1,534 research outputs found
Congenital Kidney Diseases
No full textThis chapter focuses on the prospects of new therapies that can be used for congenital kidney diseases, including gene therapies, the use of renal precursor transplantation, and some other novel strategies. Diverse methodologies are devised to introduce genes into mammalian cells, including transfection of DNA by physical means and transduction by viruses. Gene transfer is relatively easy to achieve and can be highly efficient in the artificial and controlled environment of cell culture. An alternative to genetically engineering the kidney is to rebuild a damaged or malformed kidney with new cells. Laboratories demonstrate that it is possible to harvest murine metanephroi in the first days after the organs begin to form and transplant them into sites in the postnatal animal where the embryonic organ would form mature structures, including vascular glomeruli, which filters blood to make urine. The concept of using metanephric kidney transplants to replace the function of failing host kidneys is investigated extensively in a murine model in which rudiments are transplanted into the omentum around the peritoneal cavity where they grow and connect with the host vascular system. After a period of growth, the ureter of the transplanted organ can be anastomosed surgically with the lower urinary tract of the host, and these transplants have a high enough glomerular filtration rate to maintain the life of the host when it is rendered anephric. The transplantation of fetal kidney cells may also offer the additional advantage of rendering the host “tolerant” to immune attack from the host
Development of Kidney Blood Vessels
No full textThe adult mammalian kidney is a highly vascular organ, receiving 20% of the cardiac output. This chapter discusses the anatomy of developing kidney vessels, including the genesis of renal arteries, glomerular capillaries, and the vasa recta microcirculation in the most often used experimental model—the mouse metanephros. Studies have been performed to address the origin of metanephric vessels and some experimental evidence supports the existence of both angiogenesis—the ingrowth of capillaries into the embryonic organ—and vasculogenesis—the in situ differentiation of endothelia. Diverse vascular growth factors are expressed in the developing kidney and these molecules direct the growth of renal blood vessels: they include vascular endothelial growth factor (VEGF) and the angiopoietins, which signal through receptor tyrosine kinases expressed by endothelial precursors. Less is known about cell adhesion molecules and transcription factors in the context of metanephric blood vessel development, although these classes of molecule are certainly important in vessel formation elsewhere in the embryo. The chapter focuses on the morphogenesis of the renal vasculature
Maldevelopment of the Human Kidney and Lower Urinary Tract
No full textThis chapter focuses on the maldevelopment of human kidney and lower urinary tract, which include the ureter and urinary bladder. Renal malformations are the major cause of chronic renal failure in children. With advances in technology, babies with minimal renal function can be dialyzed from birth and toddlers can receive kidney transplants from the age of one year. The chapter describes the possible causes of human kidney and lower urinary tract malformations, which can be classified into two categories: (1) mutations, and possibly polymorphisms, of genes expressed during development, and (2) environmental influences on development, which can be further subdivided into changes that originate outside the fetus, such as alterations of maternal diet, and changes within the fetus that disrupt normal development, such as impairment of normal fetal urinary flow due to physical obstruction of the urinary tract. Human kidney or lower urinary tract malformation are reported in association with teratogens—angiotensin converting enzyme inhibitors, drugs used to treat high blood pressure cocaine, corticosteroids, ethanol, gentamycin, glucose, nonsteroidal anti-inflammatory drugs, and vitamin A and its derivatives
A questionnaire survey of radiological diagnosis and management of renal dysplasia in children
Full text linkBackgroundThe entity called renal dysplasia is considered to be a frequent cause of chronic kidney disease in children. Formally, the entity is defined by histological parameters. In current nephrology practice, however, the appearance of kidneys on ultrasound scanning is often used as a basis for the diagnosis.MethodsThe European Society for Paediatric Nephrology Working Group on Congenital Anomalies of the Kidney and Urinary Tract hypothesised that the current diagnostic approach with regard to renal dysplasia was not homogeneous. Accordingly, we here report the results of a survey targeting pediatric nephrologists with 12 questions regarding their perceptions of the ultrasonographic characteristics of renal dysplasia and further tests that they might undertake.ResultsOf almost 1200 physicians who successfully received the invitation, 248 from 54 countries completed the survey. There was a notable lack of homogeneity regarding the ultrasonographic diagnosis of renal dysplasia and also of follow up tests, including genetic testing and further radiology.ConclusionsBased on the responses to this large survey, a picture emerges of nephrologist’s current clinical practise with a focus on renal dysplasia. The Working Group consider that these results serve as an important sounding board that can inform more definitive recommendations regarding the challenges to clinical diagnosis and diagnostic follow-up of the this important entity
Molecular and genetic analyses of renal capillary development: Studying the angiopoietin/Tie axis
No full textWe postulated that endothelial precursors present at the inception of nephrogenesis differentiate into capillaries when experimental conditions resemble those found in vivo [Loughna S, Hardman P, Landels E, et al: A molecular and genetic analysis of renal glomerular capillary development. Angiogenesis 1:84-101, 1997; Loughna S, Yuan HT, Woolf AS: Effects of oxygen on vascular patterning in Tie1/LacZ metanephric kidneys in vitro. Biochem Biophys Res Commun 247:361-366, 1998]. At the start of nephrogenesis, mesenchyme contains no capillaries, yet we detected vascular endothelial growth factor in uninduced mouse embryonic (E) day E11 metanephric mesenchyme; receptor tyrosine kinase markers characteristic of endothelial precursors [vascular endothelial cell growth factor receptor (VEGFR) and Tie] were also expressed. We explanted day E13 Tie-1/LacZ metanephroi when nephron precursors are surrounded by reporter gene-expressing cells but glomeruli are not yet formed. In serum-free culture in normoxia, avascular glomeruli developed but existing vessels regressed. In hypoxia, however, transgene-expressing cells between nascent tubules formed large masses with poorly developed lumens; these resembled blood islands in yolk sac which arise by vasculogenesis. Glomeruli differentiating in hypoxia were devoid of capillaries but, when we transplanted Tie-1/LacZ E11 metanephroi into nephrogenic cortex of wild-type mice, a milieu permissive for differentiation of metanephric rudiments, transgene-expressing capillary loops formed in glomeruli. These experiments support an in situ origin of renal endothelia. We speculate that metanephroi are hypoxic in vivo to permit vasculogenesis; however, other, yet to be defined, cues are required for normal microcirculation patterning. Angiopoietin-1 (Ang-1) stimulates vascular network differentiation through Tie-2, while Ang-2 modulates this activation. At day E14, the forming metanephric artery expresses Ang-2; in neonates, expression was maintained in renal artery branches and smaller cortical vessels; differentiating mesangial cells transiently expressed Ang-2 [Yuan H-T, Suri C, Landon DN, et al: Angiopoietin-2 is a site specific factor in differentiation of mouse renal vasculature. J Am Soc Nephrol 11:1055-1066, 2000]. In the first postnatal weeks there was a lineage-switch of Ang-2 expression from vessels to epithelia (especially thin descending limb of loops of Henle). Because Tie-2 is widely-expressed by differentiating renal endothelia, we hypothesized that Ang-2 deficiency would disrupt kidney vessel patterning [Pitera JE, Woolf AS, Gale NW, et al: Dysmorphogenesis of kidney cortical peritubular capillaries in angiopoietin-2 deficient mice. Am J Pathol 165:1895-1906, 2004]. The normal renal cortical peritubular space contains fenestrated capillaries with few pericytes; they receive water and solutes which proximal tubules reclaim from the glomerular filtrate. In Ang-2 null mutants, pericyte-markers [α-smooth muscle actin (α-SMA), neural/glial cell 2 chondroitin sulfate proteoglycan (NG2), platelet-derived growth factor receptor β (PDGFRβ), and desmin] were up-regulated in cortical peritubular locations near to CD31/Tie-2 expressing capillaries. Total and tyrosine-phosphorylated Tie-2 increased in null mutant kidneys, and electron microscopy confirmed disorganized capillaries. Hence, Ang-2 deficiency causes dysmorphogenesis of cortical peritubular capillaries, with adjacent cells expressing pericyte-like markers; the latter effect may be caused by disturbed paracrine signaling between endothelia and surrounding mesenchymal precursor cells
Environmental influences on renal tract development: A focus on maternal diet and the glucocorticoid hypothesis
No full textAnalysis of TSHZ2 and TSHZ3 genes in congenital pelvi-ureteric junction obstruction
No full textTasic, Velibor/0000-0002-3377-1245; Woolf, Adrian/0000-0001-5541-1358; Matevska-Geshkovska, Nadica/0000-0001-6222-8973; Lye, Claire/0000-0001-9759-3700Methods. Given the phenotype of Tshz3 mutant mice, we considered that Teashirt genes, which code for a family of transcription factors, might represent candidate genes for human PUJO. To evaluate this possibility, we used in situ hydridization to analyse the three mammalian Tshz genes in mouse embryonic ureters and determined whether TSHZ3 was expressed in the human embryonic ureter. TSHZ2 and TSHZ3 were sequenced in index cases with non-syndromic PUJO. Results. Tshz2 and Tshz3 genes were detected in mouse ureters and TSHZ3 was expressed in the human embryonic renal pelvis. Direct sequencing of TSHZ2 and TSHZ3 did not identify any mutations in an initial cohort of 48 PUJO index cases, excluding these genes as a major cause of this condition. A polymorphic missense change (E469G) in TSHZ3 was identified at a residue highly conserved throughout evolution in all Teashirt proteins, although subsequently no significant difference between the E469G allele frequency in Albanian and Macedonian PUJO index cases (3.2%) versus 633 control individuals (1.7%) was found (P = 0.18). Conclusions. Mutations in TSHZ2 and TSHZ3 are not a major cause of PUJO, at least in Albanian and Macedonian populations. Expression of these genes in the human fetal ureter emphasizes the importance of analysing these genes in other groups of patients with renal tract malformations.Medical Research CouncilMedical Research Council UK (MRC) [G0700089, G9900837
Long Pulse Laser Wire Deposition of Hard Steels
No full textAbstractLaser deposition of hard steel wires on martensitic stainless steel substrates has been investigated in order to evaluate the possibility of performing localized mold repairs. An experimental campaign has been carried out to assess the role of the deposition strategy and process parameters such as pulse duration, peak power and frequency on process outcome. The extent of the dilution layer between the substrate and deposited track, as well as tempering effects due to the mutual interaction between tracks and layers, are studied as functions of process parameters in order to assess the characteristics of the deposited tracks. In particular, it is observed that under suitable conditions hard (HV>550) deposits can be achieved with minimal tempering effects even in the case of multiple tracks and layers
The term CAKUT has outlived its usefulness:the case for the prosecution
No full textCAKUT stands for Congenital Anomalies of the Kidney and Urinary Tract, and the acronym first appeared in a review article published in 1998. Since then, CAKUT has become a familiar term encountered in the medical literature, especially in nephrology journals. I reason that the term CAKUT was conceived, not a simple description of various diseases, but more as shorthand for a bold conceptual package that linked the occurrence of diverse types of anatomical malformations with insights from genetic and developmental biology research. Moreover, the angiotensin II receptor was seen as a paradigmatic molecule in the pathobiology of CAKUT. I contend that the acronym, while appearing as an intellectually good idea at the time it was conceived, has outlived its usefulness. To reach these conclusions, I focus on the complex of research observations that led to the theory behind CAKUT, and then question whether these scientific foundations still stand firm. In addition, it is noted that not all clinicians have adopted the acronym, and I speculate why this is the case. I proceed to demonstrate that there is an incompatibility between the semantic meaning of CAKUT and the diseases for which the term was originally conceived. Instead, I suggest the acronym UTM, standing for Urinary Tract Malformation, is a simpler and less ambiguous one to use. Finally, I contend that the continued use of the acronym is a regressive step for the disciplines of nephrology and urology, taking us back two centuries when all kidney diseases were simply called Bright’s disease
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