The Kidney - From Normal Development to Congenital Disease

1 Introduction: Embryonic Kidneys and Other Nephrogenic Models

I am a reformed lover of mesoderm induction. My association with the pronephros began for opportunistic reasons with the original plan being to exploit the expression of pronephric genes as markers of the patterning and establishment of the intermediate mesoderm. However, after finding such markers and following their expression in forming pronephroi, I became more interested in how these genes contributed to the regulation of kidney morphogenesis than in simply using them as markers of earlier events. Upon exploring what was known about embryonic kidney development (very little) and what could be learned using modern molecular embryology (an enormous amount), my future research directions were established. The embryonic kidneys are an ideal system in which to explore cell signaling, specification, adhesion, shape change, morphogenesis, and of course organogenesis. In addition to being a wonderful intellectual problem, the analysis of embryonic kidney development has many advantages in terms of the availability of techniques with which to dissect the process. Some of the organisms with the most extensive and well developed embryonic kidneys are also those with the most highly advanced genetic and embryological tools—a perfect match. Finally, similar genetic networks regulate the development of all nephric organs so data gleaned from embryonic systems are as relevant to human congenital disease as they are to the understanding of a quaint model.

This first section of “The Kidney” covers the development of the embryonic kidneys, the pro- and mesonephroi, in a depth never before attempted in a text on kidney development and function. For those who no longer recall their undergraduate developmental biology course, even the names of these organs may be unfamiliar. After all, some mammals (including humans) can survive until birth without any kidneys, so of what interest are transient organs that some would posit are nothing more than evolutionary artifacts? In this introduction some of the reasons for refraining from such an opinion will be explored, as will the renaissance of research into the use of embryonic kidneys as model systems for the analysis of organogenesis. The following chapters provide a detailed description of the anatomy, development, function, and molecular biology of the transient embryonic kidneys as a resource for those willing to accept my arguments regarding relevancy. Similar arguments can be made supporting the relevance of invertebrate models of nephrogenesis, and Chapter 2 opens with a review of Malpighian tubule morphogenesis in the fruit fly, Drosophila melanogaster.

The embryonic kidney of amphibians and fish is known as the pronephros, head kidney, or vorniere, while their adult kidney is known as a mesonephros, Wolffian body, or urniere. In some instances, fish and frog permanent mesonephroi are unnecessarily referred to as opisthonephroi, a term used to distinguish them from the transient mesonephroi of amniotes, but which results in more confusion than clarification. To begin the description of the development of vertebrate embryonic kidneys, a brief description of the occurrence of pro- and mesonephroi is appropriate. All vertebrates have distinct embryonic and adult kidneys (Goodrich, 1930; Burns, 1955; Saxén, 1987). Upon development of the adult kidney, the embryonic kidney usually either degenerates or becomes a part of the male reproductive system (Burns, 1955; Balinsky, 1970). In some instances the embryonic kidney switches to a new role as a lymphoid organ (Balfour, 1882).

Well-developed, functional pronephroi are found in all fish, including dipnoids (e.g., lungfish), ganoids (e.g., sturgeon), and teleosts (e.g., zebrafish), and in all amphibians. Reptiles vary in the degree to which pronephroi form, with the more primitive reptiles having the most advanced pronephroi (Chapter 3). Birds have only a poorly developed pronephros, as do most mammals. In organisms with aquatic larvae, pronephroi are absolutely essential for survival. The pronephroi excrete copious amounts of dilute urine that allows such animals to maintain water balance. If the pronephroi are not functional, aquatic larvae die rapidly from oedema (Chapter 3).

Pronephric kidneys are very simple and form within a day or two of fertilization. They usually contain a single nephron with an external glomerulus or glomus (Fig. 1.1). This glomus filters blood in an identical manner to standard glomeruli, except that the filtrate is deposited into a cavity rather than into Bowman’s space. In some instances, this cavity is the coelom, in others, a dorsal subcompartment of the coelom known as the nephrocoel, and in yet others into the pericardial cavity. The glomeral filtrate is collected from the receptive cavity by ciliated tubules known as nephrostomes. The nephrostomes in turn are linked to the pronephric tubules. These tubules have distinct proximal and distal segments. As with a classical mammalian nephron, the proximal segment functions in solute resorption and waste excretion, whereas the distal segment resorbs water. From the distal tubule urine passes down the pronephric duct to the cloaca. The entire pronephros is in essence a single large nephron. This section uses the term pronephros to describe an embryonic kidney that either utilizes an external glomus or is anatomically distinct from the mesonephric kidney in the same organism. Details of pronephric anatomy and complete bibliographies are provided by Chapters 3 through 5.

Mesonephric kidneys are more complex in organization and consist of a linear sequence of nephrons (Fig. 1.2) linked to the nephric duct (Fig. 1.1). Mesonephric nephrons contain internal (or integrated) glomeruli, and in some instances, particularly in anterior mesonephric tubules, also link to the coelom via ciliated tubules called peritoneal funnels. Such funnels are sometimes referred to as nephrostomes, which they resemble very closely, but the correct nomenclature of the two structures allows one to specify whether the funnel links the coelom to the glomerulus or the glomerulus to the tubule. Nephrostomes are also sometimes present in mesonephroi so the distinction is important.

The mesonephros is first functional at around 7.5 days of development in the frog Xenopus (Nieuwkoop and Faber, 1994) and continues to grow along with the animal. In organisms in which the mesonephros is transient, the complexity of this organ is extremely variable, ranging from almost no nephrons in rodents to 34 in humans and 80 in pigs (Felix, 1912; Bremer, 1916; Table 1.1). The anatomy of a human mesonephros is illustrated in Fig. 1.3.

In animals in which the mesonephros is the terminal kidney, such as amphibians and fish, the final organ is very complex, containing a large number of nephrons, most of which have an internal glomerulus. In the example of the frog...