Physiologic And Pathophysiologic Changes In Renal Blood Flow And Glomerular Filtration Rate

Although GFR and RPF are normally relatively constant, they can change from their normal set point when influenced by other signaling systems. Under normal conditions, the GFR is nearly maximal so that most of the normal physiologic changes occur in the direction of decreasing GFR. Presuming there are no changes in plasma protein concentration, this could be accomplished by changes in afferent or efferent arteriolar resistance, or in the ultrafiltration coefficient Kf. The effects of arteriolar resistance changes on RBF are predictable as in any capillary bed. However, because the relative resistances of the afferent and efferent arterioles affect both glomerular capillary pressure and the average glomerular capillary plasma CoP, the effects of resistance changes on GFR are more complex. It is also likely that Kf may be altered by changes in the level of arteriolar contraction, and by the configuration of mesangial cells surrounding the glomerular capillaries, which may alter the capillary area available for filtration.

Both the arterioles and mesangial cells constrict in response to circulating catecholamines, and they receive sympathetic adrenergic innervation and constrict in response to increased firing. other hormones, including vasopressin (also called antidiuretic hormone or ADH), angiotensin II, and glucocorticoids (the latter probably by the increase in circulating angiotensin II it produces), also cause constriction of the arterioles and mesangial cells. In addition to these circulating hormones, the arterioles and mesangial cells respond to agents that are produced locally in the kidney rather than in extrarenal endocrine glands. These substances are referred to as autacoids when they act on the same cells that produce them, and as paracrine factors when they act on neighboring cells.

Effect of Changes in Afferent and Efferent Arteriolar Resistances

As illustrated previously in Fig. 4, if the efferent arteriolar resistance is constant, the glomerular capillary pressure is inversely proportional to the afferent arte-riolar resistance. Alternatively, if the afferent arteriolar resistance is constant, the glomerular capillary pressure is directly proportional to the efferent arteriolar resistance. However, if there is no offsetting decrease in the resistance of the other arteriole, as in the examples in Fig. 4, increases in either afferent or efferent resistance cause a decrease in RPF. Furthermore, as shown in Figs. 5 and 6, when RPF decreases without a proportional decrease in GFR, the resulting increase in FF leads to an increase in the average CoP in the glomerular capillaries, which diminishes the net filtration pressure.

When the afferent arteriolar resistance decreases with no change in efferent resistance, both GFR and RPF rise, and both fall when the resistance increases, as shown in Fig. 12. This can be understood easily because changes in afferent arteriolar resistance affect net filtration pressure in a direct way that parallels the effect on RPF. For example, when afferent arteriolar resistance rises, the glomerular capillary pressure falls, as does the RPF. Therefore, changes in only afferent arteriolar resistance give rise to large and parallel changes in both GFR and RPF.

The effects of changes in efferent arteriolar resistance on GFR, although sometimes difficult to understand, are predictable. As shown in Fig. 13, a decrease in the efferent arteriolar resistance with no change in afferent resistance leads to a rise in RPF and a fall in GFR, because the fall in efferent arteriolar resistance causes a fall in glomerular capillary pressure and thus a fall in net filtration pressure. GFR increases with a small increase in the efferent arteriolar resistance, but only slightly. At higher efferent arteriolar resistances, GFR falls even though glomerular capillary pressure rises. This apparent paradox occurs because the rise in CoP

Relative Afferent Arteriolar Resistance FIGURE 12 Effect of changes in the relative resistance of the afferent arteriole on GFR and RPF. The normal resistance is taken to be 1.0 so that, for example, a relative resistance of 2.0 is two times the normal resistance. The efferent arteriolar resistance in this example is presumed to remain constant. (Modified from Navar LG, Bell PD, Evan AP. The regulation of glomerular filtration rate in mammalian kidneys. In Andreoli TE et al, eds., The physiology of membrane disorders, 2nd ed. New York: Plenum, 1986, pp 637-667.)

Relative Afferent Arteriolar Resistance FIGURE 12 Effect of changes in the relative resistance of the afferent arteriole on GFR and RPF. The normal resistance is taken to be 1.0 so that, for example, a relative resistance of 2.0 is two times the normal resistance. The efferent arteriolar resistance in this example is presumed to remain constant. (Modified from Navar LG, Bell PD, Evan AP. The regulation of glomerular filtration rate in mammalian kidneys. In Andreoli TE et al, eds., The physiology of membrane disorders, 2nd ed. New York: Plenum, 1986, pp 637-667.)

caused by the decreased RPF is greater than the rise in glomerular capillary pressure, and the net filtration pressure falls. Therefore, there is only a limited capacity to increase GFR by increasing efferent arte-riolar resistance because of the opposing effects on FF and COP.

In the two examples of Figs. 12 and 13, it is assumed that only one or the other arteriolar resistance changes alone with no other changes except for COP. In most circumstances, both resistances change in parallel. Generally, when both resistances increase by 20% or less, as occurs with a moderate increase in sympathetic

FIGURE 13 Effect of changes in the relative resistance of the efferent arteriole on GFR and RPF. As in Fig. 10, the normal resistance is taken to be 1.0. At this resistance, GFR is nearly maximal so that an increase in resistance gives only a small increase in GFR and then a decrease for the reasons discussed in the text. The afferent arteriolar resistance in this example is presumed to remain constant. (Modified from Navar LG, Bell PD, Evan AP. The regulation of glomerular filtration rate in mammalian kidneys. In Andreoli TE et al, eds., The physiology of membrane disorders, 2nd ed. New York: Plenum, 1986, pp 637-667.)

Relative Efferent Arteriolar Resistance

FIGURE 13 Effect of changes in the relative resistance of the efferent arteriole on GFR and RPF. As in Fig. 10, the normal resistance is taken to be 1.0. At this resistance, GFR is nearly maximal so that an increase in resistance gives only a small increase in GFR and then a decrease for the reasons discussed in the text. The afferent arteriolar resistance in this example is presumed to remain constant. (Modified from Navar LG, Bell PD, Evan AP. The regulation of glomerular filtration rate in mammalian kidneys. In Andreoli TE et al, eds., The physiology of membrane disorders, 2nd ed. New York: Plenum, 1986, pp 637-667.)

firing via the renal nerves, GFR changes little and RPF falls. When both afferent and efferent resistances increase more than about 20%, both RPF and GFR fall because of the effects of the increased FF on the average COP.

Renal Nerves and Circulating Vasoactive Hormones

Nerve fibers from the sympathetic celiac plexus supply the kidney via renal nerves with both nonmyelinated and myelinated fibers, although the latter are not found in glomerular structures. The nerve endings are primarily «-adrenergic and secrete norepinephrine. These nerve endings are found in association with the afferent and efferent arterioles, with mesangial cells, and with the juxtaglomerular apparatus. In addition, there are nerve endings in the epithelial cell layer of both proximal and distal regions of the nephron. Because these nephron segments have receptors that respond to adrenergic and dopaminergic agonists and antagonists, the sympathetic nervous system is also involved in the regulation of reabsorptive and secretory functions, as well as with the regulation of vascular resistance.

Intravenous infusions of epinephrine and norepi-nephrine decrease RBF and GFR. However, under normal conditions renal nerve activity is so low that it exerts only minimal effects on the GFR. However, in this setting, it has been shown that a small increase in sympathetic stimulation that has little effect on RBF augments renin release. Modest increases in renal nerve activity or the infusion of low concentrations of adrenergic agonists also have little effect on GFR, although they reduce RBF because they produce equivalent constriction of both afferent and efferent arteriolar resistances. Increased sympathetic stimulation, such as that produced by occlusion of a carotid artery, increases both afferent and efferent arteriolar resistances, and RBF and GFR decrease significantly. It has also been proposed that increased renal nerve activity may decrease Kf, thus contributing to the fall in GFR seen with moderate renal nerve stimulation or epinephrine infusion.

Strong stimulation via the renal nerves can markedly increase both resistances. In the extreme, such stimulation leads to marked diminution in RPF and a cessation of GFR. This is obviously an extreme response; however, renal ''shutdown'' such as this is often observed in severe hemorrhage, as sequelae of surgical procedures (e.g., during coronary bypass), shock, or trauma. These events are common precipitants of ischemic damage to the kidney, resulting in acute renal failure.

Autocrine and Paracrine Regulators of Renal Blood Flow and Glomerular Filtration Rate

Table 2 lists several endogenous substances that have been shown to produce changes in afferent and efferent arteriolar tone. Many of these substances are autacoids and paracrine factors that are released by the glomerular capillary endothelium and that act locally on their associated arterioles and mesangial cells. Nitric oxide (NO), previously referred to as endothelial-derived relaxing factor, is also released by endothelial cells in response to increased shear stress or pressure. NO is a potent vasodilator in most arterioles including the afferent and efferent renal arterioles. The binding of acetylcholine, bradykinin, or histamine to endothelial cells results in the production of NO and decreased arteriolar resistance. Prostaglandins, particularly PGE2 and PGI2 (prostacyclin), which are produced from arachidonic acid in vascular smooth muscle, mesangial, and epithelial cells, are also important vasodilators, but they act primarily by moderating the effects of strong vasoconstrictor stimulation to the kidney. For example, prostaglandins have little vasodilator effect when administered to a normal individual, but when sympathetic tone to the kidney is high or when circulating levels of angiotensin II are reducing RBF and GFR, they have a marked antagonistic effect, as illustrated by the clinical note in this section on the effect of NSAIDs. Prostaglandin production by the kidney is stimulated by

TABLE 2 Circulating Hormones, Paracrine Factors, and Autacoids That Alter Resistances of Afferent and Efferent Arterioles

Vasoconstrictors

Vasodilators

Circulating Hormones Catecholamines Angiotensin II Vasopressin (ADH) Glucocorticoids

Paracrine Factors & Autacoids Endothelin Thromboxane A2 Leukotrienes

Circulating Hormones Dopamine

Paracrine Factors & Autacoids Nitric oxide (NO) Acetylcholine pge2

PGI2 (prostacyclin) Bradykinin angiotensin II and, conversely, renin release is inhibited by PGE2.

The most potent vasoconstrictor of endothelial origin is endothelin. Endothelin actually represents a family of 21-amino-acid peptides that are synthesized by various endothelial cells. Endothelin acts on neighboring vascular smooth muscle cells in arterioles to increase intracellular Ca2+ by releasing it from intracellular stores and thus increasing arteriolar resistance. The production of endothelin has been implicated in the nephrotoxicity of some drugs such as cyclosporine,

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