Assessment of neonatal kidney function

Background

Two thirds of drugs are eliminated by the kidneys, and their function levels must be taken into account for diagnostic and treatment plans. Kidney function level identifies acute kidney injury (AKI), or chronic kidney disease (CKD) but it cannot be measured directly, so clinicians have to calculate the clearance of a marker (for instance, inulin) over a given time period. A comprehensive review on measuring kidney function is in our extensive book chapter in Pediatric Nephrology. Briefly: In the late 1920s, Moller introduced urea clearance as a measure of kidney function and defined it as “the volume of blood that a one minute’s excretion of urine suffices to completely clear of urea.” In the 1930s, investigators searched for a biomarker that would not be reabsorbed or secreted after introduction into the tubules. The ideal glomerular filtration rate (GFR) marker must be physiologically inert, cleared only by the kidney, freely filtered at the glomerulus, and stable in terms of plasma concentration, without reabsorption or secretion by the tubules. In 1934, Richards introduced inulin because of its high molecular weight and its resistance to enzymes, and its clearance was described by Shannon in 1935. Subsequently, inulin, which is only eliminated by glomerular filtration (without undergoing any tubular absorption or secretion), became the standard for measuring kidney function. Smith introduced the inulin clearance for renal function measurement in 1956, but it is clinically impractical.

Kidney clearance describes the volume of plasma that is completely cleared of a substance by the kidneys per unit of time. The kidney clearance of a substance x (C _x ) is calculated as:

where V is the urine flow rate (mL/min), U _x is the urine concentration of the substance x, and P _x is the plasma concentration of substance x. Typically, C _x is expressed in mL/min per 1.73 m ² body surface area (BSA). C _x is equal to the GFR only when a substance is freely permeable across the glomerular capillary and not synthesized, transported, or metabolized by the kidney. The only marker that truly fulfills these requirements is inulin, ^, but its availability is very limited and prohibitively expensive. Inulin clearance was replaced in the 1970s by exogenous substances such as ⁵¹ Cr-ethylenediamine tetraacetic acid (EDTA), ⁹⁹ Tc-diethylenetriamine pentaacetic acid (DTPA), ¹²⁵ I-iothalamate, and iohexol. Most of these substances are labeled with a radioisotope. Iohexol can be used both hot and cold. Although now serving as the new standard, these methods are impractical for daily clinical use, especially in neonates.

Importantly, GFR only accounts for a fraction of the removal of toxins or drugs from the body, as most toxic substances are highly bound to plasma protein and require tubular secretion rather than glomerular filtration. Homer W. Smith clearly demonstrated that paraaminohippuric (PAH) acid was the most suitable agent for the evaluation of kidney plasma flow and introduced the PAH clearance, which is still used in some centers today. In the past, inulin and PAH clearance studies were performed concurrently. PAH clearance more closely reflects nephron endowment when compared with GFR. Due to the autoregulation of the kidney, GFR can be maintained across a wider range of nephron endowment. Only when the filtration fraction is normal (the ratio of GFR/PAH clearance is ∼16%) and there is no hyperfiltration will GFR accurately reflect PAH clearance. Hyperfiltration may result in inappropriately high GFR. Glomerular hyperfiltration can be caused by vasodilation of the afferent arterioles, as in patients with diabetes or after a high-protein meal and/or by efferent arteriolar vasoconstriction owing to activation of the renin-angiotensin-aldosterone system, leading to glomerular hypertension.

We take for granted that kidney function should be indexed to BSA. However, does this make sense when (1) gaining body weight increases BSA, which would automatically increase GFR, and (2) the body fat does not participate in renal clearance? The biological principle of a finite number of nephrons at 36 weeks of gestation and with subsequent slow attrition is not reflected in the life course of GFR. Bird et al. questioned indexing GFR to BSA for some time and proposed to use the extracellular volume (ECV) instead. ^, Indexing GFR to ECV reflects this biological principle, whereas GFR indexed to BSA remains the same until young adulthood. Peters et al. published a robust formula for the calculation of ECV, but indexing GFR to ECV rather than BSA is rarely utilized.

Nephron development in utero

The development of the kidneys and urinary tract is complex as we relive evolution during embryogenesis. Three different embryonic stages are reported and the first two involute: pronephros, ^, mesonephros, and metanephros. Each time, arteries, veins, and ureters are formed, which could be the explanation for the high rate of congenital anomalies of the kidney and urinary tract. Importantly, the ureteric bud invades the mass of metanephric mesenchyme, which induces multiple generations of dichotomous branching of the bud and the formation of layers of nephrons at the ureteric bud tips. The majority of the nephrons of the final kidney, the metanephros, form between weeks 20 and 36 of gestation. Previously it was thought that nephrogenesis stops with preterm birth, but a recent study shows that some reduced and altered nephrogenesis continues for a maximum of 4–6 weeks postdelivery but results in abnormal glomeruli.

Urine production occurs at mesonephros and metanephros stages, beginning at approximately 9 weeks of gestational age. The kidneys produce a significant proportion of the amniotic fluid. The fetal metanephros produces dilute urine, which slowly increases from approximately 15 mL/h at 20 weeks of gestation to about 50 mL/h at term. The large volume of hypotonic urine is essential for normal fetal fluid maintenance and amniotic fluid amount.

Only 3% of the cardiac output in fetal lambs (weighing 80–450 g) accounts for the renal blood flow and GFR is low, and the adult lamb has 25% of the cardiac output going to the kidneys. Studies in humans do not exist, but the principle is the same for all mammals. An adult human also distributes 25% of the cardiac output to the kidneys.

Hereditary and in utero factors affecting nephron endowment

According to the hyperfiltration theory, the number of functioning nephrons determines kidney function at all life stages. Other factors such as hereditary disease, maternal/congenital conditions, in utero exposures, and prematurity play a significant role in nephron endowment and lifelong renal function.

Nephron endowment is affected by maternal health conditions and even diet. Maternal diabetes has been associated with congenital anomalies of the kidney and urinary tract. Pregnant women with CKD or nephrotic syndrome are at risk to develop maternal (e.g., preeclampsia, AKI, cellulitis, and premature rupture of membranes) and/or neonatal morbidity (e.g., low birth weight, intrauterine growth retardation). Maternal CKD is a risk factor for preterm deliveries or intrauterine growth retardation, especially if the mothers have hypertension. Maternal protein restriction and famine in animal models have also been associated with reduced nephron endowment. Rodent models suggest that maternal obesity may be related to CKD later in life. Also, leptin deficiency impairs kidney development in animal models. In other words, both famine and feast during pregnancy affect the nephron endowment.

In utero exposure to medications such as immunosuppressants (mycophenolate mofetil and cyclosporine), antihypertensives (e.g., angiotensin converting enzyme inhibitors or angiotensin receptor blockers), aminoglycosides, prostaglandin synthetase inhibitors, dexamethasone, furosemide, antiepileptics, Adriamycin], and cyclophosphamide are known to cause fetopathies, kidney dysfunction, or even end-stage kidney disease in the neonate. Substance use during pregnancy such as alcohol, nicotine, and illicit drugs have also been associated with abnormal kidney development.

Multiple risk factors may also affect nephron endowment after birth including prematurity, neonatal sepsis, AKI, drugs, and therapeutic interventions. In a multivariate analysis, Cuzzolin et al. determined that maternal use of nonsteroidal antiinflammatory drugs (NSAIDs) and/or neonatal intubation, respiratory distress syndrome, low Apgar score, and use of NSAIDs were associated with reduced nephron endowment.

Prematurity and nephrogenesis

The incidence of prematurity has increased and remains the second largest direct cause of child mortality. Premature deliveries occur in 11% of pregnancies. In prematurity, nephrogenesis is incomplete and responsible for adult kidney pathologies. It was believed that the stress of premature delivery induced apoptosis and termination of nephrogenesis, but this may not uphold. In a baboon model, Gubhaju et al. demonstrated modified nephrogenesis after preterm delivery. The glomeruli were abnormal with a cystic Bowman space and shrunken glomerular tuft, especially in the superficial renal cortex, where the latest generation of nephrons would form. Extreme prematurity especially alters nephrogenesis. Metabolic factors complicating preterm birth also have additional consequences for the nephrogenesis. In a baboon model, Callaway et al. demonstrated that hyperglycemia alone has a significant impact on normal nephrogenesis and did not find increased apoptosis in that animal model. In summary, prematurity affects normal nephrogenesis, reduces nephron endowment, and is a risk factor for reduced longevity/abnormal kidney function later in life, sometimes manifesting as early as 11 years of age with CKD and hypertension. Finally, nephron endowment can be reduced with in utero growth.

Adaptation of renal function in infancy in the first year of life

When indexed to BSA, GFR remains constant from 18 months to 18 years of age, which is substantially different during the neonatal and infancy periods. During pregnancy and in the first 18 months of life, kidney function undergoes substantial developmental changes from 3% blood flow to 25% blood flow. After birth, there is a delicate balance between vasoconstrictive and vasodilatory renal forces, resulting in ongoing high vascular resistance in renal vessels. The low GFR of the neonate limits the postnatal adaptation of kidney function to endogenous and exogenous stress. Systemic vascular resistance decreases markedly in the first 7 days of life, resulting in a redistribution of blood flow to the kidneys. The low effective renal blood flow and GFR are responsible for altered pharmacokinetics of drugs excreted by the kidney in the neonate, and significant tubular reabsorption in the distal nephron blunts the neonate’s ability to excrete an acute saline load. Therefore 5% or 10% dextrose solutions without any sodium or low saline concentrations are utilized in neonates.

The measured GFR and estimated GFR (eGFR) in full-term neonates is 30%–40% of adult values, and it is even lower in preterm neonates when factored for body surface area. Tubular function is also immature. Tubular secretion is immature at birth (even for full-term neonates) and approaches adult values by 7 months of age. Tubular secretion capacity in children and adolescents can exceed that of adults. Tubular reabsorption can be both an active or passive process. In preterm infants (<34 weeks of gestation), the glucose transport system is immature, resulting in tubular glycosuria.

Kidney function measurement in clinical practice

Kidney function measurement allows AKI recognition, drug dosing, and research, particularly since two-thirds of drugs are cleared by the kidney. Kidney function determines the progression of CKD and predicts outcomes in heart failure. ^, Clinicians must be familiar with the methods of assessing kidney function, be aware of the strengths and limitations of the various techniques, and be mindful about technical aspects when using either endogenous or exogenous markers. ^, Although exogenous markers can determine the clearance of the substance over time through the kidneys, these have rarely been used in the neonatal period; therefore, we will start with endogenous biomarkers of GFR next.