Postnatal Development of Glomerular Filtration Rate in Neonates

Introduction

The production of urine begins with the formation of an ultrafiltrate of plasma by the glomerulus. The function of the tubule is to modify this ultrafiltrate to allow an efficient excretion of waste products and the retention of those substances required to maintain constant body fluid volume and homeostasis. Glomerular filtration is also essential for the elimination of drugs. Alterations in glomerular filtration rate (GFR) have severe consequences for body fluid homeostasis. An estimate of GFR may be required to prescribe fluids, electrolytes, or drugs excreted by the kidney. This chapter reviews the factors that regulate GFR and the methods available to assess GFR in the newborn infant. It also briefly discusses the factors that may impair GFR during early development.

Physiology of Glomerular Filtration

Each kidney contains approximately 1 million nephrons (227,327 to 1,825,380) consisting of a glomerulus and a tubule. The number of nephrons correlates with birth weight ( Fig. 96.1 ), ^, the count increasing by 25,743 for each 100 g of birth weight. The glomerulus is a unique structure made out of a capillary network, the glomerular capillaries, supplied and drained by two resistance vessels, the afferent and the efferent arterioles. This specialized bundle of capillaries is contained within the Bowman capsule. Urine formation starts with the production of an ultrafiltrate of plasma across the permselective glomerular capillary wall. ^, This wall consists of three layers: (1) the endothelial cell lining of the glomerular capillaries; (2) the glomerular basement membrane (GBM), composed of connective, noncellular tissues; and (3) the visceral epithelial cells of the Bowman capsule. The endothelial cells have numerous fenestrae with a diameter of 70 to 100 nm. The capillary endothelium acts as a screen to prevent blood cells and platelets from entering into contact with the GBM. The endothelial cells contain on their surface negatively charged sialoproteins and proteoglycans. The endothelial glycocalyx contributes to a primary glomerular anionic barrier, which diminishes the load of macromolecules being passed to the GBM and through the slit diaphragms. Underneath the endothelium, the GBM forms a continuous layer that probably behaves as the filtration barrier for large molecules. It is an amorphous, 300- to 350-nm–thick extracellular structure formed of negatively charged glycoproteins, mainly triple-helical type IV collagen, proteoglycans, laminins, and fibronectins. The GBM-specific heparin sulfate proteoglycan 2 (perlecan) and agrin probably contribute to its charged selectivity because of the negatively charged heparan sulfate side chains they contain. The GBM is the main filtration barrier. The epithelium is formed by highly specialized visceral cells called podocytes, which are attached to the GBM by foot processes known as pedicels. Membrane proteins such as nephrin and podocin are found in the foot processes and slit membranes. Mutations in these proteins result in massive proteinuria. Adjacent pedicels are separated by filtration slits measuring approximately 25 nm by 60 nm in width, and a thin diaphragm bridges each gap. The diaphragms, in turn, contain rectangular “pores” with a dimension of 4 nm by 14 nm. Thus the filtration slits with their diaphragms could also constitute a size-selective filtration barrier. The podocytes may help in the phagocytosis of macromolecules. The size of the apertures in the glomerular filtration “barrier” is not the only factor that limits the passage of compounds through the glomerular capillary wall. The shape of the molecule, its flexibility and deformability, and its electric charge also play important roles. The molecular mass cutoff for the glomerular filter is approximately 70,000 Da. Thus albumin, with a molecular mass of 69,000 Da, passes through the filter in minute quantities. Smaller molecules pass through the filter more easily. Molecules with a molecular mass of less than 7000 Da pass through the filter freely. The glomerular ultrafiltrate thus initially contains small solutes and ions in the same concentration as present in the plasma.

Fig. 96.1, In humans the number of nephrons correlates positively with birth weight, here expressed in percentiles.

The central part of the glomerular tuft is composed of irregularly shaped cells, the mesangial cells that hold the delicate glomerular structures. By contracting, the mesangial cells can modify the filtering surface area of the glomerular capillaries. The mesangial cells also act as phagocytes to prevent the accumulation of macromolecules in the GBM that have escaped from the capillaries.

The rate of ultrafiltration is governed by several factors: the balance of Starling forces across the capillary wall, the rate at which plasma flows into the glomerular capillaries, the permeability of the glomerular capillary wall to water and small solutes, and the total surface area of the capillaries. The ultrafiltration coefficient ( K _f ) is defined as the product of the glomerular capillary permeability and the area of the capillary available for filtration. The permeability of the glomerular capillaries is approximately 100 times greater than the permeability of other capillaries elsewhere in the body. The hydrostatic pressure within the glomerulus favors filtration. It is opposed by the oncotic pressure within the lumen of the glomerular capillary. Δ P and Δ π represent the glomerular transcapillary hydrostatic and oncotic pressure, respectively. The net ultrafiltration pressure ( P _UF ) is defined as Δ P − Δ π . GFR is proportional to the sum of the Starling forces across the glomerular capillaries (Δ P − Δ π ) times K _f .

GFR = K_{f} (Δ P - Δ π)

$GFR = K_{f} (Δ P - Δ π)$

In normal conditions, P _UF and GFR are highly dependent on the arterial pressure within the glomerular capillaries, on renal blood flow (RBF), and on the glomerular plasma flow rate. The transcapillary hydrostatic pressure is also regulated by the balance between the afferent and efferent arteriolar resistance ( Fig. 96.2 ). Pathologic conditions and drugs can affect GFR by modifying the pressure within the glomerular capillary (severe hypotension), K _f (drugs, diseases), or the oncotic pressure within the glomerular capillary (changes in the concentration of plasma proteins).

Fig. 96.2, Effects of changes in the afferent or efferent arteriolar tone on renal blood flow (RBF) and glomerular filtration rate (GFR) . P GC , Glomerular capillary hydraulic pressure.

Vasoactive Agents

Several vasoactive agents modulate GFR and RBF during fetal and postnatal life. Such agents include angiotensin II, the prostaglandins, atrial natriuretic peptide, endothelin, nitric oxide, bradykinin, and adenosine. Sympathetic nerves can also affect vascular tone. All these factors modulate GFR by affecting afferent or efferent vascular tone (see Fig. 96.2 ), as well as mesangial contractility. The main actions of the vasoactive agents are as follows:

Angiotensin II: This peptide is a very potent constrictor of the afferent and efferent arterioles, acting on two types of receptors, the AT ₁ and the AT ₂ receptor subtypes. The AT ₁ receptors are widely distributed and appear to mediate most of the biologic effects of angiotensin II. The exact role of the AT ₂ receptors remains uncertain. Angiotensin II predominantly vasoconstricts the efferent arteriole, thereby increasing the intraglomerular pressure. This mechanism serves to maintain GFR when the renal perfusion pressure decreases to low levels. Angiotensin also constricts the mesangial cells, with a consequent decrease in the ultrafiltration coefficient K _f . It also increases the sensitivity of the tubuloglomerular feedback mechanism.
Prostaglandins: The prostaglandins are potent vasoactive metabolites of arachidonic acid. In the kidney, prostaglandins are synthesized through the cyclooxygenase pathway by vascular smooth muscle cells, mesangial cells, and tubular and interstitial cells of the renal medulla. They are of major importance for maintaining constant the GFR of the newborn kidney perfused at low arterial pressures. They further protect the kidney when vasoconstrictor forces are activated (e.g., with hypotension, hypovolemia, sodium depletion states, and congestive heart failure).
Atrial natriuretic peptide: This 28–amino acid polypeptide is released by atrial myocytes in response to increased arterial pressure and effective circulating volume. It increases GFR by producing afferent vasodilation and relative efferent vasoconstriction, thus increasing GFR without significantly affecting RBF. At high levels, atrial natriuretic peptide decreases systemic arterial pressure and increases the permeability of the glomerular capillaries. The kidney also produces a 32–amino acid natriuretic peptide, urodilatin, with the same local actions as atrial natriuretic peptide.
Nitric oxide: Nitric oxide is a very potent vasodilator synthesized from l -arginine in endothelial cells throughout the body. In superficial nephrons, nitric oxide appears to decrease the preglomerular resistance but has much less effect on the postglomerular resistance. In juxtamedullary nephrons, nitric oxide decreases the resistance in afferent and efferent arterioles. Nitric oxide appears essential to fine-tune the vasoconstrictor action of angiotensin II. ^,
Bradykinin: This vasodilator and diuretic peptide is produced in the kidney by the effect of the enzyme kallikrein on kininogen. Bradykinin exerts its renal effects via β ₂ receptors. The expression of β ₂ receptors is higher in neonatal kidneys than in adult kidneys, a finding suggesting a role for this peptide during renal development. Bradykinin vasodilates the newborn kidney, as evidenced by the renal vasoconstriction that results from β ₂ -receptor blockade. Therefore bradykinin decreases the ultrafiltration coefficient.
Adenosine: Adenosine is an end product of adenosine triphosphate metabolism. Adenosine decreases GFR by vasodilating the efferent arteriole via A ₂ -receptor stimulation and by vasoconstricting the afferent arteriole via A ₁ -receptor stimulation. By constricting the mesangial cells, adenosine further decreases the ultrafiltration coefficient.
Endothelin: This peptide released from endothelial cells constricts the afferent and the efferent arterioles, thereby decreasing both GFR and RBF. However, there is circumstantial evidence that, at low endogenous concentrations, endothelin may actually vasodilate the glomerular vessels in fetuses and neonates. ^, Endothelin stimulates whole-kidney production of vasodilating prostaglandins that can partially balance its vasoconstrictive effects.
Sympathetic nervous system: The sympathetic nerve endings are primarily of the α ₁ -adrenergic and β-adrenergic subtypes and secrete norepinephrine. Modest increases in renal nerve activity produce equivalent constrictions of both the afferent and the efferent arterioles, reducing RBF without significantly affecting GFR. At elevated concentrations, as occurs in severe acute hemorrhage fetal distress and asphyxia, norepinephrine vasoconstricts the mesangial cells, thus decreasing GFR.

Autoregulation of Glomerular Filtration Rate and Renal Blood Flow

Autoregulation is necessary to prevent changes in GFR and RBF when blood pressure varies abruptly. Two systems are responsible for renal autoregulation: (1) a myogenic mechanism and (2) a tubuloglomerular feedback mechanism.

The myogenic mechanism refers to the intrinsic ability of arteries to constrict when blood pressure rises and to vasodilate when it decreases. This phenomenon modulates changes in RBF and GFR when blood pressure varies. The vascular constriction present in the myogenic response is effected by the opening of stretch-activated, nonselective cation channels in vascular smooth muscle.

The tubuloglomerular feedback mechanism involves the juxtaglomerular apparatus made of the macula densa and the juxtaglomerular cells. The macula densa cells sense the changes in sodium chloride delivery to the distal tubule that follow changes in blood pressure. When blood pressure increases, the macula densa cells actually sense the higher luminal concentrations of sodium or chloride that result from increased luminal flow. A drop in blood pressure and the consequent decrease in sodium chloride delivery stimulate angiotensin II formation by the juxtaglomerular cells. By constricting the efferent arteriole, angiotensin II increases the intraglomerular hydrostatic pressure and thus returns GFR toward normal levels.

Concept of Clearance

The most common measurement of GFR is based on the concept of clearance, which relates the quantitative urinary excretion of a substance per unit time to the volume of plasma that, if “cleared” completely of the same contained substance, would yield a quantity equivalent to that excreted in the urine. The clearance ( C ) of a substance is expressed by the following formula:

C = U \cdot V / P,

$C = U \cdot V / P,$

where U represents the urinary concentration of the substance, V the urine flow rate, and P the plasma concentration of the substance. For its clearance to be equal to GFR, a substance must have the following properties: (1) it must be freely filterable through the glomerular capillary membranes—that is, not be bound to plasma proteins or sieved in the process of ultrafiltration; (2) it must be biologically inert and neither reabsorbed nor secreted by the renal tubules; and (3) it must be nontoxic and not alter renal function when infused in quantities that permit adequate quantification in plasma and urine.

Several substances, endogenous or exogenous, have been claimed to have the foregoing properties: inulin, creatinine, iohexol, diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, and sodium iothalamate. The experimental evidence that this is true has been produced only for inulin. The most commonly used markers in neonates are creatinine and inulin.

Glomerular Markers

Inulin

Inulin, a fructose polysaccharide derived from dahlia roots and Jerusalem artichokes, has an Einstein-Stokes radius of 1.5 nm and a molecular mass of approximately 5200 Da. Inulin is inert, is not metabolized, and can be recovered quantitatively in the urine after parenteral administration.

The rate of excretion of inulin is directly proportional to and a linear function of the plasma concentration of inulin over a wide range. The clearance of inulin (U · V / P) is consequently independent of its plasma concentration. Evidence that inulin is neither reabsorbed nor secreted by the renal tubules has been obtained in experimental micropuncture studies showing that (1) the concentration of inulin was identical in the Bowman space fluid and plasma, (2) 99.3% of inulin injected in the proximal tubule was collected in the distal tubule, and (3) the rate of recovery was the same when the peritubular plasma was loaded with inulin.

Because the renal excretion of inulin thus occurs exclusively by glomerular filtration, its clearance is the most accurate index of GFR. Estimates of inulin clearance provide the basis for a standard reference against which the route or mechanisms of excretion of other substances can be ascertained. It should be stressed that inulin is a gold marker of GFR only when the $C = U . V / P,$ $C = U . V / P,$ formula is used.

Inulin as a Marker of Glomerular Filtration Rate in Neonates

The same conclusion was reached from studies in preterm infants that showed that higher-molecular-mass inulin did not accumulate in the plasma of very immature babies into whom inulin was infused for several days, thus excluding any retention of the larger molecules. ^, In clinical practice, sinistrin, a readily soluble preparation of polyfructosan with side branching (extracted from bulbs of Urginea maritima ), is more widely used. The clearance of sinistrin is identical to that of inulin. Because complicated analytic methods are required for its measurement, inulin and sinistrin cannot be used for routine clinical purposes. In neonates, only creatinine has been used broadly to assess GFR.

Creatinine

Creatinine is the anhydride of creatine, a compound that exists in skeletal muscle as creatine phosphate. It has a molecular mass of 113 Da. Conversion of creatine to creatinine is nonenzymatic and irreversible. The serum creatinine level reflects total body supplies of creatine and correlates with muscle mass. Creatinine is excreted through the kidneys in quantities proportional to the serum content. The renal excretion of endogenous creatinine is very similar to that of inulin in humans and several animal species. However, in addition to being filtered through the glomerulus, creatinine is secreted in part by the renal tubular cells. In spite of this, creatinine clearance correlates well with inulin clearance when the GFR is normal. This agreement results from the balance of two factors: (1) the excretion rate of creatinine is higher than the filtered rate because of the occurrence of tubular secretion of creatinine, and (2) the measured plasma creatinine concentration is higher than the true creatinine concentration because of the presence of non-creatinine chromogens that interfere with the colorimetric analysis of creatinine (Jaffe reaction).

Overestimation of GFR by creatinine clearance is usually more evident at low GFR. As GFR falls progressively during the course of renal disease, the renal tubular secretion of creatinine contributes an increasing fraction to urinary excretion, so creatinine clearance may substantially exceed the actual GFR.

The use of creatinine clearance to estimate GFR may be poorly reliable in uremic patients. Creatinine is uniformly distributed in the body water, and it diffuses into the gut. At a normal plasma concentration, the amount of creatinine entering the gut is negligible; it may become significant during renal failure, when the plasma creatinine concentration increases. This phenomenon may also explain why creatinine clearance overestimates true GFR in patients with renal failure.

Although in use for decades, the methods available for the chemical determination of creatinine still present important drawbacks. As noted above, the traditional assay for measuring creatinine (the Jaffe reaction) substantially overestimates true serum creatinine levels because of the presence of interfering pseudochromogenic constituents in the blood. The major drawback for routine use in neonates is interference by bilirubin. Adaptations of the alkaline picrate assay have reduced the overestimation without totally eliminating the interference. Although more specific than the Jaffe method, the enzymatic techniques are still biased by various interfering substances. A new method coupling high-performance liquid chromatography and isotope dilution mass spectrometry appears to have an excellent specificity and low relative standard deviation.

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