Impact of preterm birth on kidney health and development

Abstract

Preterm birth, defined as birth before the gestational age of 37 weeks, affects 11% of the newborns worldwide. While extensive research has focused on the immediate complications associated with prematurity, emerging evidence suggests a link between prematurity and the development of kidney disease later in life. It has been demonstrated that the normal course of kidney development is interrupted in infants born prematurely, causing an overall decrease in functional nephrons. Yet, the pathogenesis leading to the alterations in kidney development and the subsequent pathophysiological consequences causing kidney disease on the long-term are incompletely understood. In the present review, we discuss the current knowledge on nephrogenesis and how this process is affected in prematurity. We further discuss the epidemiological evidence and experimental data demonstrating the increased risk of kidney disease in these individuals and highlight important knowledge gaps. Importantly, understanding the intricate interplay between prematurity, abnormal kidney development, and the long-term risk of kidney disease is crucial for implementing effective preventive and therapeutic strategies.

Keywords: acute kidney injury; chronic kidney disease; nephrogenesis; nephron; premature infant; preterm birth.

Figure 1

Perinatal definitions. (A) Gestational age (GA) is the time elapsed since the first day of the last menstrual period before pregnancy. Chronological age (CA) or postnatal age is the time elapsed after birth (days, weeks, months, years). Postmenstrual age (PMA) is the gestational age plus the chronological age. (B) Hypothetical cases of two patients having the same PMA, with different GA and CA.

Figure 2

Hypotheses for cessation of nephrogenesis. Four models have been envisaged to explain synchronous cessation of nephrogenesis. In the first model, nephrogenesis terminates when a certain ratio of NPC to UB tips is achieved through gradual recruitment and hence depletion of NPC. In this model, a change in the concentration of critical niche factors brought about by the reduction in CM/UB ratio ends nephrogenesis by shifting the balance towards differentiation. In the second model, a de novo active trigger abruptly ends self-renewal of the homogenous progenitor population and causes an exit from the progenitor-like state. In the third model, the NPC population gradually transitions to more committed, transiently amplifying cells, causing a depletion of the self-renewing fraction within the cap mesenchyme to the point that no true progenitors remain. In the last model, cessation of nephrogenesis is a community decision taken once a critical number of NPC have acquired an “old” phenotype. In this model, “young” NPC have high transcript levels of niche-retention factors (e.g., FGF9 and FGF20) whereas “old” NPC have an increased transcription and translation of Wnt agonists, resulting in a stronger perception of the Wnt signals arising from the ureteric bud, promoting NPC differentiation and niche exit. Once a critical number of NPC have exited the niche, all the remaining cells follow.

Figure 3

Overview of interactions between preterm birth, nephrogenesis and kidney disease. Preterm birth, along with its associated prenatal, perinatal and postnatal factors, causes a disruption in the normal trajectory of human kidney development. Although after preterm birth nephrogenesis can persist postnatally, the course is accelerated, and glomerular generation and tubular maturation are impaired. Overall, these histological abnormalities translate into a lower number of functional nephrons. The effect of preterm birth on absolute nephron number is currently still unclear. The clinical renal consequences of preterm birth are both short-term and long-term and include an increased risk of neonatal acute kidney injury (AKI) as well as a higher risk of developing chronic kidney disease (CKD) later in life. The mechanisms underlying these clinical manifestations are likely multifaceted and an area of active research. Additionally, the occurrence of neonatal AKI is, by itself, a risk factor for developing CKD later in life and therefore acts as a positive effect modifier in the relationship between prematurity and CKD.