Postnatal Nephrogenesis in Preterm Infants: The Need to Safeguard Kidney Development After Birth

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Preterm birth, occurring before the completion of 37 weeks of gestation, disrupts fetal growth and development, and increases the risk of infant mortality and disability. Although medical advancements have notably improved survival rates for infants born between 22 and 28 weeks of gestation,¹ the rate of preterm birth remains unacceptably high. In 2022 and 2023, the United States received a March of Dimes preterm birth grade of D+ with 1 in 10 babies born prematurely.^2,3 The interruption of intrauterine development and associated postnatal complications experienced by these infants contribute to permanent structural and functional alterations in developing organs, resulting in lasting adverse effects.

From the perspective of kidney development, prematurity and low birthweight serve as clinical indicators of a reduced nephron count. This diminished nephron number confers an elevated risk of adverse health outcomes that include hypertension, proteinuria, cardiovascular disease, and chronic kidney disease.4, 6, 5 Although we have some insight into the late gestational development of various organs such as the lungs and brain, there is a significant gap in our understanding of human kidney development. In addition, the absence of available therapeutics that can accelerate nephrogenesis in low birthweight and premature neonates compounds this challenge.

The average number of nephrons per adult kidney is estimated to be approximately 1 million, yet observed counts vary more than tenfold among individuals.⁷ This remarkable range suggests that numerous genetic and environmental factors influence the efficiency of intrauterine kidney development. In babies born at term, nephrogenesis is thought to be complete by 34 to 36 weeks of gestation, and the nephron count is also closely linked to birthweight.⁸ However, in babies born prematurely, the trajectory and completion of nephrogenesis is uncertain. A study of extremely preterm kidneys revealed that glomerulogenesis could persist for up to 40 days after birth.⁹ Glomeruli in these kidneys were noted to be enlarged and abnormal in appearance, suggesting the presence of compensatory mechanisms due to physiologic stress and accelerated renal maturation processes.

In this edition of Kidney International Reports, Carpenter and colleagues present a histological analysis of kidneys obtained from extremely preterm infants delivered between approximately 24 and 28 weeks who survived more than 40 days (cases) and from infants delivered between 30 and 36 weeks who survived fewer than 4 days (controls).¹⁰ Kidneys from these 2 groups were matched for postmenstrual age. Kidneys from the 7 extremely preterm cases were larger than controls (normalized for both body weight and length). They also displayed morphological differences in glomerular size and tubule hypertrophy. The presence of ongoing nephrogenesis was assessed histologically by measuring the width of the nephrogenic zone and by molecular staining using the ureteric tip marker RET.

In 3 of the preterm cases, there was no evidence of ongoing nephrogenesis; either the nephrogenic zone was absent or nearing completion, and all 3 lacked RET expression. Conversely, the remaining 4 preterm kidneys had wider nephrogenic zones and exhibited RET+ staining within the cortex. The discovery of active nephrogenesis on postnatal day 62 in an infant born at 25 weeks is striking and suggests that an intrinsic developmental program persists for a significantly longer period than previously reported.⁹

This study is subject to limitations inherent to retrospective autopsy investigations. The limited availability of kidneys that met inclusion criteria resulted in a small sample size and precluded power analysis. Variability in tissue handling and fixation can also pose technical challenges for cellular and molecular analyses. Limited access to original medical records and incomplete documentation in autopsy reports can also hinder consideration of confounding factors, such as differences in medications administered and the clinical course among neonates. It is challenging to ascertain neonatal glomerular filtration rate, and acute kidney injury in preterm infants is often underrecognized.S1,S2 Moreover, how can glomerular filtration rate measurements hold significance when kidney development is still underway? Despite these limitations, the study’s findings present compelling evidence of ongoing postnatal nephrogenesis in premature infants. Notably, the observation of active nephrogenesis at postnatal day 62 underscores the persistence of an intrinsic developmental clock,S3,S4 regardless of the intrauterine or postnatal environment of the individual.

Antenatal corticosteroids are routinely administered to improve neonatal outcomes in anticipated preterm births, with specific recommendations varying based on gestational age. Studies have shown that antenatal corticosteroids can reduce the incidence of respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, and improve survival rates.S5 However, the impact of antenatal corticosteroids on kidney function and nephron maturation in premature neonates remains unclear,S6–S8 and we lack therapeutic interventions that can aid kidney development. Given the correlation between low nephron count and the burden of associated chronic diseases, further investigation into the molecular pathways that regulate the timeline of kidney development is crucial, particularly for survivors of extreme prematurity.

At birth, the transition of nutrition and homeostatic control from the placenta to the neonate imposes significant physiologic stress on the infant. The postnatal environment is especially challenging for very low birthweight and premature babies who also contend with stressors associated with complicated pregnancies. In the days and weeks following birth, many of these infants are also exposed to nephrotoxins that can cause acute kidney injury and potentially disrupt ongoing developmental processes. Therefore, it is essential to establish guidelines and take protective measures against kidney injury during this critical developmental window. First, it is imperative to avoid nonsteroidal anti-inflammatory drugs and other nephrotoxic agents in premature neonates whenever possible, even if creatinine levels fall within the normal reference range. Second, as these children grow, it is critical to provide appropriate pediatric care and to screen for chronic kidney disease and cardiovascular disease. Finally, there is a pressing need for further studies to establish optimal nutritional guidelines for premature infants from birth to early childhood. As technological advancements continue to improve survival rates for preterm neonates, the urgent need for new therapies to support and accelerate kidney development becomes increasingly apparent.

Disclosure

All the authors declared no competing interests.

Supplementary Material

Supplem entary Reference.