Morphological ciliary muscle changes associated with form deprivation-induced myopia.

Myopic children have larger ciliary muscles than non-myopic children, suggesting that the ciliary muscle may have an impact on or be affected by refractive error development. The guinea pig represents an attractive model organism for myopia development research. The purpose of the study was to investigate whether form deprivation-induced myopia in one or more strains of guinea pig causes thickening of the ciliary muscle as seen in human myopia. Thirty-nine guinea pigs were bred from in-house progenitors obtained from Cincinnati Children's Hospital (Cincinnati) and the United States Army (Strain 13). At 2-4 days of age the right eyes of animals were exposed to form deprivation for 7 days while the fellow eyes served as controls. Refractive error was determined with retinoscopy while vitreous chamber depth (VCD) and axial length (AL) were determined with A-scan ultrasound. Ciliary muscle characteristics (ciliary muscle length, cross-sectional area, volume, cell number, cell size, and smooth muscle actin concentration) were determined histologically with antibody labeling and analyzed according to whether the animal developed axial myopia (anisometropia > -2.00 D with VCD and/or AL differences > 0.1 mm) or was unresponsive. This analysis method yielded four groups with Group 1 having no induced myopia but with axial elongation (n = 11), Group 2 having myopia without vitreous or axial elongation (n = 8), Group 3 having myopia with either vitreous or axial elongation (n = 11), and Group 4 having myopia with both vitreous and axial elongation (n = 8). There were no post-treatment inter-ocular differences between strains or for the overall group of animals for any ciliary muscle variable; however, a higher response group number in multivariate ordinal regression was related to having a treated compared to fellow eye that had a lower smooth muscle actin concentration (p = 0.006), with a shorter ciliary muscle length (p = 0.042), and a less oblate eye shape (p = 0.010). Guinea pig ciliary muscle length and smooth muscle actin concentration were significantly less in the treated eyes of axially myopic animals suggesting that 7 days of form deprivation induced ciliary muscle cellular atrophy or inhibited ciliary muscle growth. Form deprivation myopia in the guinea pig does not result in the increase in ciliary muscle thickness associated with human juvenile and adult myopia.

Krt5+ urothelial cells are developmental and tissue repair progenitors in the kidney.

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5+) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)+ RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk+ RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk+ RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk+ RUCs derive from embryonic and neonatal Krt5+ RUCs, whereas Krt5+ RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5+ RUCs break their lineage restriction and robustly differentiate into Upk+ RUCs. Thus, Krt5+ RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk+ RUCs in a temporally restricted manner.

Common clinical markers predict end-stage renal disease in children with obstructive uropathy.

BACKGROUND: Obstructive uropathy (OU) is a common cause of end-stage renal disease (ESRD) in children. Children who escape the newborn period with mild-to-moderate chronic kidney disease (CKD) continue to be at increased risk. The predictive ability of clinically available markers throughout childhood is poorly defined. METHODS: Patients with OU were identified in the Chronic Kidney Disease in Children Study. The primary outcome of interest was renal replacement therapy (RRT) (cases). Controls were age matched and defined as patients within the OU cohort who did not require RRT during study follow-up. RESULTS: In total, 27 cases and 41 age-matched controls were identified. Median age at baseline and age at outcome measurement were 10 vs. 16 years, respectively. First available glomerular filtration rate (GFR) (36.9 vs. 53.5 mL/min per 1.73 m2), urine protein/creatinine (Cr) (0.40 vs. 0.22 mg/mg) and microalbumin/Cr (0.58 vs. 0.03 mg/mg), and serum CO2 (20 vs. 22 mmol/L) and hemoglobin (12.4 vs. 13.2 g/dL) differed significantly between cases and controls, respectively. GFR declined 3.07 mL/min per 1.73 m2/year faster in cases compared to that in controls (p < 0.0001). Urine protein/Cr and microalbumin/Cr increased by 0.16 and 0.11 per year more in cases compared to those in controls, respectively (p ≤ 0.001 for both). Serum phosphate increased by 0.11 mg/dL and serum albumin and hemoglobin decreased by 0.04 (g/dL) and 0.14 (g/dL) per year more for cases compared to those for controls, respectively (p < 0.05 for all). CONCLUSIONS: Age-specific baseline and longitudinal measures of readily available clinical measures predict progression to ESRD in children with mild-to-moderate CKD from OU.

The uroplakin plaque promotes renal structural integrity during congenital and acquired urinary tract obstruction.

Urinary tract obstruction represents a common cause of kidney injury across the human life span, resulting in chronic kidney disease and end-stage renal disease. Yet, the extent of obstructive renal damage can be heterogeneous between individuals, implying the existence of unknown mechanisms that protect against or accelerate kidney injury. In this study, we investigated the role of urothelial remodeling in renal adaptation during congenital and acquired obstruction. In the Megabladder ( Mgb-/-) model of congenital obstruction and unilateral ureteral ligation model of acute obstruction, progressive hydronephrosis is strongly associated with dynamic reorganization of the renal urothelium, which elaborates a continuous uroplakin (Upk) plaque. This led us to postulate that the Upk plaque prevents parenchymal injury during urinary tract obstruction. To test this hypothesis, we interbred Mgb-/- and Upk1b-/- mice, which lack the critical Upk1b subunit for Upk plaque formation. Upk1b-/-; Mgb-/- mice experienced an accelerated onset of bilateral hydronephrosis with severe (>67%) parenchymal loss, leading to renal failure and mortality in adolescence. To investigate the function of the renal Upk plaque during acute obstruction, we destabilized the Upk plaque by Upk1b deletion or genetically depleted Upk+ cells following unilateral ureteral obstruction. Both of these strategies accelerated renal parenchymal loss following ureteral ligation, attesting to a conserved, stabilizing role for Upk plaque deposition in the acutely obstructed kidney. In aggregate, these complementary experiments provide the first evidence that the Upk plaque confers an essential, protective adaptation to preserve renal parenchymal integrity during congenital and acquired urinary tract obstruction.

Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

The signaling networks regulating antimicrobial activity during urinary tract infection (UTI) are incompletely understood. Interleukin-6 (IL-6) levels increase with UTI severity, but the specific contributions of IL-6 to host immunity against bacterial uropathogens are unknown. To clarify this we tested whether IL-6 activates the Stat3 transcription factor, to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI. Transurethral inoculation of uropathogenic Escherichia coli led to IL-6 secretion, urothelial Stat3 phosphorylation, and activation of antimicrobial peptide transcription, in a Toll-like receptor 4-dependent manner in a murine model of cystitis. Recombinant IL-6 elicited Stat3 phosphorylation in primary urothelial cells in vitro, and systemic IL-6 administration promoted urothelial Stat3 phosphorylation and antimicrobial peptide expression in vivo. IL-6 deficiency led to decreased urothelial Stat3 phosphorylation and antimicrobial peptide mRNA expression following UTI, a finding mirrored by conditional Stat3 deletion. Deficiency in IL-6 or Stat3 was associated with increased formation of intracellular bacterial communities, and exogenous IL-6 reversed this phenotype in IL-6 knockout mice. Moreover, chronic IL-6 depletion led to increased renal bacterial burden and severe pyelonephritis in C3H/HeOuJ mice. Thus, IL-6/Stat3 signaling drives a transcriptional program of antimicrobial gene expression in infected urothelium, with key roles in limiting epithelial invasion and ascending infection.

An illustrated anatomical ontology of the developing mouse lower urogenital tract.

Malformation of the urogenital tract represents a considerable paediatric burden, with many defects affecting the lower urinary tract (LUT), genital tubercle and associated structures. Understanding the molecular basis of such defects frequently draws on murine models. However, human anatomical terms do not always superimpose on the mouse, and the lack of accurate and standardised nomenclature is hampering the utility of such animal models. We previously developed an anatomical ontology for the murine urogenital system. Here, we present a comprehensive update of this ontology pertaining to mouse LUT, genital tubercle and associated reproductive structures (E10.5 to adult). Ontology changes were based on recently published insights into the cellular and gross anatomy of these structures, and on new analyses of epithelial cell types present in the pelvic urethra and regions of the bladder. Ontology changes include new structures, tissue layers and cell types within the LUT, external genitalia and lower reproductive structures. Representative illustrations, detailed text descriptions and molecular markers that selectively label muscle, nerves/ganglia and epithelia of the lower urogenital system are also presented. The revised ontology will be an important tool for researchers studying urogenital development/malformation in mouse models and will improve our capacity to appropriately interpret these with respect to the human situation.

Inflammation drives renal scarring in experimental pyelonephritis.

Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis.

Role of renal urothelium in the development and progression of kidney disease.

The clinical and financial impact of chronic kidney disease (CKD) is significant, while its progression and prognosis is variable and often poor. Studies using the megabladder (mgb -/- ) model of CKD show that renal urothelium plays a key role in modulating early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical, and molecular characterization of Upk1b RFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/asymmetric membrane unit (AUM) formation, and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence that Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis, and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in normal development and pathogenesis of the urinary tract and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression.

Polymorphisms in α-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.

Uroplakin 1b is critical in urinary tract development and urothelial differentiation and homeostasis.

Proper development and maintenance of urothelium is critical to its function. Uroplakins are expressed in developing and mature urothelium where they establish plaques associated with the permeability barrier. Their precise functional role in development and disease is unknown. Here, we disrupted Upk1b in vivo where its loss resulted in urothelial plaque disruption in the bladder and kidney. Upk1b(RFP/RFP) bladder urothelium appeared dysplastic with expansion of the progenitor cell markers, Krt14 and Krt5, increased Shh expression, and loss of terminal differentiation markers Krt20 and uroplakins. Upk1b(RFP/RFP) renal urothelium became stratified with altered cellular composition. Upk1b(RFP/RFP) mice developed age-dependent progressive hydronephrosis. Interestingly, 16% of Upk1b(RFP/RFP) mice possessed unilateral duplex kidneys. Our study expands the role of uroplakins, mechanistically links plaque formation to urinary tract development and function, and provides a tantalizing connection between congenital anomalies of the kidney and urinary tract along with functional deficits observed in a variety of urinary tract diseases. Thus, kidney and bladder urothelium are regionally distinct and remain highly plastic, capable of expansion through tissue-specific progenitor populations. Furthermore, Upk1b plays a previously unknown role in early kidney development representing a novel genetic target for congenital anomalies of the kidney and urinary tract.

Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy.

BACKGROUND: Congenital obstructive nephropathy (CON) is a leading cause of pediatric chronic kidney disease (CKD). Despite optimal surgical and medical care, there is a high rate of CKD progression. Better understanding of molecular and cellular changes is needed to facilitate development of improved biomarkers and novel therapeutic approaches in CON. METHODS: The megabladder (mgb) mouse is an animal model of CKD with impaired bladder emptying, hydronephrosis, and progressive renal injury. In this study, we characterize a particular microRNA, miR-205, whose expression changes with the degree of hydronephrosis in the mgb(-/-) kidney. RESULTS: Expression of miR-205 is progressively increased in the adult mgb(-/-) mouse with worsening severity of hydronephrosis. miR-205 expression is correlated with altered expression of cytokeratins and uroplakins, which are markers of cellular differentiation in urothelium. We describe the spatial pattern of miR-205 expression, including increased expression in renal urothelium and novel miR-205 expression in medullary collecting duct epithelium in the congenitally obstructed kidney. CONCLUSION: miR-205 is increased with severity of CON and CKD in the mgb(-/-) mouse and may regulate urothelial differentiation.

Loss of Notch2 and Notch3 in vascular smooth muscle causes patent ductus arteriosus.

The overlapping roles of the predominant Notch receptors in vascular smooth muscle cells, Notch2 and Notch3, have not been clearly defined in vivo. In this study, we use a smooth muscle-specific deletion of Notch2 together with a global Notch3 deletion to produce mice with combinations of mutant and wild-type Notch2/3 alleles in vascular smooth muscle cells. Mice with complete loss of Notch3 and smooth muscle-expressed Notch2 display late embryonic lethality and subcutaneous hemorrhage. Mice without smooth muscle-Notch2 and only one wild-type copy of Notch3 die within one day of birth and present with vascular defects, most notably patent ductus arteriosus (DA) and aortic dilation. These defects were associated with decreased expression of contractile markers in both the DA and aorta. These results demonstrate that Notch2 and Notch3 have overlapping roles in promoting development of vascular smooth muscle cells, and together contribute to functional closure of the DA.

Ribonucleases 6 and 7 have antimicrobial function in the human and murine urinary tract.

Recent evidence suggests antimicrobial peptides protect the urinary tract from infection. Ribonuclease 7 (RNase 7), a member of the RNase A superfamily, is a potent epithelial-derived protein that maintains human urinary tract sterility. RNase 7 expression is restricted to primates, limiting evaluation of its antimicrobial activity in vivo. Here we identified ribonuclease 6 (RNase 6) as the RNase A superfamily member present in humans and mice that is most conserved at the amino acid level relative to RNase 7. Like RNase 7, recombinant human and murine RNase 6 has potent antimicrobial activity against uropathogens. Quantitative real-time PCR and immunoblot analysis indicate that RNase 6 mRNA and protein are upregulated in the human and murine urinary tract during infection. Immunostaining located RNase 6 to resident and infiltrating monocytes, macrophages, and neutrophils. Uropathogenic E. coli induces RNase 6 peptide expression in human CD14(+) monocytes and murine bone marrow-derived macrophages. Thus, RNase 6 is an inducible, myeloid-derived protein with markedly different expression from the epithelial-derived RNase 7 but with equally potent antimicrobial activity. Our studies suggest RNase 6 serves as an evolutionarily conserved antimicrobial peptide that participates in the maintenance of urinary tract sterility.

Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation.

Congenital obstructive nephropathy remains one of the leading causes of chronic renal failure in children. The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications. Even so, a number of diagnostic, prognostic, and therapeutic quandaries still exist in the management of congenital obstructive nephropathy. Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure. Megabladder mice represent a valuable functional model for the study of congenital obstructive nephropathy. Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

Guinea pig ciliary muscle development.

PURPOSE: The purpose of this study was to develop a method for quantifying guinea pig ciliary muscle volume (CMV) and to determine its relationship to age and ocular biometric measurements. METHODS: Six albino guinea pigs' eyes were collected at each of five ages (n = 30 eyes). Retinoscopy and photography were used to document refractive error, eye size, and eye shape. Serial sections through the excised eyes were made and then labeled with an α-smooth muscle actin antibody. The ciliary muscle was then visualized with an Olympus BX51 microscope, reconstructed with Stereo Investigator (MBF Bioscience), and analyzed using Neurolucida Explorer (MBF Bioscience). Full (using all sections) and partial (using a subset of sections) reconstruction methods were used to determine CMV. RESULTS: There was no significant difference between the full and partial volume determination methods (p = 0.86). The mean (±SD) CMV of the 1-, 10-, 20-, 30-, and 90-day-old eyes was 0.40 (±0.16) mm, 0.48 (±0.13) mm, 0.67 (±0.15) mm, 0.86 (±0.35) mm, and 1.09 (±0.63) mm, respectively. Ciliary muscle volume was significantly correlated with log age (p = 0.001), ocular length (p = 0.003), limbal circumference (p = 0.01), and equatorial diameter (p = 0.003). It was not correlated with refractive error (p = 0.73) or eye shape (p = 0.60). Multivariate regression determined that biometric variables were not significantly associated with CMV after adjustment for age. CONCLUSIONS: Three-dimensional reconstruction was an effective means of determining CMV. These data provide evidence that ciliary muscle growth occurs with age in tandem with eye size in normal albino guinea pigs. Additional work is needed to determine the relationship between CMV and abnormal ocular growth.

3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis.

BACKGROUND: Disorders of the urinary tract represent a major cause of morbidity and impaired quality of life. To better understand the morphological events responsible for normal urinary tract development, we performed 3-D reconstructive analysis of developing mouse bladders in control, mgb-/-, and Fgfr2(Mes-/-) mice. RESULTS: Detrusor smooth muscle differentiation initiated in the bladder dome and progressed caudally with the leading edge extending down the right posterior surface of the bladder. Gender-specific differences in detrusor smooth muscle development were observed during early embryonic development. Bladder trigone morphology transitioned from an isosceles to equilateral triangle during development due to the preferential lengthening of the urethra to ureter distance. The primary defect observed in mgb-/- bladders was a significant reduction in detrusor smooth muscle differentiation throughout development. Deviations from normal trigone morphology correlated best with VUR development in Fgfr2(Mes-/-) mice, while alterations in intravesicular tunnel length did not. CONCLUSIONS: Multivariate morphometric analysis provides a powerful tool to quantify and assess urinary tract development.

Instructional Approaches: Anatomy Education of Physical Therapists.

The profession of physical therapy has undergone an evolution since its inception. Since the early 1900s it has grown from a technical training program to a doctorate level degree. Human anatomy courses remain a requirement for physical therapist educational curricula. However, changes in anatomy pedagogy have been trending within health profession educational models, leading to questions regarding which method is best for student learning. The objective of this study was to determine if anatomy instructional method used within physical therapist educational curricula impacted current anatomy knowledge. Licensed physical therapists were recruited to complete a demographic survey and a questionnaire to demonstrate their knowledge of anatomy topics. Anatomy topics included six regional components: (1) upper limb; (2) lower limb; (3) thorax and abdomen; (4) pelvis; (5) spine; and (6) head. Each regional component contained five questions regarding systemic subsets related to joints and osteology, muscles, nervous system, vasculature, and special areas (e.g., spatial orientations, structures within spaces, pathways of nerves). Within the thorax and abdominal region, data analysis indicated that the dissection instruction method, when compared to no laboratory instruction, led to statistically significant greater anatomical knowledge (P = 0.02). Dissection also showed greater means when compared to the no laboratory method (P = 0.02) and the prosection method in the head region (P = 0.01). However, the variance explained by instructional method was small. This study adds empirical evidence regarding current anatomy knowledge exhibited by physical therapists as the level of anatomical knowledge exhibited small differences based on instructional methods.

Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract.

Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram-positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility.

Current perspectives on congenital obstructive nephropathy.

Congenital obstructive nephropathy is the leading cause of chronic renal disease in children. As a result, it represents a tremendous societal burden in terms of morbidity and mortality, as well as in health care expenses of caring for children with chronic kidney disease and end-stage renal disease. The various diagnostic, prognostic, and therapeutic challenges associated with congenital obstructive nephropathy highlight the importance of developing effective experimental models for studying this disease process. In this review, we define the clinical entity that is congenital obstructive nephropathy, outline the current standards of diagnosis and care, and discuss the utilization of current experimental models designed to help clarify some of the clinical conundrums associated with this important disease.

The demographics and costs of inpatient vesicoureteral reflux management in the USA.

This study evaluates the impact of vesicoureteral reflux (VUR) on the economy and inpatient healthcare utilization in the USA. A retrospective analysis was performed on children ≤ 18 years of age, hospitalized with the principal discharge diagnosis of VUR between 2000 and 2006, using the Healthcare Cost and Utilization Project Kids' Inpatient Database. The results are stratified as follows. First, by hospitalizations: between 2000 and 2006, 6,655 ± 720 (standard error) children/year were hospitalized with VUR. Since 2003, both the length of each hospitalization and the number of hospitalizations have decreased. Second, by related procedures/diagnoses: ureteral reimplantation was the most common procedure, accounting for 89% of hospitalizations. Congenital genitourinary anomalies, disorders of the kidney/ureter/bladder, and urinary tract infections (UTI) were the most common related diagnoses. Thirdly, by hospital economics: since 2000, hospital charges for VUR increased despite decreased lengths of hospitalization. By 2006, hospital charges rose to $18,798/hospitalization, and aggregate national charges exceeded $100 million. Our results indicate that fewer children with VUR are requiring inpatient management. Children with VUR are often hospitalized for ureteral reimplantation or the management of related diagnoses. Since 2000, hospital charges for inpatient VUR management have increased. More efforts are needed to evaluate cost-effective strategies for the evaluation and management of VUR.