Extending Nephron Development In Preterm Babies May Prevent Kidney Disease Later

Extending Nephron Development In Preterm Babies May Prevent Kidney Disease Later

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Highlights:
  • Study identifies possible therapeutic target to increase nephron numbers in the developing kidney of preterm infants.
  • Statistics estimate about one in 10 infants (approximately 387000 births) are born preterm before 37 week in the U.S each year. Of these, nearly 109,000 are considered "early" preterm births (before 34 weeks).
  • Preterm infants are at increased risk of developing kidney failure later in life due to interrupted kidney development, needing dialysis and renal transplant.
Targeting the protein hamartin could extend kidney development in preterm babies and reduce the risk of kidney failure later in life according to a recent study by scientists at Cincinnati Children's. The team are currently trying  to understand the driving factors (genetic and environmental) behind preterm birth and see if it would be possible to reduce the incidence of preterm deliveries.
Extending Nephron Development In Preterm Babies May Prevent Kidney Disease Later

The findings of the study appear in the journal PNAS.

Aim of Study

The team hope to find what factors determine the number of nephrons we have as adults and how this number could be increased in preterm infants.

"All the nephrons you or I have were generated while we were in our mother's uterus. Prematurity terminates this process too early. As a result, adults that were born prematurely are at high risk for hypertension, heart disease and end stage renal disease," says Raphael Kopan, PhD, Director of the Division of Developmental Biology at Cincinnati Children's, and senior author of today's study.

"The question we tried to address is how we generate the specific number of nephrons we have as adults, and how can we increase this number in premature babies."

Discovering Possible Factors That Regulate Nephron Formation - Details of Study

The team studied mice to determine how nephron numbers in the kidney are regulated.
  • The scientists discovered that a protein called hamartin plays a key role in shutting down the nephron formation process.
Until now, this protein was primarily known as a factor associated with tuberous sclerosis complex, a rare genetic condition that causes benign tumors to grow in the kidneys, brain, heart, and other organs.
  • In the current study, when mice were programmed to produce decreased amounts of hamartin, their kidneys developed 25 percent more number of nephrons than a control group.
  • However, when the mice were programmed to produce no hamartin at all, the mice developed lethal kidney defects.
Thus, the findings of the study appear to suggest that reducing the amount of hamartin either during pregnancy or after delivery could promote kidney development. These findings were seen in mice with two different genetic backgrounds, suggesting that hamartin function was not influenced by the method the research team used to reduce its level.

"This study provides important new information that will improve outcomes for all babies born prematurely," says Louis Muglia, MD, PhD, Co-Director of the Perinatal Institute at Cincinnati Children's and Director of the Center for Prevention of Preterm Birth. "Optimizing pregnancy outcomes is a central focus shared by the basic scientists and clinicians in the Perinatal Institute, and this work reflects that shared commitment."

Nephrons - The Functional Units of The Kidneys

Nephrons are the microscopic functional units of the kidneys that convert toxic and waste products in the blood into urine, regulate our blood pressure and maintain electrolyte balance.

Each kidney contains 1 million nephrons, all of which develop in-utero between weeks 25 to 36 of gestation. Unfortunately, the nephron formation is interrupted when babies are born preterm, which consequently puts them at higher risk of developing kidney disease later  in life.

"We never make another nephron after we are 36 weeks old," Kopan says. "It would be necessary to target at-risk premature babies to try to prolong their nephron-generating window."

Scope of Study

Although the findings of the study suggest that reducing hamartin levels would increase kidney development, there is a flip side. Reducing hamartin levels in people increases the risk of developing tuberous sclerosis.
  • The team plans to develop a safe drug to potentially target hamartin levels that could be delivered shortly after birth of the preterm baby.
  • In related research around the world, scientists are working to see if MRI scans can be used measure nephron numbers in the kidneys. Currently studies are focused on adults, but if proven safe, they could become applicable in newborns.
All this would take considerable time and research before the results are deemed safe and effective to use on patients.

Other Innovative Research At Cincinnati Children's

Cincinnati Children's is a leading collaborator in Cradle Cincinnati, a community-wide partnership that aims to reduce high preterm birth rates and infant mortality in Hamilton County.
  • Measures such as smoking cessation, having at least a year's gap between successive pregnancies and safe sleeping habits have helped in reducing preterm births and infant deaths.
  • In a large genetic study, scientists have identified six genomic locations that could possibly affect birth timing.
It remains to be seen how these discoveries will help reduce preterm births. However, Cradle Cincinnati's programs and the current study are examples how research and innovation can help identify ways to reduce some of the complications associated with premature birth and improve the quality of life for these children as well as their families.

Reference:
  1. Helping Preterm Infants Grow Bigger Kidneys Would Prevent Kidney Disease Later in Life - (https://www.cincinnatichildrens.org/news/release/2018/preterm-infants-kidneys)

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