Renal function in the fetus and neonate – the creatinine enigma

doi:10.1016/j.siny.2016.12.002

Seminars in Fetal and Neonatal Medicine

Volume 22, Issue 2, April 2017, Pages 83-89

https://doi.org/10.1016/j.siny.2016.12.002 Get rights and content

Abstract

The use of serum creatinine levels to estimate glomerular function in infants is admittedly fraught with inherent inaccuracies which are both physiological and methodological in nature. This characteristic can understandably reduce the neonatal clinician's confidence in the ability of serum creatinine levels to provide useful information relevant to their patients' medical care. The aim of this review is to provide further insight into the peculiarities of serum creatinine trends in both premature and term infants with special focus on the maturational and developmental changes occurring in the kidney during this crucial time-period. Though newer markers of glomerular function are gaining increasing traction in the clinical realm, the most prominent of which is currently cystatin C, creatinine nonetheless remains an important player in the scientific evolution of glomerular filtration rate (GFR) estimation. Not only do its limitations provide a level of distinction for newer markers of GFR, but its advantages persist in refining the precision of newer GFR formulae which incorporate multiple patient characteristics.

Introduction

Creatinine has long been used as the bedside standard to estimate glomerular filtration rate (GFR) in the clinical arena, not only due to its biochemical properties, but also the ease and widespread availability of serum sampling methods. In this regard, the limitations of creatinine have been well described in the medical literature, and, for our purposes, are perhaps at their most significant in the respectively “smaller” arena of approximating GFR in neonates. We begin with a general review of creatinine as a biomarker of glomerular filtration, followed by a discussion on the use of creatinine in neonates relative to the developmental and maturational changes occurring in the kidney during the perinatal period. We conclude with a review of alternative methods that may be useful in the evaluation of glomerular filtration in term and premature infants.

Section snippets

Use of creatinine clearance to estimate glomerular filtration rate

Creatinine is an endogenous, low molecular weight substance (113 Da) produced through muscle catabolism at a rate proportional to total muscle mass. It is freely filtered in the glomerulus, is not plasma protein bound, nor is it metabolized by the kidney. These properties make it a useful molecule in the estimation of GFR, primarily through the use of formulae that directly measure or approximate the volume of plasma from which creatinine must be removed to account for its appearance in

Use of serum creatinine in the infant population

The interpretation of serum creatinine levels poses an additional quandary in premature and term infants. Not only are infants at significant risk for wide variations in fluid status, protein catabolism, and hepatic function over time (especially in the neonatal intensive care unit), but, for the first several days of a neonates' life, S_cr levels are more reflective of the mother's renal function than that of the child, primarily related to placental transfer of creatinine. Furthermore, in

Variations in serum creatinine values based on assay method

Another important limitation associated with the use of creatinine as a marker of GFR concerns the variation in sampling methods that are used to calculate serum levels. Earlier sampling methods utilize the Jaffe reaction, a colorimetric assay which can quantify the content of chromogens within serum. This method provides relatively imprecise results, as chromogens other than creatinine (bilirubin, for example) contribute to the reaction, in effect falsely elevating creatinine concentrations by

Developmental physiology of glomerular filtration

Glomerular filtration rate is currently the best measurement we possess to determine the magnitude of a patient's functional renal mass. As GFR is a moving target in the neonatal population, it is important to further outline the developmental physiology of glomerular filtration in order to understand how GFR changes over time in the fetus and neonate.

In biological systems, filtration is governed by the Starling principle of microvascular fluid exchange, as demonstrated by the equation: $J_{v} = k_{f} [(P_{c}$

Use of bedside serum creatinine formulas to estimate GFR in infants

As mentioned earlier, S_cr is more widely employed to estimate GFR (eGFR) using experimentally determined bedside formulas, the most popularized of which in pediatrics is the Schwartz formula: $eGFR = k ({L/S}_{cr})$ where eGFR is the estimated glomerular filtration rate standardized to mL/min/1.73 m², L is the patient's length in centimeters, S_cr is the patient's serum creatinine concentration in mg/dL, and k is a correction constant determined in order to balance the L/Scr ratio with experimentally

The role of cystatin C in the determination of GFR

Cystatin C is a comparatively new marker being utilized to estimate GFR. It is a constitutively expressed cysteine protease inhibitor produced in all nucleated cells. At a molecular weight of 13.3 kDa, cystatin C is nearly freely filtered within the glomerulus (sieving coefficient of 0.94), and is almost completely resorbed and catabolized by the proximal tubules. As such, urine studies do not provide direct insight into baseline GFR measurements (though there may be a place for urine cystatin

Use of cystatin C to estimate GFR in infants

Cystatin C does appear to cross the placenta (though this is a point of ongoing debate), though to a lesser extent than creatinine, which would suggest that initial cystatin C levels obtained after birth are more likely to indicate the infant's own renal function as opposed to that of the infant's mother. Indeed, cord blood samples of cystatin C showed no correlation to maternal levels in a 1999 study by Cataldi et al. Interestingly, many studies have shown no significant difference in serum

Bedside formulae utilizing cystatin C to estimate GFR in infants

Schwartz et al., Zappitelli et al., and Treiber et al. have derived several eGFR formulae in children incorporating S_cysC (Table 3). Many of these formulae also incorporate S_cr and blood urea nitrogen (BUN) in order to temper the inaccuracies introduced by each marker were they to be used alone. Indeed, Schwartz et al. demonstrated that the most accurate formula derived from their data incorporated all three of these markers, in addition to patient height. Likewise, Abitbol et al. determined

Beta-trace protein

Beta-trace protein (BTP) is another up-and-coming marker of glomerular filtration that may offer some benefit in infancy, as it does not appear to cross the placental barrier to any extent. BTP is not widely available for on-site analysis at most medical centers at the current time, and thus will not be reviewed extensively here, but the reader is encouraged to refer to Filler et al.'s 2014 review for more information [48].

Stratification of GFR in infancy

Standards to define appropriate pediatric GFRs across various ages and levels of prematurity are difficult to realize. Currently, the Pediatric-modified Risk, Injury, Failure, Loss, and End stage (pRIFLE) criteria serve as the most robust standard by which to delineate abnormal GFR values in patients ranging in age from 1 month to 21 years. Briefly, the pRIFLE criteria utilize the original Schwartz equation (eGFR = k(L/S_cr)) to segregate eGFR changes from baseline in order to stratify

Future implications

Despite the many hurdles inherent to arriving at an ideal solution for the assessment of neonatal glomerular function, the current research environment has created a stable framework through which continuing improvements in serum GFR marker measurements, eGFR equations, and novel biomarkers of AKI are being achieved. Together, these strengthening pillars of knowledge will provide ever more accessible and definitive methods with which to quantify glomerular filtration rate in neonates, and

Conflict of interest statement

None declared.

Funding sources

None.

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Our results are consistent with Azizi [10], Sliman and Khatib [23], and El-Hazmi et al's findings [24], who concluded that Ramadan fasting does not affect renal functions despite the insignificant changes in the serum urea and creatinine levels, thus providing further support to their conclusions that Ramadan fasting is safe amongst healthy subjects. The increase in the serum level of urea could be attributed to the catabolism of body mass [5] or a direct result of the dehydration status of the body and decreased renal blood flow during fasting [25], which was partially prevented in the hydrated group, resulting in a much lower increase in the serum urea compared with the controls. Creatinine is a low-molecular weight, nonprotein-bound endogenous substance produced in the body through muscle breakdown and is freely filtered by the glomerulus.
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This randomized controlled trial included 58 healthy subjects who were randomly divided into 2 groups of 29. The hydrated group drank 2 to 3 L of fluid from sunset to the dawn of the next day. Kidney function was measured before, during, and 1 month after Ramadan.
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Population pharmacokinetic modeling of caffeine in preterm infants with apnea of prematurity: New findings from concomitant erythromycin and AHR genetic polymorphisms
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Therefore, further evaluation and comparison with serum levels of Cystatin C would be complementary to investigate the role of this molecule as a biomarker of glomerular function in preterm neonates. Considering all the limitations in using serum creatinine concentration to evaluate renal function, which are even more relevant in preterm neonates,1–3,10–12 the search for novel biomarkers of renal function is of utmost importance. Furthermore, biomarkers that may allow early detection of changes in renal function, with accuracy and in a non-invasive way are the ideal goal of recent studies in this field.11–15
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Renal function in the fetus and neonate – the creatinine enigma

Abstract

Introduction

Section snippets

Use of creatinine clearance to estimate glomerular filtration rate

Use of serum creatinine in the infant population

Variations in serum creatinine values based on assay method

Developmental physiology of glomerular filtration

Use of bedside serum creatinine formulas to estimate GFR in infants

The role of cystatin C in the determination of GFR

Use of cystatin C to estimate GFR in infants

Bedside formulae utilizing cystatin C to estimate GFR in infants

Beta-trace protein

Stratification of GFR in infancy

Future implications

Conflict of interest statement

Funding sources

Lancet

J Pediatr

J Urol

Pediatr Clin North Am

J Pediatr

Clin Biochem

Clin Biochem

Kidney Int

Clin Biochem

Am J Kidney Dis

Clin Biochem

Kidney Int

Clin Perinatol

Measurement and estimation of GFR in children and adolescents

Clin J Am Soc Nephrol

Acute kidney injury in critically ill newborns: what do we know? What do we need to learn?

Pediatr Nephrol

Defining acute renal failure: physiological principles

Intensive Care Med

Progression of renal function in preterm neonates with gestational age < or = 32 weeks

Pediatr Nephrol

Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children

Archs Dis Child

Neonatal kidney size and function in preterm infants: what is a true estimate of glomerular filtration rate?

J Pediatr

How to estimate GFR in children

Nephrol Dial Transpl

Pediatric nephrology

Vander's renal physiology

Revision of the Starling principle: new views of tissue fluid balance

J Physiol

How to measure glomerular filtration rate

Morphogenesis and molecular mechanisms involved in human kidney development

J Cell Physiol