Norman David Rosenblum

• Doctor of Medicine
• Professor at University of Toronto

Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased lev...

Antenatal hydronephrosis (HN) impacts up to 5% of pregnancies and requires close, frequent follow-up monitoring to determine who may benefit from surgical intervention. To create an automated HN Severity Index (HSI) that helps guide clinical decision-making directly from renal ultrasound images. We applied a deep learning model to paediatric renal...

Polycystic kidney diseases (PKD) are genetic disorders characterised by the formation of fluid-filled cysts, which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicate...

Hearing loss affects nearly 1.6 billion people and is the third-leading cause of disability worldwide. Chronic kidney disease (CKD) is also a common condition that is associated with adverse clinical outcomes and high health-care costs. From a developmental perspective, the structures responsible for hearing have a common morphogenetic origin with...

Congenital anomalies of the kidney and urinary tract (CAKUT) are characterised by a spectrum of structural and histologic abnormalities and are the major cause of childhood kidney failure. During kidney morphogenesis, the formation of a critical number of nephrons is an embryonic process supported, in part, by signalling between nephrogenic precurs...

Storytelling is a powerful means to evoke empathy and understanding among people. When patient partners, which include patients, family members, caregivers and organ donors, share their stories with health professionals, this can prompt listeners to reflect on their practice and consider new ways of driving change in the healthcare system. However,...

Congenital anomalies of the urinary tract are a major cause of chronic kidney disease in both adults and children. Ureteropelvic junction obstruction, usually detected as urinary tract dilatation in utero , is one of the most common forms of CAKUT. As antenatal ultrasound technology advances and screening becomes more widespread, increasing numbers...

CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling...

Congenital anomalies of the kidneys and urinary tract, otherwise known as CAKUT, are disorders of development, the most common cause of kidney failure in children, and an antecedent cause of kidney dysfunction in adults. CAKUT consists of a polymorphic group of unilateral or bilateral disorders characterized by phenotypic and genetic heterogeneity...

Congenital anomalies of the kidney and urinary tract encompass a broad spectrum of developmental conditions that together account for the majority of childhood chronic kidney diseases. Kidney abnormalities are the most commonly diagnosed congenital anomaly in children, and detection of this anomaly is increasing as a result of improved antenatal ca...

Congenital anomalies of the kidney and urinary tract or “CAKUT” describes a spectrum of developmental disorders with a range of associated clinical presentations and functional consequences. CAKUT underlies the majority of chronic kidney disease and kidney replacement therapy requirement in children, but functional deterioration can also emerge in...

Pallister‐Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI‐Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anom...

Purpose of program Given the growing interest in patient-oriented research (POR) initiatives, there is a need to provide relevant training and education on how to engage with patients as partners on research teams. Sources of information As part of its mandate to develop appropriate training materials, the patient-oriented renal research network,...

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 centu...

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 centu...

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 centu...

Background: 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...

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, prov...

Purpose of program: 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 R...

COVID-19 has halted research around the globe and forced researchers out of their laboratories. Non-emergency medical appointments were canceled. 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...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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-spec...

Cerebellar granule cell (GC) development relies on precise regulation of Sonic Hedgehog (Shh)-Gli signaling activity, failure of which is associated with motor disorders and medulloblastoma. Mutations in pathway regulator Sufu, which modulates Gli activators and repressors, are linked to cerebellar dysfunction and tumourigenesis. The mechanism by w...

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation...

Human induced pluripotent stem cells (iPSCs) are a promising tool to investigate pathogenic mechanisms underlying human genetic conditions, such as congenital anomalies of the kidney and urinary tract (CAKUT). Currently, iPSC-based research in pediatrics is limited by the invasiveness of cell collection. Urine cells (UCs) were isolated from pediatr...

Translational research (TR) is a multidirectional and multidisciplinary integration of basic research, patient-oriented research and population-based research, with the long-term goal of improving human health. Unfortunately, the current scientific training system does not adequately align with the goals of TR. To address this issue, an organizatio...

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 continuu...

Induced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSCs, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional...

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...

Clinician-scientists-health care professionals expert in research and clinical practice-can play a vital role in translating research outcomes to clinical practice. Concerns about the sustainability of the clinician-scientist workforce have been expressed in the literature for decades. Although many have made recommendations to increase the clinici...

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 an...

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 inte...

For over 60 years, MD-PhD programs have provided integrated clinical and research training in order to produce graduates primed for physician-scientist careers. Yet the nature of this integrated training is poorly characterized, with no program theory of integrated MD-PhD training to guide program development or evaluation. The authors address this...

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...

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...

Nonobstructive hydronephrosis, defined as dilatation of the renal pelvis with or without dilatation of the ureter, is the most common antenatal abnormality detected by fetal ultrasound. Yet, the etiology of nonobstructive hydronephrosis is poorly defined. We previously demonstrated that defective development of urinary tract pacemaker cells (utPMCs...

Purpose of review: 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. Issue: Chronic kidney disease (CKD) is a complex disorder that affects more than 4 million Canadians and costs the Canadia...

Purpose of review 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. Issue Chronic kidney disease (CKD) is a complex disorder that affects more than 4 million Canadians and costs the Canadian hea...

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 t...

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 pro...

Physician-scientists are individuals who actively participate in patient care, have undergone additional research training, and devote the majority of their time to research. Physician-scientists are traditionally the primary catalysts in bridging the translational gap-that is, the failure to link fundamental new knowledge in the pathobiology of di...

Background: Deficiency of Suppressor of Fused (SuFu), an intracellular mediator of Hedgehog signaling, in the murine mid-hindbrain disrupts cerebellar morphogenesis and cell differentiation in a manner that is rescued by constitutive expression of GLI3 transcriptional repressor (GLI3R). Here, we determined SuFu functions in cerebellar radial precu...

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...

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 r...

End goal of translational medicine is to combine disciplines and expertise to eventually promote improvement of the global healthcare system by delivering effective therapies to individuals and society. Well-trained experts of the translational medicine process endowed with profound knowledge of biomedical technology, ethical and clinical issues, a...

The paper by Jones and colleagues, published in this edition of Clinical Investigative Medicine, contributes to our understanding of Canadian MD/PhD Programs. While there has been little published on this subject by the Canadian programs, themselves, this paper is the most recent in a series by leaders of the Clinical Investigator Trainee Associati...

Background: Physicians have traditionally been at the forefront of medical research, bringing clinical questions to the laboratory and returning with ideas for treatment. However, we have anecdotally observed a decline in the popularity of basic science research among trainees. We hypothesized that fewer resident physicians have been pursuing basic...

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 abou...

The clinician-scientist role is critical to the future of health care, and in 2010, the Carnegie Report on Educating Physicians focused attention on the professional identity of practicing clinicians. Although limited in number, published studies on the topic suggest that professional identity is likely a critical factor that determines career sust...

Unlabelled: Host-pathogen interactions can induce epigenetic changes in the host directly, as well as indirectly through secreted factors. Previously, uropathogenic Escherichia coli (UPEC) was shown to increase DNA methyltransferase activity and expression, which was associated with methylation-dependent alterations in the urothelial expression of...

FimH+ UPEC mutants demonstrated intracellular persistence at 6 days post-inoculation in HT-5637 cells cultured in Media with Gentamycin. FimH+ and FimHΔ complemented SLC2 derivatives of UPEC were detected by anti-E.coli-biotin LPS antibodies with Cy3-conjugated Streptavidin, with nuclear Hoechst 33342 dye shown. Images were acquired by confocal mic...

EZH2 and PCNA expression increase at day one post-inoculation in HT-5637 cells. 5X105 host cells were inoculated with 2 moi of uropathogenic E.coli (UTI89). Immunostaining was performed at 0, 1, 2 and 3 days post-inoculation. N = 8. (PDF)

Primer Sequences for QPCR. (PDF)

Cell viability of HT-5637 urothelial cells to varying doses of EZH1/2 and KDM6A/B inhibitors, UNC1999 (Figures A and B) and GSK J4 (Figure C), respectively. Cell viability was assayed by detecting resorfin production from raszurin, as measured on a fluorescent plate reader. Dosages in the range that did not affect basal viability of the cells were...

EZH2 and PCNA expression increased at day one post-inoculation in HT-5637 cells. 105 host cells were inoculated with 2 moi of uropathogenic E.coli (UTI89). Immunofluorescent staining was performed at 0, 1, 2 and 3 days post-inoculation. N = 8. (PDF)

UNC1999 was well tolerated by host cells. Figure A. Cell viability at day 2 was not significantly altered by UNC1999 treatment. Figure B. EZH2 expression was not altered by UNC1999 treatment at 2 day post-inoculation in HT-5637 cells. 105 host cells were inoculated with 2 moi of uropathogenic E.coli (UTI89). QPCR was performed on samples harvested...

In this chapter, disorders of kidney formation, so-called congenital anomalies of the kidney and urinary tract (CAKUT) are defined including their epidemiology and long-term outcome. A detailed review of the molecular signaling pathways that lead to normal kidney and urinary tract formation is included with a focus on those genes and proteins that...

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of all birth defects, constituting 23 % of all such defects [ 1 ]. As a group, CAKUT are the cause of 30-50 % of all cases of end-stage renal disease (ESRD) in children [ 2 ]. Further, they are the most frequent malformations detected by ultrasound in utero [ 3 ]...

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...

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-ac...

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 standar...

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 ure...

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 SIO...

Purpose: A number of indicators suggest that the physician scientist career track is threatened. As such, it is an opportune time to evaluate current training models. Perspectives on physician scientist education and career path were surveyed in trainees at the University of Toronto, home to Canada's longest standing physician scientist training p...

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...

Usually inaugural editorials are written by the Editor-in-Chief to describe the scope and vision for the journal to potential authors and readers. This editorial is written by the Editor-in-Chief, the Deputy Editors and the Associate Editors collaboratively as a clear signal that this is a unique and different journal. We will build this journal on...

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 dysplas...

Coordinated ureteric peristalsis propels urine from the kidney to the bladder. Cells in the renal pelvis and ureter spontaneously generate and propagate electrical activity to control this process. Recently, c-kit tyrosine kinase and hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) were identified in the upper urinary tract. Bot...

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 abnormal...

The primary cilium is required during early embryo patterning, epithelial tubulogenesis, and growth factor-dependent signal transduction. The requirement for primary cilia during renal epithelial-mesenchymal tissue interactions that give rise to nephrons is undefined. Here, we used Cre-mediated recombination to generate mice with Kif3a deficiency t...

Primary cilia are present in both ureteric epithelial and metanephric mesenchyme cells in the developing murine kidney. (A–D) Schematic of ureteric bud epithelial cells (black), metanephric mesenchyme cells and metanephric-derived nephrogenic stuctures during progressive stages of kidney development (green). (A’–D’’) Primary cilia (acetylated α-tub...

Decreased nephron number in both Kif3a−/−UB and Kif3a−/−MM kidneys. (A–F) Histological sections, stained with hematoxylin and eosin demonstrate a qualitative decrease in the number of glomeruli (arrows) at E15.5 (A,B,C) and E18.5 (D,E,F) in both Kif3a−/−UB (B, E) and Kif3a−/−MM (C, F) mice compared to WT (A, D). (G–I) The decrease in mature glomeru...

Cell proliferation and SIX2-positive nephrogenic progenitor cells in Kif3a−/−MM kidney tissue. (A, B) In situ BrdU incorporation assay in E13.5 kidney tissue. Ureteric bud tip is demarcated by the yellow dotted line. (C) Quantification of BrdU-positive cap mesenchyme cells reveals no significant difference between Kif3a−/−MM and WT mice. (D, D’) SI...

Expression of Fgf8, Wnt4, Lim1 and Wnt9b mRNAs in E13.5 Kif3a−/−MM mice. Expression was determined by in situ hybridization. Expression of Fgf8 is mildly decreased in Kif3a−/−MM mice (A’) compared to WT (A) but expression of Wnt4. (B, B’), Lim1 (C, C’) and Wnt9b (D, D’) is unchanged. Scale bars: 50 micrometer. (TIF)

Expression of Kif3a in kidney tissue. Ureteric bud was dissected free of metanephric mesenchyme in E11.5 kidney tissue of WT, Kif3a−/−UB, and Kif3a−/−MM mice. Kif3a mRNA expression was analyzed by quantitative RT-PCR and quantified. Kif3a is not expressed in the ureteric bud of Kif3a−/−UB mice but is expressed in metanephric mesenchyme. Kif3a is no...

Table S1, Primers used to genotype the various mutant mouse lines. Table S2, The primers and their RT-PCR products used to estimate the mRNA expression in kidneys and in MM cells. (DOC)

Background: The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridization (aCGH) and microarray technology. Contiguous gene deletions involving the gene ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability, wh...

Background: The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridisation (aCGH) and microarray technology. Contiguous gene deletions involving ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), while...

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...

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 av...