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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Curr Opin Pediatr. Author manuscript; available in PMC 2017 April 1.
Published in final edited form as:
PMCID: PMC4814929
NIHMSID: NIHMS770454

Neonatal Nephrology

The transition from the aqueous environment of the mother’s womb to dry land creates many challenges for the neonate. The infant must have a means to regulate the composition and volume of the extracellular fluid; a task performed by the kidney. The neonate ingests mother’s milk, which is a fluid with essential nutrients for growth, but milk is quite hypotonic with a very low sodium content. Thus, the neonatal kidney must be able to excrete free water and conserve sodium while retaining filtered organic solutes. The neonatal kidney is also faced with changes to its environment as occurs during volume depletion where the kidney must increase salt retention further and may also have to excrete a concentrated urine rather than dilute urine.

To maintain homeostasis of the extracellular fluid volume the kidney functions by filtering huge volumes of blood creating an ultrafiltrate of plasma. This ultrafiltrate is delivered to the renal tubules, which reabsorb much of the salts and organic solutes necessary for survival. We assess kidney function by measuring glomerular filtration rate. The glomerular filtration rate is the volume of blood that is completely cleared of a solute in a given time. In an adult this is normally 100–120 ml/min/1.73 m2 (an average adult body surface area). This translates to 150–180 liters of ultrafiltrate generated per day. Most of the filtered fluid, salts and organic solutes are reabsorbed. The kidney can also secrete some solutes, which must be excreted but are protein bound and thus have limited glomerular filtration. By comparison, the full term neonate has a glomerular filtration rate of only 2 ml/minute. When we normalize this for body surface area of an adult, the glomerular filtration rate of a full term neonate is approximately 20 ml/min/1.73 m2 [1]. The premature neonate has a much lower glomerular filtration rate than the term neonate and also has evidence of immature tubules compared to the term neonate which results in glucosuria in neonates born before 30 weeks gestation and impaired potassium secretion resulting in hyperkalemia.

Accurate assessment of renal function (i.e. the glomerular filtration rate) requires a solute that is freely filtered by the glomerulus (i.e. small and not protein bound), the solute cannot be absorbed, nor can it be secreted. The gold standard for assessing GFR is inulin, but it is not a substance that is natural to our body and must be delivered intravenously. In addition, inulin is very hard to measure unless it is tagged with a radioactive label. Thus, other means must be utilized to estimate glomerular filtration rate. Creatinine seems to be a good choice as it is a solute that is not protein bound and is thus freely filtered by the glomerulus. Creatinine has a steady concentration in our blood and is easy to measure. Creatinine is not reabsorbed by the renal tubules, but about 10% of the creatinine in our urine is secreted by renal tubules resulting in an overestimation of the glomerular filtration rate. What is more problematic for assessment of renal function in neonates is the fact that they are born with their mother’s creatinine. Thus, assessment of renal function in a neonate, which may have perinatal renal injury, is potentially confounded by the fact that the creatinine will in large part reflect the mother’s creatinine for several days after birth. In addition, creatinine is made in muscle and the plasma creatinine not only reflects renal function but also muscle mass. Thus a neonate may have significant renal injury but only a small increase in creatinine since the muscle mass is small. Thus the same degree of renal injury causing a rise in creatinine from 1.0 mg/dl to 2.0 mg/dl in an adult may only result in an increase in creatinine from 0.3 mg/dl to 0.6 mg/dl in a young infant. Clearly, other means of assessing renal function in neonates are needed and in the article by Dr. Filler and colleagues, discusses new markers to assess renal function such as cystatin C which is made in all nucleated cells and is thus not dependent on muscle mass. He describes provides evidence that this is potentially a more accurate way to estimate renal function in the neonate.

Accurate assessment of glomerular filtration rate is especially important in the neonate especially premature neonates that are at risk for exposure to nephrotoxic drugs. Since an accurate marker for glomerular filtration rate is lacking especially in neonates, the diagnosis of acute kidney injury can also be problematic. Acute kidney injury was once thought to be a reversible insult that usually resulted in return of renal function to normal especially when the toxin or insult was removed. Unfortunately, that is proving not to always be the case. Even when there is return of serum creatinine to near normal levels there is increased risk for progressive chronic kidney disease and an increased likelihood of death. Acute kidney injury is associated with an increased risk of death in neonates and adults. Avoidance of nephrotoxins, when possible, and early detection of renal injury is an important especially in treating neonates. Dr. Hanna and her colleagues discuss drug induced acute kidney injury in this issue. In addition to discussing a number of frequently used drugs that cause acute kidney injury, they discuss approaches to decrease the likelihood of causing acute kidney injury in neonates and premature neonates.

The fetal kidney starts to make urine by about 10 weeks of age. Nephrogenesis continues until 34–36 weeks gestation. This will result in a final nephron number of about 1 million nephrons per kidney. If a fetus is born before 34 weeks, nephrogenesis can occur in the premature infant but this is limited to about 40 days so that a premature infant born at 24 weeks will only have the number of nephrons as a 31 week gestation fetus when nephrogenesis stops. This will result in half of the total complement of nephrons as a full term neonate. Furthermore there is evidence that even in preterm neonates there is morphologic evidence for compensatory changes consistent with hyperfiltration, a harbinger of stress on the remaining glomeruli [2]. As with the fetus, premature neonates do not form new nephrons after 34–36 weeks after conception.

The formation of the nephron is quite complex requiring interaction between the metanephric blastema and the ureteric bud. Dozens of genes are turned on and off at precise times leading to glomerular and tubular formation and ultimately a mature kidney and collecting system. With such a complex developmental task, there is likelihood that something can go wrong. If the error is severe and at an unfortunate time during development, then one can have a malformed kidney with no function or no kidney at all. This type of malformation, at its worst, is a dysplastic kidney which has no function and may be cystic which is referred to as a multicystic dysplastic kidney. A number of genes leading to renal dysplasia and hypoplasia have been identified. Drs. Phua and Ho provide an excellent review of renal development and the pathogenesis of renal dysplasia in this issue of Current Opinion in Pediatrics.

David Barker made seminal observations showing that small for gestational age neonates are at increased risk for developing cardiovascular disease in later life [3;4]. These small infants were not premature since when the studies were performed premature infants did not survive but were by and large small because of maternal malnutrition during pregnancy. In subsequent studies in humans, it has been shown that infants that are small for gestational age are at risk for hypertension, diabetes, obesity, and dyslipidemia. Small for gestational age infants also have fewer nephrons at birth and there is a greater likelihood of developing end stage renal disease. In this issue of Current Opinion in Pediatrics, Dr. Jorg Dotsch and colleagues discuss a number of common prenatal insults that have been shown to reduce nephron number and increase the likelihood for developing chronic and even end stage renal disease. He also discusses how animal models have been developed that mimic many of the insults that are seen in humans to better understand the pathogenesis of how prenatal insults program diseases in later life.

What are the ramifications of a reduced number of nephrons? If one surgically removes 5/6ths of the renal mass of an adult rat, the rat will develop a lesion of focal and segmental glomerulosclerosis over several months. This is likely due to an increase in glomerular capillary pressure resulting as the remaining nephrons increase their glomerular filtration rate to make up for the loss of the removed nephron mass. The reduction in nephron number due to either extreme prematurity or small for gestational age neonates is much less dramatic and the ramifications of a low nephron number at birth may manifest until adulthood. Nonetheless, a reduction in nephron endowment at birth can result in progressive renal injury. A recent study evaluated six young adults for heavy proteinuria. All of the patients had renal biopsies that revealed focal and segmental glomerulosclerosis, a progressive renal disease. The adults had no known risk factors for renal disease. The common feature of all of the patients was that they were all premature infants and thus likely had a reduced nephron endowment at birth [5]. This is the same lesion seen in rats with a surgically induced reduction in nephron number. It is becoming apparent that a low nephron endowment at birth is a not only a potential risk factor for progressive renal disease but also a risk factor for hypertension, cardiovascular disease and a shortened life span.

Prenatal sonograms are routinely performed in many parts of the world and a common finding is hydronephrosis. The fetus has a greater urine output per body surface area, which contributes to the majority of the amniotic fluid. The high urine output can result in pelviectasis, which may or may not resolve after birth. Pathologic hydronephrosis is usually the result of ureteropelivic junction obstruction but can also result from severe vesicoureteral reflux. The evaluation of the fetus and neonates with hydronephrosis and the issue of when surgical intervention is indicated is discussed in the article by Dr. Oliveira and his colleagues.

Hematuria and proteinuria are rather rare problems in the neonatal period. The glomerulus makes an ultrafiltrate of plasma and even in the premature neonate provides a barrier between for the filtration of protein. Proteinuria when it occurs in the neonate can be substantial and can result in hypoalbuminemia and edema. Minimal change nephrotic syndrome is the most common type of nephrotic syndrome in children and the proteinuria is rather selective for small molecular weight proteins. Finnish congenital nephrotic syndrome is due to a mutation in nephrin and the proteinuria can be much more substantial than in minimal change disease. There is a lack of selectivity leading to a loss of large molecular weight proteins such as immunoglobulins, which is one of several factors predisposing the infant with congenital nephrotic syndrome to infections. The treatment for congenital nephrotic syndrome is supportive. Most cases of neonatal nephrotic syndrome have a genetic basis and result in a mutation in a protein necessary for the integrity of the glomerular filtration barrier. However, neonatal nephrotic syndrome can be the result of congenital infections. As for hematuria, the cause is rarely glomerular in origin and is more likely due to a bleeding disorder. Hematuria can also be iatrogenic resulting from placement of an umbilical artery or venous catheter. The differential diagnosis of hematuria and proteinuria in the neonate are discussed by Drs. Joseph and Gattineni.

Acknowledgments

This work was supported by NIH grant DK41612 and DK78596, a grant from Children’s Medical Center and the O’Brien Center P30DK079328.

Financial support and sponsorship: None

Footnotes

Conflicts of interest: None

Reference List

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