Victoria F. Norwood

Developmental consequences of the renin-angiotensin system

Molecular, cellular, and physiological studies indicate that the renin-angiotensin system (RAS) is highly expressed during early kidney development. We propose that a major function of the RAS during early embryonic development is the modulation of growth processes that lead the primitive kidney into a properly differentiated and architecturally organized organ suited for independent extrauterine life. As development progresses, the RAS acquires new and overlapping functions such as the endocrine and paracrine regulation of blood pressure and renal hemodynamics. Disease states in adult mammals often result in expression of RAS genes and phenotypic changes resembling the embryonic pattern, emphasizing the importance of undertaking developmental studies. Because of their importance in health and disease, the immediate challenge is to identify the mechanisms that regulate the unique development of the RAS and its role(s) in normal and abnormal growth processes.

Development of the kidney vasculature

Renal vascularization and nephrogenesis occur simultaneously following a tightly regulated developmental program influenced by growth factors, extracellular matrix components and cell membrane receptors. Both processes of angiogenesis and vasculogenesis probably participate in the formation of renal vessels. The origin and fate of the various renal vascular cells and the molecular mechanisms that initiate and guide intrarenal vascularization are fundamental questions that remain to be answered. Microsc. Res. Tech. 39:254–260, 1997.

Zis: a developmentally regulated gene expressed in juxtaglomerular cells

Renal juxtaglomerular (JG) cells are specialized myoepithelioid cells located in the afferent arteriole at the entrance to the glomerulus. Their main function and distinctive feature is the synthesis and release of renin, the key hormone-enzyme of the renin-angiotensin system that regulates arterial blood pressure. Despite their relevance to health and disease, not much is known about factors that confer and/or maintain JG cell identity. To identify genes uniquely expressed in JG cells, we used a cell culture model and RNA differential display. JG cells cultured for 2 days express renin and renin mRNA, but after 10 days in culture they no longer contain or release renin and renin mRNA is reduced 700-fold. We report one cDNA differentially expressed in the 2-day JG cell culture that detects a 2.6-kb mRNA expressed at higher levels in newborn than adult kidney. Screening a 2-day culture JG cell cDNA library yielded clones representing differentially spliced transcripts. These cDNAs encode one unique protein (Zis) containing zinc fingers and domains characteristic of splicing factors and RNA binding proteins. Northern blot analysis confirmed Zis mRNA expression in differentiated JG cells, and identified an additional unique 1.5-kb transcript. The Zis transcripts are developmentally regulated in kidney and a number of other organs. The features of the Zis protein and its organ distribution suggest a possible role in regulation of transcription and/or splicing, both important steps for controlling developmentally expressed genes.

Hypocomplementemic urticarial vasculitis: report of a pediatric case

Abstract Hypocomplementemic urticarial vasculitis syndrome (HUVS) is well described in adults but is quite rare in children. We report a pediatric case of HUVS initially diagnosed as juvenile rheumatoid arthritis and then as Henoch-Schönlein purpura. Beginning at 3 years of age, our patient developed polyarthritis with hypocomplementemia. She subsequently experienced an intermittent purpuric rash beginning at age 4 years, and she continued to have episodic arthritis and rash for years. Hematuria and proteinuria were noted at 12 years of age; renal biopsy revealed membranoproliferative glomerulonephritis with membranous features. Serum complement evaluation revealed activation of the classical pathway, consistent with HUVS. Therapy with oral dapsone led to improvement in proteinuria. HUVS should be considered in the differential diagnosis of pediatric patients with glomerulonephritis, urticarial rash, arthritis/arthralgias, and obstructive pulmonary disease.

Single kidney and sports participation : Perception versus reality

OBJECTIVES. Physician opinions and practice patterns regarding the participation of children and adolescents with single, normal kidneys in contact/collision sports are widely varied. We hypothesize that limitation of participation from play based only on the presence of a single kidney is not supported by available data. We sought to determine recommendations of pediatric nephrologists regarding the participation of patients with single, normal kidneys in contact/collision sports and review the literature to determine the rate of sports-related kidney injury compared with other organs. METHODS. Members of the American Society of Pediatric Nephrology were surveyed regarding their recommendations for participation of patients with single, normal kidneys in contact/collision sports. Medical and sports literature databases were searched to determine sports-related kidney, brain, spinal cord, and cardiac injury rates and the sports associated with kidney injury. RESULTS. Sixty-two percent of respondents would not allow contact/collision sports participation. Eighty-six percent of respondents barred participation in American football, whereas only 5% barred cycling. Most cited traumatic loss of function as the reason for discouraging participation. The literature search found an incidence of catastrophic sports-related kidney injury of 0.4 per 1 million children per year from all sports. Cycling was the most common cause of sports-related kidney injury causing >3 times the kidney injuries as football. American football alone accounted for 0.9 to 5.3 fatal brain injuries and 4.9 to 7.3 irreversible spinal cord injuries per 1 million players per year. Commotio cordis causes 2.1 to 9.2 deaths per year. CONCLUSIONS. Most pediatric nephrologists prohibit contact/collision sports participation by athletes with a single kidney, particularly football. The available evidence suggests that cycling is far more likely to cause kidney injury. In addition, kidney injury from sports is much less common than catastrophic brain, spinal cord, or cardiac injury. Restricting participation of patients with a single, normal kidney from contact/collision sports is unwarranted.

The Maturing Kidney: Development and Susceptibility

Kidney morphogenesis is accomplished by the coordinated interaction of molecular signals that culminate in the production of an organ that is architecturally and functionally ready for extrauterine, free life. In humans, nephrogenesis is completed before birth. However the kidney continues to mature both from a functional and anatomical point of view. Throughout its development, the kidney is susceptible to a variety of injurious agents. This brief review considers the basic mechanisms of kidney organogenesis and functional maturation. To illustrate some concepts, the renal alterations caused by interference with a normal regulatory system, the renin-angiotensin system is discussed.

Recent advances in renal development.

Anatomical development of the kidney is achieved by the reciprocal induction of the ureteric bud and the metanephric mesenchyma. This interaction triggers the process of nephrogenesis and culminates in the formation of the mature kidney. In vivo, nephrogenesis is coordinated with renal vascularization. In fact, vascular precursors, epithelial progenitors, and mesenchymal cells communicate with one another in a highly organized fashion. As a result of this complex interaction, a mature kidney, architecturally and functionally ready for extrauterine life, is produced. This review deals with the relevant molecules and mechanisms governing nephrovascular development.

Factors Influencing Pediatric Nephrology Trainee Entry into the Workforce

BACKGROUND AND OBJECTIVES Emerging needs in pediatric nephrology (PN) have made the number of nephrologists entering the workforce of critical importance. This study aimed to discern factors that influence PN fellows to choose their career path and decide to enter the PN workforce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A survey was sent to the American Society of Pediatric Nephrology list of PN fellows (n = 103) in 2008. The 57 fellows (55%) who completed the survey were representative of the group. RESULTS The majority decided on a career in PN as senior residents, most commonly due to their interest in renal physiology and academics. They felt residents chose other fields due to lack of interest/exposure to PN, financial constraints, and perceived PN workload. Fellows identified workload and their perception of faculty dissatisfaction as important concerns with PN. None of the respondents planned to leave fellowship, but 21% have considered this. Twenty-eight percent knew a PN fellow who resigned, thought to be due to workload, personal conflicts, and perceived faculty dissatisfaction. CONCLUSIONS Exposing residents to PN earlier in training and emphasizing positive features may create greater interest in PN. PN programs should be cognizant of workload and the influence of faculty dissatisfaction. Ongoing evaluation of PN fellow perceptions can assist in efforts to enhance recruitment and retention.

Evolution of the urinary proteome during human renal development and maturation: variations with gestational and postnatal age

Background:Low birth weight is associated with deficits in nephron number in the infant kidney and increased risk of adulthood hypertension and renal dysfunction. Urinary biomarkers may be potential indicators of renal reserve, but little is known about the influence of gestational and postnatal age on the expression of urinary proteins. The aims of this study were to determine the relationships between selected urinary proteins and renal maturation. We hypothesized that urinary protein patterns would change over time during late nephrogenesis and renal maturation.Methods:Urine samples were collected at birth and over 12 mo from preterm (33–35 wk) and term (38–40 wk) infants. Candidate urinary proteins were identified by antibody array and quantified with enzyme-linked immunosorbent assay.Results:Preterm infants at birth were found to have relatively elevated levels of insulin-like growth factor binding protein-1, -2, and -6, monocyte chemotactic protein-1, CD14, and sialic acid-binding Ig-like lectin 5. These markers gradually decline to levels similar to those of full-term infants by 2–6 mo of life. In contrast, many urinary markers in healthy full-term infants remain stable over the first year of life.Conclusion:Gestational and postnatal age must be considered when evaluating the utility of urinary biomarkers.

Predictors of retention and BMI loss or stabilization in obese youth enrolled in a weight loss intervention

SUMMARY OBJECTIVE To evaluate predictors for intervention dropout and successful reduction of metabolic syndrome risk factors among obese children enrolled in a short-term, clinic-based weight-loss intervention. DESIGN, SETTING, SUBJECTS Retrospective database review of 1080 children 8 months to 17 years. seen a pediatric obesity clinic. INTERVENTIONS Behavior modification counseling to induce change in dietary and exercise choices. MAIN OUTCOME MEASURES (1) Pre-/post-intervention change in body mass index (BMI), waist circumference, blood pressure, glucose, insulin, and cholesterol (LDL, HDL, & total). (2) Predictors of successful decrease in BMI and clinic drop-out. ANALYSIS Paired t-tests for pre-/post-intervention comparisons. Linear regression to assess predictors of success and predictors of drop-out, with adjustment for age, gender, race, insurance status, and service area. RESULTS Among children evaluated, adolescent females were most likely to achieve successful decrease in BMI, insulin level, and LDL cholesterol post-intervention. Nearly 40% of children dropped out early in the intervention. Predictors of drop out included age <6 years, public insurance status, follow-up scheduled during summer months, and residence in a tertiary service area. CONCLUSIONS Clinic-based weight loss interventions can lead to successful improvements in BMI and other metabolic parameters in pediatric populations and may be more likely among adolescent females than in younger children or males. Drop-out is common, particularly among younger children, children with public insurance and children scheduled for follow-up in the summer. Identification of these drop-out predictors in individual patients may help in targeting children likely to succeed in short-term, clinic-based, weight-loss interventions.