Shaping of the nephron – a complex, vulnerable, and poorly explored backdrop for noxae impairing nephrogenesis in the fetal human kidney

Abstract

Background: The impairment of nephrogenesis is caused by noxae, all of which are significantly different in molecular composition. These can cause an early termination of nephron development in preterm and low birth weight babies resulting in oligonephropathy. For the fetal human kidney, there was no negative effect reported on the early stages of nephron anlage such as the niche, pretubular aggregate, renal vesicle, or comma-shaped body. In contrast, pathological alterations were identified on subsequently developing S-shaped bodies and glomeruli. While the atypical glomeruli were closely analyzed, the S-shaped bodies and the pre-stages received little attention even though passing the process of nephron shaping. Since micrographs and an explanation about this substantial developmental period were missing, the shaping of the nephron in the fetal human kidney during the phase of late gestation was recorded from a microanatomical point of view. Results: The nephron shaping starts with the primitive renal vesicle, which is still part of the pretubular aggregate at this point. Then, during extension of the renal vesicle, a complex separation is observed. The medial part of its distal pole is fixed on the collecting duct ampulla, while the lateral part remains connected with the pretubular aggregate via a progenitor cell strand. A final separation occurs, when the extended renal vesicle develops into the comma-shaped body. Henceforth, internal epithelial folding generates the tubule and glomerulus anlagen. Arising clefts at the medial and lateral aspect indicate an asymmetrical expansion of the S-shaped body. This leads to development of the glomerulus at the proximal pole, whereas in the center and at the distal pole, it results in elongation of the tubule segments. Conclusions: The present investigation deals with the shaping of the nephron in the fetal human kidney. In this important developmental phase, the positioning, orientation, and folding of the nephron occur. The demonstration of previously unknown morphological details supports the search for traces left by the impairment of nephrogenesis, enables to refine the assessment in molecular pathology, and provides input for the design of therapeutic concepts prolonging nephrogenesis.

The mutual patterning between the developing nephron and its covering tissues—valid reasons to rethink the search for traces left by impaired nephrogenesis

“…Although surprisingly, the analysis of pertinent literature further revealed that the role of the nephrogenic zone in the fetal human kidney in nephron formation and consequently as the primary target region for noxae impairing nephrogenesis has been hardly explored. Before this background, it is understandable that the contained stages of nephron anlage and the shaping of the nephron were only introduced over the past few years as the first systematic morphological information dealing with the specifics of the nephrogenic zone [ 8 – 10 ]. The results generated indicate that each stage of nephron anlage is the subject of an individual positioning, orientation, and shaping.…”

“…Covered by the renal capsule, it is built up by transverse layers of embryonic, maturing, and matured parenchyma and stroma. In the external nephrogenic zone, the process of nephron formation starts [ 9 ] and can be recognized by the transient stages of nephron anlage [ 10 , 11 ]. In the subjacent maturation zone, the conversion of the S-shaped body as the last stage of nephron anlage into the lasting nephron occurs.…”

“…When vertical lines are drawn, the nephrogenic zone can be divided into numerous nephrogenic compartments [ 10 , 11 , 15 ]. These are aligned side by side in a row.…”

“…Dotted line: border between the external nephrogenic zone and the subjacent maturation zone. Individual images have been previously published [ 10 ] …”

“…The district of progenitor cell recruitment represents a prone rectangle, which principally maintains its size during the formation of a nephron (Fig. 2 a) [ 10 , 11 ]. It is in direct contact with the inner side of the renal capsule and shows a transverse length of about 80 µm.…”