Glomerular Filtration Rate In Neonates Research Articles

Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates.

Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different Km (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15mg/L) provided a better fit than the model with equal Km (15mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00-8.12%)), followed by total gentamicin (0.20% (0.00-4.10%)), C1a (0.11% (0.00-7.57%)), and C1 (0.04% (0.00-1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.

Prediction of glomerular filtration rate maturation across preterm and term neonates and young infants using inulin as marker

Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CLinulin). To this end, published GFR maturation models were evaluated by comparing their predicted GFR with CLinulin retrieved from literature. The best model was subsequently optimized in NONMEM V7.4.3 to better fit the CLinulin values. Our study evaluated seven models and collected 381 individual CLinulin values from 333 subjects with median (range) birthweight (BWb) 1880 g (580–4950), gestational age (GA) 34 weeks (25–43), current weight (CW) 1890 g (480–6200), postnatal age (PNA) 3 days (0–75), and CLinulin 2.20 ml/min (0.43–17.90). The De Cock 2014 model (covariates: BWb and PNA) performed the best in predicting CLinulin, followed by the Rhodin 2009 model (covariates: CW and postmenstrual age). The final optimized model shows that GFR at birth is determined by BWb, thereafter the maturation rate of GFR is dependent on PNA and GA, with a higher GA showing an overall faster maturation. To conclude, using individual CLinulin data, we found that a model for neonatal GFR requires a distinction between prenatal maturation quantified by BWb and postnatal maturation. To capture postnatal GFR maturation in (pre)term neonates and young infants, we developed an optimized model in which PNA-related maturation was dependent on GA.Graphical abstract

Maturation of glomerular filtration rate in neonates and infants: an overview.

Glomerular filtration rate (GFR) increases progressively throughout fetal life, matures rapidly after birth according to gestational and post-menstrual age, and reaches adult values by 1-year post-natal age. GFR is considered the best marker of kidney function, and in clinical practice, estimated GFR is useful to anticipate complications, establish prognosis, and facilitate treatment decisions. This review article summarizes the maturation of glomerular filtration and the factors and conditions that modulate and impair developing glomerular filtration, and discusses the techniques available to assess GFR in neonates and infants. We focused on simple, reliable, easily available, and cheap techniques to estimate GFR, which may provide valuable information on the renal aspects of the clinical care of this group of patients.

Estimated glomerular filtration rate in apparently healthy term neonates in Nigeria

Background: Glomerular filtration rate (GFR) is the best measure of renal function. However, the ideal exogenous markers are not routinely used to estimate GFR in clinical settings. Outside Africa, GFR estimates for neonates have been calculated from formulae using creatinine as well as cystatin C. There is a paucity of data on estimated GFR in neonates in Africa. This study was conducted to estimate GFR in healthy term African neonates using cystatin C-based equations. Methods: One hundred and thirteen apparently healthy term babies with normal Apgar scores were recruited at birth. Cystatin C was measured in cord blood at birth and in venous samples from neonates on the third day of life. GFR was estimated using the Filler and Lepage as well as the Zappitelli et al. cystatin C-based equations. These estimates were compared with a reference GFR estimate of 41 ± 15 mL/min/1.73 m 2 . Results: The median (interquartile range) estimated GFR values based on cord blood and day 3 venous samples using the Filler and Lepage equation were 44.67 (36.35–72.44) and 51.29 (38.90–72.44) mL/min/1.73 m 2 , respectively. When the Zappitelli equation was applied, the estimates were 38.18 (31.84–61.34) and 43.82 (33.75–61.34) mL/min/1.73 m 2 , respectively. The GFR estimates derived from both equations did not differ in respect of the gestational age, sex and postnatal ages of the babies. Conclusions: GFR estimates using the Zappitelli equation had values that were closely related to reference GFR measures for neonates whereas the GFR estimates using the Filler and Lepage equation had higher values.

IS-011 Evaluation Of Kidney Functions In Neonates

<h3></h3> In neonates, renal perfusion, glomerular filtration rate and urine output strongly depend on the vaso-dilative effects of prostaglandins on the afferent glomerular arterioles. Glomerular filtration rate in neonates is very low (2–4 mL/min or 20 ml/min/1.73 m²) and can only be maintained due to a delicate balance between vasodilatory effects at the afferent and vasoconstrictor effects at the efferent glomerular arterioli. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. We still commonly used creatinine as a biomarker of renal clearance capacity. However, before creatinaemia values can be used to estimate renal drug elimination capacity, there are some methodological issues that need to be considered. Creatinaemia at birth does not yet reflect neonatal but maternal creatinine clearance and because of passive tubular back leak instead of active secretion, creatinine clearance does not yet fully reflects GFR. Finally, absolute creatinine values also depend on the technique used. The move towards harmonisation through IDMS (isotope dilution mass spectrometry) traceability has helped, but not completely solved this problem. More research is needed to document the potential add on benefit of more advanced biomarkers (e.g. Cystatin C) or renal tubular function markers. In the meanwhile, clinical driven interpretation combined clinical and biochemical indicators seems the most appropriate approach.

β-trace protein may be a more suitable marker of neonatal renal function

To determine the relationship between maternal and neonatal cystatin C (CysC) and β-trace protein (BTP), markers of glomerular filtration rate (GFR) on day 1 of life. Blood levels of CysC, BTP, and creatinine (Cr) were analyzed from 128 healthy term and preterm neonates admitted to the neonatal intensive care unit (NICU) (36% female) to determine the relationship between gestational age and maternal levels on day 1 of life. Maternal Cr correlated positively and significantly with neonatal Cr (r = 0.677, p < 0.0001) and CysC (r = 0.246, p < 0.012) on day 1 of life. Maternal BTP did not correlate with neonatal BTP. Gestational age correlated positively and significantly with neonatal Cr (0.427, p < 0.0001), CysC (r = 0.321, p = 0.001); and with maternal Cr (r = 0.452, p < 0.0001), CysC (r = 0.613, p < 0.0001), and BTP (r = 0.442, p < 0.0001). No correlation was found between gestational age and neonatal BTP. Upon considering the following age groups; 24 - 32, 33 - 36, and ≥ 37 weeks, maternal Cr continued to correlate with neonatal Cr, across all age groups, while no correlation was found with BTP, and CysC correlations were no longer significant. Throughout, neonatal values for CysC and BTP were higher, suggesting that low neonatal GFR was the main determinant for the variance. There was no difference in the median neonatal BTP across all age groups. Maternal Cr and CysC may both cross the placenta while BTP may not. Placental crossing of Cr seems to be independent of gestational age. The reasons for the different placental handling of BTP and CysC remain unknown.

Creatinine reference values in ELBW infants: impact of quantification by Jaffe or enzymatic method

Objective: Serum creatinine (Scr) reflects to a certain extent glomerular filtration rate in neonates, but postnatal observations also depends on the technique used to quantify Scr (Jaffe colorimetry or enzymatic quantification). Methods: In an attempt to quantify differences between these techniques, we compared postnatal Scr trends in two consecutive cohorts of extremely low birth-weight (ELBW) neonates before and following a switch from uncompensated Jaffe to enzymatic Scr quantification. Postnatal Scr (Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 21, 28, and 42) in 151 ELBW neonates (uncompensated Jaffe) was compared to 116 more recently admitted ELBW neonates (enzymatic). Results: Although clinical characteristics were similar between both cohorts, median postnatal Jaffe Scr values were significantly higher compared to enzymatic quantification (all days, at least p < 0.001) throughout postnatal life. While both cohorts displayed a similar trend with an initial increase with a Scr peak on Days 3 and 4 and a subsequent decrease, the difference in within-day median values fluctuated between 11 and 24 mmol.L−1. There is neither fixed nor relative difference in Scr between both techniques. Conclusions: When using Scr to estimate renal function in ELBW neonates, clinicians should in addition to the postnatal changes and other covariates of renal function, also consider the technique applied. We provide reference values and comparison between both techniques.

Maturation of the Glomerular Filtration Rate in Neonates, as Reflected by Amikacin Clearance

During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.

Core Concepts: Neonatal Glomerular Filtration Rate

Although the placenta is the primary organ responsible for fetal clearance and electrolyte homeostasis, fetal kidneys contribute to amniotic fluid production and fetal hemodynamics. Maternal factors can significantly influence fetal urinary output and blood pressure. Maturation of neonatal glomerular filtration rate (GFR) depends on the development of renal blood flow (RBF). After birth, a marked increase in systemic blood pressure and decrease in renal vascular resistance results in elevated RBF and consequent increases in GFR. Vasoactive factors, including renin, angiotensin II, glucocorticoids, nonsteroidal anti-inflammatory drugs, nitric oxide, prostaglandins, bradykinin, and endothelin, each play vital roles in the regulation and development of neonatal GFR. Prematurity and intrauterine growth restriction (IUGR) may affect renal endowment and place infants at risk for hypertension and accelerated loss of renal function later in life.

Predictability of vancomycin pharmacokinetics in neonates

Dear Editor, We read with great interest the paper of Cunha et al. on the cost-ineffectiveness of measuring serum vancomycin trough concentrations in adult hospitalized patients receiving parenteral vancomycin. Based on a retrospective analysis of observations collected in 351 patients, the authors illustrated that vancomycin dosed by creatinine clearance estimations, based on serum creatinine values, was acceptably accurate [1]. We would like to add to the discussion that the conclusions formulated by Cunha et al. in adults might be extrapolated to neonatal populations in whom vancomycin dosed by creatinine clearance estimations is acceptable once serum creatinine values reflect renal function. Since glycopeptides are almost exclusively eliminated according to the glomerular filtration rate (GFR), developmental changes in renal clearing capacity in the neonate have to be taken into account. We therefore would like to report here our recently published data on vancomycin clearance in the first month of life in 214 neonates and compare them with the findings of Cunha et al. [1, 2]. Size explained 49.8%, postmenstrual age 18.2%, and renal function (serum creatinine values) 14.1% of vancomycin clearance variability, resulting in over 80% of explained variability in vancomycin clearance in the first 4 weeks of postnatal life [2]. In children and adults, serum creatinine values serve as a useful and reliable marker of renal clearance. In neonates, however, serum creatinine values at birth mainly reflect the maternal renal function and only turn into a reliable marker of renal clearance after the first week of life [3]. The overall high predictability of vancomycin clearance in this cohort of neonates therefore mainly relates to the fact that this drug is only very rarely administered in the very first days of life when creatinaemia does not yet reflect neonatal GFR and is in contrast to the limited predictability of renal drug clearance at birth [4]. The bactericidal activity of glycopeptide antibiotics is based on the inhibition of bacterial cell-wall synthesis. Glycopeptide antibiotics are the drugs of choice for methicillin-resistant staphylococcal infections and are widely used as empiric treatment for infections related to the central venous line in neonates. These infections are often caused by coagulase-negative staphylococci. Taking these epidemiological factors into account, vancomycin is only rarely administered in the first days of life but is a frequently administered drug in neonates for the abovementioned pathogens [5]. We therefore suggest extrapolating the conclusions formulated by Cunha et al. in adults to all populations in whom vancomycin dosed by creatinine clearance estimations is acceptably accurate hereby excluding the first days of postnatal life in addition to other specific conditions such as extracorporeal membrane oxygenation. Eur J Clin Microbiol Infect Dis (2007) 26:847–848 DOI 10.1007/s10096-007-0367-4

DIAGNOSTIC SIGNIFICANCE OF BETA 2-MICROGLOBULIN IN THE ASSESSMENT OF NEONATAL RENAL FUNCTION

Serum and urinary beta 2-microglobulin (β2M) levels were measured by enzyme immunoassay in 28 normal neonates at days 1 to 2 and 3 to 4 of life in relation to gestational age (GA) and postnatal age (PNA). There were 10 preterm (P) and 18 term (T) infants with a mean GA of 34.5 and 39.1 weeks respectively. The serum β2M, glomerular filtration rate (GFR) and filtered load of β2M increased with increasing GA and PNA. No correlation was found between the serum β2M levels and the GFR as measured by endogenous creatinine clearance. Urinary β2M increased with increasing PNA. In both P and T infants the increase in β2M excretion paralleled an increase in filtered β2M. The β2M excretion in relation to GA showed a variable response. There was no correlation between serum and urinary β2M levels. Fractional excretion (%FE) β2M decreased as a function of both the GA and the PNA. A significant inverse correlation was found between %FE β2M and GA for infants <37 weeks, (r=0.9716, P<0.005). The fall in %FE β2M reached a plateau at 0.7% by 38 weeks of gestation. The highest %FE β2M (8.65%) was observed in infants of 32 weeks gestation, yet had the lowest filtered load of the protein. We conclude that 1) serum β2M level is a poor predicator of GFR in neonates <4 days of life. 2) glomerulotubular balance for β2M is established in infants with GA of 37 weeks or more. 3) %FE β2M can be used as a marker to assess the renal functional maturation in neonates in the early days of life.