By Dr. Namrata Todurkar
For many decades, neonatal kidneys appeared to be forgiving organs that tolerated the various complications of prematurity and excreted the various medications administered during a baby’s stay in NICU. However, it is now very clear that kidneys are not tolerant organs after all. Kidney health is influenced by co-morbidities and multiple interventions in the NICU, and in-turn, kidneys influence the well-being of all the other organ systems in a preterm infant. Infants who suffer acute kidney injury are at a higher risk of death and chronic kidney disease.
The discovery of surfactant helped take huge strides in surviving the smallest babies in the past half century. Obviously, managing respiratory distress syndrome at birth is crucial for survival and huge interest was generated in the scientific community leading to significant research and focus on optimal management of preterm lungs. Kidneys look a backseat for a number of years in neonatal research and innovation, and to this day, neonatal acute kidney injury is a commonly underestimated morbidity in the NICU.
The development of kidneys begins as early as the third week of embryonic development. They are complete by 36 weeks of gestation. This means that if a baby is born, say at around 30 weeks, they have a lower number of functional units in the kidneys, known as ‘nephrons’, and those present are small.
To make things worse, their kidneys may be exposed to toxic agents, such as antimicrobials (Gentamicin, Vancomycin, Acyclovir, Amphotericin-B, etc.) as well as anti-inflammatory agents (I.e., Ibuprofen, Indomethacin) in the NICU. They may also have issues pertinent to prematurity, like PDA (Patent ductus arteriosus), Sepsis, shock, etc.
This sets a baby up for significant kidney damage which has long-term implications on health and quality of life. Regarding healing, the kidney tissue is like the brain tissue. Once injured, the kidneys cannot go back to normal. Every episode of kidney injury or severe urinary tract infection leaves a scar on the kidney; this is exactly why preventing damage as well as long-term follow-up is necessary.
There is no standard definition of neonatal acute kidney injury (AKI). Therefore, no precise data regarding the actual incidence in NICU exists. A landmark study that led to a worldwide storm of research in neonatal kidney injury was the ‘AWAKEN STUDY’. ‘AWAKEN’ stands for Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates. It was a large, multicenter, multinational, observational study which involved more than 2000 infants from 24 neonatal units. This study described that neonatal acute kidney injury incidence peaked in infants born between 22 to 29 weeks of gestation and peaked again in infants born after 36 weeks of gestation. According to the AWAKEN study, nearly one-third of critically ill neonates have acute kidney injury, and those who do, are four times more likely to die compared with normal controls.
The kidneys act as a filtering organ. They help maintain a balance of fluid and salts in the body. There are various stages of kidney injury. However, even the slightest amount of injury can disturb the fluid and salt distribution in an infant. Inability to excrete the excessive fluids that a baby receives in the NICU as part of management, results in fluid accumulating in various compartments in the body. Thus, spilling into vital organs like the lungs, overloading the heart and diluting the body fluids if left untreated.
Very low sodium (caused by dilution) can result in the swelling of the brain. This has been associated with poor neurodevelopmental outcomes. Even though kidney injury has devastating outcomes, it is often diagnosed late. Important reasons for this are the unavailability of good biomarkers suggesting injured kidneys as well as inaccurate urine output measurement in neonates. Serum creatinine that is often used as an indicator of kidney functions remains normal until at least 50% of kidney function is impaired. Urine output is often inaccurate when using diaper-weighing technique. As there are no dialysis machines available for low birth weight infants, managing them becomes very difficult.
Identifying all degrees of kidney injuries and documenting them in the discharge summary is very important to ensure adequate follow up of common complications of kidney disease, such as growth failure, high blood pressure, fragile bones, protein leakage in urine, gradual worsening of kidney functions (leading to chronic kidney disease and/or kidney transplant), and to prevent further exposure to kidney toxic agents.
Congenital anomalies of kidneys and urinary tract are usually identified very early after birth or during antenatal scans. Therefore, such infants are referred to Pediatric Nephrology specialists at an appropriate time. It is the rest of the newborn cohort, who suffer kidney injury due to multiple causes, that often do not get referred to Pediatric Nephrologists.
In a study published in the American Journal of Perinatology in 2017, a survey of nephrologists and neonatologists in Australia, Canada, New Zealand, India, and the United States was reported (1). The research paper identified that neonatologists were less likely to use categorical definitions of neonatal AKI or diagnose stage 1 AKI than pediatric nephrologists. Nephrologists were more likely to consider follow-up after AKI than neonatologists. Also, 92% and 86% of neonatologists and nephrologists, respectively, reported no standardization or infrastructure for long-term renal follow-up.
In another survey of Neonatologists published on Frontiers in Pediatrics in 2020, most respondents underestimated the risk of AKI due to various risk factors such as prematurity, asphyxia, sepsis, cardiac surgery, and medications (2). Only half of the respondents were aware of the risk of Chronic Kidney Disease in preterm neonates and were unaware of the need to follow up with a pediatric nephrologist.
The story of neonatal kidneys reiterates the fact that every organ is fragile and prone to injury in neonates. Sooner or later this is manifested through complications if not monitored closely. Going forward, there should be more acceptance of novel biomarkers like Cystatin C in blood and urine NGAL (Neutrophil gelatinase-associated lipocalin) for early detection of AKI. There is a need for innovation to make hemodialysis available for the smallest and sickest neonates.
Am J Perinatol.2018 Jan;35(1):1-9.doi: 10.1055/s-0037-1604260.Epub 2017 Jul 14.
Dr. Namrata Todurkar, MBBS, MD (Pediatrics), DNB (Pediatrics). Fellowship in Neonatology from National Neonatology Forum India. Fellow in Neonatal-Perinatal Medicine at the University of British Columbia. Areas of interest: Neonatal nutrition, Fluid and Electrolyte Management, Inborn Errors, Neurodevelopmental follow-up of preterm infants. Dr. Todurkar is a volunteer blogger at CPBF.