Action Plan for Prolongation of Nephrogenesis in Preterm and Growth Restricted Babies: Explore Ultrastructure of the Nephrogenic Zone, Identify a Molecular Target, Select a Viable Drug and Find a Path for Administration

Abstract

A large amount of investigations informs about primary steps of mammalian kidney development such as anlage of the organ and initial nephron formation, while only few data exists about the late phase of human kidney development. In particular, little attention was up to date addressed to the decrease of morphogenic activity in the nephrogenic zone short before birth and the vanishing of all stem cell niches aligned beyond the organ capsule. There is evidence that molecular controlling of this normal but degenerative developmental process also plays a decisive role in the kidneys of preterm and growth restricted babies. Although they are born in a phase of active nephrogenesis, a substantial percentage of them evolves oligonephropathy, formation of atypical glomeruli and immaturity of parenchyma. Pathologic findings point out that independent from chemical nature all suspected hampering influences sublimate in the nephrogenic zone. However, it is unknown, whether impaired nephrogenesis is locally caused by harming interstitial fluid, disturbance of morphogen signaling, unbalanced synthesis of extracellular matrix or limited cell to cell communication. Thus, first of all these issues must be resolved, then save application of medicines prolonging nephrogenesis waits for realization. Due to the unexpectedly complex microanatomy and physiology of the nephrogenic zone, it will be a particular challenge for the future.

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

“…However, a basic prerequisite for the research is to fully understand the damaged stage(s) of nephron anlage, the injured cells, the molecular binding sites of noxae, the altered signal transmission, and the affected metabolic pathways. A special challenge is not only to select eligible drugs, which prolong nephrogenesis, but also to find out a suitable path to administer them in the poorly vascularized nephrogenic zone [53]. Within the last years, a series of viable options have been proposed with regard to aiding regeneration of renal parenchyma [54].…”

Reading First Coordinates from the Nephrogenic Zone in Human Fetal Kidney

“…Finally, knowledge about microanatomy of the nephrogenic zone is a prerequisite, when local drug delivery prolonging nephrogenesis in preterm infants is in the focus of an innovative therapeutic approach [30]. Although it is not often taken into consideration, one must bear in mind that the nephrogenic zone has an incomplete vascular supply that makes controlled drug delivery difficult [68].…”

“…However, before this therapeutic process can lead to success, a series of questions need to be answered. For example, whether the process of early delivery, harming metabolites in interstitial fluid or a too early switch off process declining morphogenetic activity in stem cell niches are causing impairment of nephrogenesis has yet to be explored [28-30]. The real problem is that necessary data dealing with the nephrogenic zone and contained stem cell niches of the human fetal kidney are not available.…”