Functional development of the meso- and metanephros

 This review highlights the important roles the mesonephros may play in development. In the ovine fetus it is an excretory and endocrine organ and may contribute to the formation of normal gonads and adrenals. The metanephros of the ovine fetus has the important function of providing large quantities of dilute urine for the maintenance of amniotic and allantoic fluid volumes, essential for normal placentation and development. Received: 16 March 1998 / Revised: 7 May 1998 / Accepted: 7 May 1998     

Role of the renin-angiotensin system in the development of the ureteric bud and renal collecting system

Genetic, biochemical and physiological studies have demonstrated that the renin-angiotensin system (RAS) plays a fundamental role in kidney development. All of the components of the RAS are expressed in the metanephros. Mutations in the genes encoding components of the RAS in mice or pharmacological inhibition of RAS in animals or humans cause diverse congenital abnormalities of the kidney and lower urinary tract. The latter include renal vascular abnormalities, abnormal glomerulogenesis, renal papillary hypoplasia, hydronephrosis, aberrant UB budding, duplicated collecting system, and urinary concentrating defect. Thus, the actions of angiotensin (ANG) II during kidney development are pleiotropic both spatially and temporally. Whereas the role of ANG II in renovascular and glomerular development has received much attention, little is known about the potential role of ANG II and its receptors in the morphogenesis of the collecting system. In this review, we discuss recent genetic and functional evidence gathered from transgenic knockout mice and in vitro organ and cell culture implicating the RAS in the development of the ureteric bud and collecting ducts. A novel conceptual framework has emerged from this body of work which states that stroma-derived ANG II elicits activation of AT₁/AT₂ receptors expressed on the ureteric bud to stimulate branching morphogenesis as well as collecting duct elongation and papillogenesis.     

Role of mitotic, pro-apoptotic and anti-apoptotic factors in human kidney development

The expression pattern of mitotic Ki-67 and anti-apoptotic bcl-2 proteins, as well as apoptotic caspase-3 and p53 proteins, were investigated in the human mesonephros and metanephros of 5–9 week-old human conceptuses. Apoptotic cells were additionally detected using the terminal deoxynucleotidyl transferase (TdT) nick-end labelling (TUNEL) method. Between the 5th and 7th developmental weeks Ki-67, caspase-3 and TUNEL-positive cells characterized all mesonephric structures, indicating importance of cell proliferation in the growth of the mesonephros and role of apoptosis in nephrogenesis. From the 7th week on, p53 and bcl-2 positive cells appeared in the mesonephros as well. Regressive changes in the mesonephros could be regulated by activation of p53, while bcl-2 could contribute to selective survival of some tubules giving rise to adult structures. In the early human metanephros (5–7 weeks), Ki-67 positive cells characterized all metanephric structures, indicating a role of cell proliferation in branching of the ureteric bud and in nephron formation. During the same period bcl-2, caspase-3 and TUNEL-positive cells were found only in the metanephric mesenchyme and nephrons. Bcl-2 protein probably protected nephrons from apoptosis, while caspase-3 protein controlled cell death in the mesenchyme. At later stages (7–9-weeks), appearance of p53-expressing cells could participate in further morphogenesis of the metanephric collecting system. The factors investigated had a spatially and temporally restricted pattern of appearance in developing kidneys. Changes in that pattern might lead to serious disturbances of kidney formation and function in early childhood.     

Kidney regeneration by xeno-embryonic nephrogenesis

Establishment of a functional whole kidney de novo has not received much attention because of the formidable challenges and the slow pace of advances in this field of research. This situation has changed recently with publication of data revealing the catastrophic nature of Medicaid costs for dialysis-related diseases. An innovative approach is needed in our search for therapies for kidney diseases and to provide a substitute for dialysis as soon as possible. Regenerative medicine offers great hope for realizing this goal. We established a system by which human mesenchymal stem cells can differentiate into a functional renal unit using a program of nephrogenesis in a developing xeno-embryo. In this article, recent research in the field of developing whole kidneys is reviewed, and possible therapeutic applications for kidney diseases are proposed in combination with our knowledge of the emerging field of kidney stem cell biology.     

Molecular regulation of kidney development: is the answer blowing in the Wnt?

Development of the metanephric kidney is a complicated process regulated by reciprocal signals from the ureteric bud and the metanephric mesenchyme that regulate tubule formation and epithelial branching morphogenesis. Over the past several years, several studies have suggested that Wnt signaling is involved in multiple aspects of normal kidney development as well as injury response and cancer progression. We will review these data here.     

A Thermoreversible Polymer Mediates Controlled Release of Glial Cell Line‐Derived Neurotrophic Factor to Enhance Kidney Regeneration

Previously, we reported that human mesenchymal stem cells (hMSCs) that were cultivated in growing embryos differentiated in an appropriate developmental milieu, thereby facilitating the development of a functional renal unit. However, this approach required transfection with an adenovirus that expressed glial cell line‐derived neurotrophic factor (GDNF) to enhance the development of hMSC‐derived renal tissue, and safety issues restrict the clinical use of such viral vectors. To circumvent this problem, we tested an artificial polymer as a means to diffuse GDNF. This GDNF‐polymer, which exists in liquid form at 4°C but becomes a hydrogel upon heating to 37°C, was used as a thermoreversible switch, allowing the injection of hMSCs at low viscosity using a mouth pipette, with subsequent slow diffusion of GDNF as it solidified. The polymer, which was dissolved in a solution of GDNF at 4°C and then maintained at 37°C, acted as a diffuser of GDNF for more than 48 h. LacZ‐transfected hMSCs and the GDNF‐polymer (at 4°C) were placed in the nephrogenic sites of growing rat embryos that were maintained at 37°C. Forty‐eight hours later, the resultant kidney anlagen were dissected out and allowed to continue developing for 6 days in vitro. Whole‐organ X‐Gal staining and fluorescence activated cell sorter analysis showed that the number of hMSC‐derived cells was significantly increased in developed anlagen that have been generated from hMSCs plus GDNF‐polymer compared with those from hMSCs plus GDNF‐containing medium and was comparable to those from adenovirus‐transfected hMSCs. These findings suggest that the GDNF‐polymer can be used as a diffuser of GDNF for kidney organogenesis.     

Transplantation of renal precursor cells: a new therapeutic approach

The number of kidney transplantations performed per year is limited due to availability of donor organs. One possible solution to the organ shortage is the use of renal xenografts. However, the transplantation of xenografts is complicated by hyperacute and acute rejection. It has been postulated that the host immune response might be attenuated following the transplantation of renal precursor cells or embryonic kidneys (metanephroi) instead of developed (adult) kidneys. Transplanted metanephroi become chimeric organs in that their blood supply originates, at least in part, from the host. It is possible to transplant a developing metanephros, without the use of immunosuppression, from one rat to another. Transplanted metanephroi grow, develop, become vascularized, and function in host rats. Transplantation of metanephroi may be a promising novel therapeutic approach for the treatment of chronic renal failure. Received: 29 December 1999 / Revised: 13 March 2000 / Accepted: 13 March 2000     

Ultrastructural and biochemical observations on the metanephros of normal and cultured chick embryos

Summary A comparative electron microscopical study was conducted on the metanephros from chick embryos differentiated either in shell-less culture or in ovo. Developmental characteristics were very similar in both cases. Up to stage 37 (Hamburger-Hamilton) the metanephros contained large numbers of immature nephrons; their renal corpuscles were crescent-shaped and consisted of an outer layer of flat cells and an inner one of cuboidal cells. In more advanced corpuscles also found at this stage the inner layer had formed numerous rudimentary pedicels and the tunica media of the glomerular arteriole contained juxta-glomerular cells with numerous, small, electron dense granules.In the metanephros from embryos at stage 38 or older, large numbers of nephrons had completed their differentiation; their rounded renal corpuscles had fully differentiated podocytes with thin interdigitating pedicels and the proximal convoluted tubules had numerous apical microvilli, vesicles, vacuoles and tubular invaginations indicating an active process of resorption. These results appear to indicate that both in culture and in ovo-developed embryos, the metanephri start to function around stage 38. In the case of normal embryos this conclusion agrees with previous physiological and biochemical determinations. The injection of 20 USP parathyroid hormone into 16-day old chick embryos produced an increase in the concentration of cyclic AMP in the metanephros. This favours the idea that the regulation of kidney function by the hormone begins during the embryonic period.     

Treatment for end-stage renal disease: an organogenesis/tissue engineering odyssey

The means by which kidney function can be replaced in humans with end-stage renal disease (ESRD) include dialytic therapies and renal allotransplantation. Dialysis, is lifesaving, but often poorly tolerated. Transplantation of human kidneys is limited by the availability of donor organs. During the past decades, several different approaches have been applied towards new means to replace renal function through organogenesis and tissue engineering. These include: (1) incorporation of new nephrons into the kidney; (2) growing new kidneys in situ; (3) use of stem cells; (4) generation of histocompatible tissues using nuclear transplantation; and (5) bioengineering of an artificial kidney. The development of these approaches has depended upon understanding and integrating discoveries made in a diversity of scientific disciplines. The means by which such integration has driven advances in the treatment of ESRD provides a generic roadmap for the successful application of organogenesis and tissue engineering to organ replacement therapy.     

儿童后肾腺瘤五例报告

目的 探讨儿童后肾腺瘤临床病例特点,提高对儿童后肾腺瘤的认识.方法 回顾性分析2008年5月至2016年1月收治的5例儿童后肾腺瘤的临床资料,并进行文献复习.5例患儿中,男4例,女1例;年龄小于2岁2例,8～10岁3例;肿瘤位于左侧2例,右侧3例.以腹部包块就诊1例,超声偶然发现4例.术前均行超声和增强CT,2例考虑肾母细胞瘤,2例考虑肾细胞癌,1例考虑肾囊肿合并出血.结果 肿瘤直径小于5 cm者4例.行保留肾单位的肿瘤剜除术3例,行瘤肾切除术2例.病理检查报告:后肾腺瘤4例,后肾腺瘤合并乳头状肾细胞癌1例.术后平均随访4年5个月,均无复发和转移.结论 后肾腺瘤罕见,临床表现及影像缺乏特异性,术前诊断困难,确诊依靠病理及免疫组织化学.后肾腺瘤为良性病变,手术完整切除为治疗原则.有合并恶性成分的病例报道,术后需长期随诊复查.