The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.

Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.

Background and objectives Standard clinical assessments do not predict surgical intervention in patients with a moderate degree of upper tract hydronephrosis. This study investigated whether combined measures of renal calyceal dilation and anteroposterior diameter (APD) of the renal pelvis at the first postnatal ultrasound better predict surgical intervention beyond standard assessments of the APD or Society of Fetal Urology (SFU) grading system. Design, setting, participants, & measurements A retrospective cohort of 348 children with antenatal hydronephrosis followed from 2003 to 2013 were studied. Using Cox regression, the risk for surgery by APD, SFU, and combined grading on the basis of the first postnatal ultrasound was calculated. The predictive capability of each grading system for surgery was determined by calculating the positive likelihood ratio (LR+). Results The combination of APD≥6–9 mm and diffuse caliectasis had a hazard ratio (HR) of 19.5 (95% confidence interval [95% CI], 3.94 to 96.9) versus 0.59 (95% CI, 0.05 to 6.53) for APD≥6–9 mm alone and a similar risk of 8.9 for SFU grade 3 (95% CI, 3.84 to 20.9). The combination of APD≥9–15 mm and diffuse caliectasis had an HR of 18.7 (95% CI, 4.36 to 80.4) versus 1.75 (95% CI, 0.29 to 10.5) for APD≥9–15 mm alone. The LR+ for surgery for diffuse caliectasis and APD≥6–9 mm was higher than for APD≥6–9 mm alone (HR=2.62; 95% CI, 0.87 to 7.94 versus HR=0.04; 95% CI, 0.01 to 0.32) and was higher for APD≥9–15 mm and diffuse caliectasis than APD≥9–15 mm alone (HR=2.0; 95% CI, 1.15 to 3.45 versus HR=0.14; 95% CI, 0.04 to 0.43). Both combined groups of moderate hydronephrosis (APD≥6–9 mm or ≥9–15 mm with diffuse caliectasis) had only slightly higher LR+ than SFU grade 3 (HR=1.89; 95% CI, 1.17 to 3.05). Conclusions These results suggest a grading system combining APD and diffuse caliectasis distinguishes those children with moderate degrees of upper tract hydronephrosis that are at higher risk of surgery.

Shh signaling induces proliferation of many cell types during development and disease, but how Gli transcription factors regulate these mitogenic responses remains unclear. By genetically altering levels of Gli activator and repressor functions in mice, we have demonstrated that both Gli functions are involved in the transcriptional control of N-myc and Cyclin D2 during embryonic hair follicle development. Our results also indicate that additional Gli-activator-dependent functions are required for robust mitogenic responses in regions of high Shh signaling. Through posttranscriptional mechanisms, including inhibition of GSK3-beta activity, Shh signaling leads to spatially restricted accumulation of N-myc and coordinated cell cycle progression. Furthermore, a temporal shift in the regulation of GSK3-beta activity occurs during embryonic hair follicle development, resulting in a synergy with beta-catenin signaling to promote coordinated proliferation. These findings demonstrate that Shh signaling controls the rapid and patterned expansion of epithelial progenitors through convergent Gli-mediated regulation.

Standardized evaluation of all newborns with antenatally recognized hydronephrosis (ANH) at The Hospital for Sick Children (HSC) has included voiding cystourethrography (VCUG). This paper reviews this protocol to determine: (1) the prevalence of vesicoureteral reflux (VUR) in isolated ANH and (2) the value of performing VCUG in cases of mild hydronephrosis, defined as renal pelvis dilatation

Renal dysplasia, the most frequent cause of childhood renal failure in humans, arises from perturbations in a complex series of morphogenetic events during embryonic renal development. The molecular pathogenesis of renal dysplasia is largely undefined. While investigating the role of a BMP-dependent pathway that inhibits branching morphogenesis in vitro, we generated a novel model of renal dysplasia in a transgenic (Tg) model of ALK3 receptor signaling. We report the renal phenotype, and our discovery of molecular interactions between effectors in the BMP and WNT signaling pathways in dysplastic kidney tissue. Expression of the constitutively active ALK3 receptor ALK3(QD), in two independent transgenic lines caused renal aplasia/severe dysgenesis in 1.5% and 8.4% of hemizygous and homozygous Tg mice, respectively, and renal medullary cystic dysplasia in 49% and 74% of hemizygous and homozygous Tg mice, respectively. The dysplastic phenotype, which included a decreased number of medullary collecting ducts, increased medullary mesenchyme, collecting duct cysts and decreased cortical thickness, was apparent by E18.5. We investigated the pathogenesis of dysplasia in these mice, and demonstrated a 30% decrease in branching morphogenesis at E13.5 before the appearance of histopathogical features of dysplasia, and the formation of beta-catenin/SMAD1/SMAD4 molecular complexes in dysplastic renal tissue. Increased transcriptional activity of a beta-catenin reporter gene in ALK3(QD);Tcf-gal mice demonstrated functional cooperativity between the ALK3 and beta-catenin-dependent signaling pathways in kidney tissue. Together with our results in the dysplastic mouse kidney, our findings that phospho-SMAD1 and beta-catenin are overexpressed in human fetal dysplastic renal tissue suggest that dysregulation of these signaling effectors is pathogenic in human renal dysplasia. Our work provides novel insights into the role that crucial developmental signaling pathways may play during the genesis of malformed renal tissue elements.

Objective. The Department of Pediatrics at the Hospital for Sick Children, which is funded by an alternative payment plan, has implemented a novel career development and compensation program (CDCP). Job activity profiles were used to more clearly define job expectations, benchmarks guided career development, and peer review was used to assess performance. The objective of this study was to evaluate the departmental pediatricians’ satisfaction with the CDCP. Methods. Pediatricians, all of whom had undergone CDCP annual reviews, could participate if they had undergone the in-depth triennial CDCP review. Each received a 5-point Likert scale-based questionnaire that asked how well the CDCP had conformed to the principles identified by the department during the development of the CDCP. Anonymous, confidential responses were collated and used to guide focus groups that discussed areas of greatest concern and attempted to identify solutions. Focus groups were led by external facilitators who were experienced in qualitative research. They audiotaped the sessions, transcribed the comments, and analyzed the data with the assistance of a qualitative analysis application. Results. Sixty of the eligible 88 pediatricians participated, and 74% of their responses were that the CDCP had addressed the original principles “somewhat,” “to a great extent,” or “extremely well.” The remainder indicated that some of the principles were either “not addressed” or “only to a small extent” by the CDCP. Results from the 11 focus groups (46 participants) indicated that the CDCP was an improvement over the previous method of career development and determination of the rate of remuneration. Most were also still in agreement with the purpose and design principles. Although they did not want the CDCP to undergo a major redesign, they identified areas that need improvement. Short-, medium-, and long-term action plans to address these areas are under way. Conclusion. Pediatricians at the health science center of the Hospital for Sick Children remain supportive of the CDCP.

Beckwith-Wiedemann syndrome (BWS) is a somatic overgrowth syndrome characterized by a variable incidence of congenital anomalies, including hemihyperplasia and renal malformations. BWS is associated with disruption of genomic imprinting and/or mutations in one or more genes encoded on 11p15.5, including CDKN1C (p57(KIP2)). It was hypothesized that genotypic and epigenotypic abnormalities of the 11p15.5 region affecting CDKN1C were associated with renal abnormalities. Medical records for 159 individuals with BWS were reviewed. All underwent at least one abdominal ultrasonographic evaluation. Testing for paternal uniparental disomy (UPD) at 11p15.5, CDKN1C mutations, and imprinting defects at KvDMR1 was performed for 96, 32, and 47 patients, respectively. Of the 159 patients, 67 (42%) exhibited renal abnormalities, mainly nephromegaly (25%), collecting system abnormalities (11%), and renal cysts (10.5%). The frequency of renal lesions among patients who were tested for genetic abnormalities did not differ from that among patients who were not tested. Paternal UPD was demonstrated in 22 of 96 cases (23%), CDKN1C mutations in eight of 32 cases (25%), and KvDMR1 imprinting defects in 21 of 47 cases (45%). The 22 UPD-positive patients exhibited a significantly higher incidence of renal abnormalities (P = 0.0026). Surprisingly, the eight patients with CDKN1C mutations exhibited no significant increase in the incidence of renal lesions (P = 0.29). Imprinting defects at KvDMR1, which might downregulate CDKN1C, were also not associated with a significant difference in the incidence of renal disease. Whereas UPD at 11p15.5 in BWS was associated with a higher incidence of renal abnormalities, mutations at CDKN1C and KvDMR1 imprinting defects were not, suggesting that imprinted genes on 11p15.5 other than CDKN1C are critical for renal development.

The molecular mechanisms that control renal development are largely undefined. The discovery of mutations in the gene encoding glypican-3 (Gpc3) in humans with Simpson-Golabi-Behmel syndrome (SGBS) and renal dysplasia, and the establishment of a genetic mouse model of GPC3 deficiency has provided an opportunity to define the role of GPC3 during renal development. Glypicans are a family of cell surface heparan sulfate proteoglycans that control growth factor signalling in nonrenal tissues. Mutational inactivation of Gpc3 causes somatic overgrowth and cystic renal dysplasia, as observed in SGBS. Overgrowth of the ureteric bud and its branches and increased ureteric bud cell proliferation is observed during the early stages of renal development. Subsequently, during corticomedullary differentiation, cortical collecting duct cell proliferation is increased, while medullary collecting duct cells proliferate at a reduced rate and undergo apoptosis resulting in degeneration of the medulla. However, cells that constitute medullary cysts are characterized by enhanced cell proliferation and a lower rate of apoptosis. Thus, the phenotype arising from Gpc3 inactivation demonstrates that tight regulation of cell proliferation and apoptosis is critical during formation of the renal medulla.

The kidney of the Gpc3−/ mouse, a novel model of human renal dysplasia, is characterized by selective degeneration of medullary collecting ducts preceded by enhanced cell proliferation and overgrowth during branching morphogenesis. Here, we identify cellular and molecular mechanisms underlying this renal dysplasia. Glypican-3 (GPC3) deficiency was associated with abnormal and contrasting rates of proliferation and apoptosis in cortical (CCD) and medullary collecting duct (MCD) cells. In CCD, cell proliferation was increased threefold. In MCD, apoptosis was increased 16-fold. Expression of Gpc3 mRNA in ureteric bud and collecting duct cells suggested that GPC3 can exert direct effects in these cells. Indeed, GPC3 deficiency abrogated the inhibitory activity of BMP2 on branch formation in embryonic kidney explants, converted BMP7-dependent inhibition to stimulation, and enhanced the stimulatory effects of KGF. Similar comparative differences were found in collecting duct cell lines derived from GPC3-deficient and wild type mice and induced to form tubular progenitors in vitro, suggesting that GPC3 directly controls collecting duct cell responses. We propose that GPC3 modulates the actions of stimulatory and inhibitory growth factors during branching morphogenesis.