Brenner and Rector's The Kidney, 8th ed.

CHAPTER 3. The Renal Circulations and Glomerular Ultrafiltration

Rujun Gong   Lance D. Dworkin   Barry M. Brenner   David A. Maddox



Major Arteries and Veins, 91



Organization and Function of the Intrarenal Microcirculations, 92



Hydraulic Pressure Profile of the Renal Circulation, 92



Structure of the Glomerular Microcirculation, 93



Cortical Postglomerular Microcirculation, 94



Medullary Microcirculation, 98



Total Renal Blood Flow, 101



Intrarenal Blood Flow Distribution, 101



Cortical Blood Flow, 101



Redistribution of Cortical Blood Flow, 102



Medullary Blood Flow, 102



Regulation of Renal Circulation and Glomerular Filtration, 102



Vasomotor Properties of the Renal Microcirculations, 102



Role of Endothelial Factors in the Control of Renal Circulation and Glomerular Filtration, 105



Tubuloglomerular Feedback Control of Renal Blood Flow and Glomerular Filtration, 106



Other Hormones and Vasoactive Substances Controlling Renal Blood Flow and Glomerular Filtration, 113



Neural Regulation of Glomerular Filtraion Rates, 117



Determinants of Glomerular Ultrafiltration, 117



Hydraulic Pressures in the Glomerular Capillaries and Bowman Space, 118



Glomerular Capillary Hydraulic and Colloid Osmotic Pressure Profiles, 119



Determination of the Ultrafiltration Coefficient, 119



Selective Alterations in the Primary Determinants of Glomerular Ultrafiltration, 120

Under resting conditions, about 20% of the cardiac output in humans perfuses the kidneys, organs that constitute only about 0.5% of the human body mass. This rate of blood flow, approximately 400 mL/100 g of tissue per minute, is much greater than that observed in other vascular beds ordinarily considered to be well perfused, such as heart, liver, and brain.[1] From this enormous blood flow (about 1 L/minute) only a small quantity of urine is formed (about 1 mL/minute). Although the metabolic energy requirement of urine production is great—about 10% of basal O2 consumption—examination of the renal arteriovenous O2 difference reveals that blood flow far exceeds metabolic demands. In fact, the high rate of blood flow is essential to the process of urine formation.

Traditionally, reviews of the renal circulation have focused on whole-organ blood flow, as measured by arterial flowmeters or by clearance techniques, and on the variations in this flow induced by pharmacologic agents. Technologic advances, however, now permit both a more precise definition of renal vascular anatomy and direct measurements of microvascular pressures, flows, resistances, and permeabilities in regions of mammalian kidneys previously considered inaccessible. The results obtained make it clear that the kidney contains several distinct microvascular networks, including the glomerular microcirculation, the cortical peritubular microcirculation, and the unique microcirculations that nourish and drain the inner and outer medulla. In this chapter, we consider (1) the intrarenal organization of these discrete microcirculatory networks, (2) the total and regional renal blood flows, and (3) the physiologic factors that regulate these flows. For detailed discussions of the effects of pharmacologic agents on renal blood flow and intrarenal blood flow distribution, the reader is referred to Chapters 45 and 46 .


The human renal artery usually divides just before entry into the renal parenchyma. The anterior main branch further divides into four segmental arteries, which supply the apex of the kidney, the upper and middle segments of the anterior surface, and the entire lower pole, respectively. The posterior main branch supplies the remainder of the kidney; an occasional branch from this trunk supplies blood to the apex. These segmental arteries are end arteries, there being no anastomoses between their branches at any level of division.[2] Therefore, obstruction of an arterial vessel should lead to complete ischemia and infarction of the tissue in its area of distribution. In fact, ligation of individual segmental arteries has frequently been performed in the rat to reduce renal mass and produce the remnant kidney model of chronic renal failure. Morphologic studies in this model reveal the presence of ischemic zones adjacent to the totally infarcted areas. These regions contain viable glomeruli that appear shrunken and crowded together, demonstrating that some portions of the renal cortex may have partial dual perfusion.[3]

The anatomic distribution of segmental arteries just described is most common; however, other patterns may occur. [4] [5] Not infrequently, “accessory” renal arteries may result from precocious division of the renal artery at the aorta. These vessels, which most often supply the lower pole,[6] are not in fact accessory because each is the sole arterial supply of some part of the organ.[2] Such additional arteries are found in 20% to 30% of normal individuals.

Within the renal sinus of the human kidney, division of the segmental arteries gives rise to the interlobar arteries, which extend toward the cortex along the columns of Bertin located between adjacent medullary pyramids. These vessels, in turn, give rise to the arcuate arteries, whose several divisions tend to lie in a plane parallel to the kidney surface at the border between the cortex and outer medulla. From the arcuate arteries, the interlobular arteries branch more or less sharply, most often as a common trunk that divides two to five times as it extends toward the kidney surface [7] [8] [9] [10] ( Fig. 3-1 ). Afferent arterioles leading to glomeruli arise from the smaller branches of the interlobular arteries ( Fig. 3-2 ). Except for the terminal portion of the afferent arteriole, the wall structure of the intrarenal arteries and the afferent arterioles resembles that of vessels of similar size in other locations.



FIGURE 3-1  Low-power photomicrograph of silicone-injected vascular structures in human renal cortex. The tissue has been made transparent by dehydration and clearing procedures after injection. Interlobular arteries (some indicated by arrows) arise from arcuate arteries (not seen) and extend toward the kidney surface. The glomeruli, visible as small round objects, arise from the interlobular vessels at all cortical levels. (Magnification ×5.)  (Courtesy of R Beeuwkes, Ph.D.)




FIGURE 3-2  Photomicrograph of a single interlobular artery and glomeruli arising from it as seen in a cleared section of a silicone rubber-injected human kidney. Afferent arterioles (arrows) extend to glomeruli. Efferent vessels emerging from glomeruli branch to form the cortical postglomerular capillary network. The photomicrograph is oriented so that the outer cortex is at the top and the inner cortex is at the bottom. (Magnification ×25.)  (Courtesy of R Beeuwkes, Ph.D.)


The capillary network of each glomerulus is connected to the postglomerular (peritubular) capillary circulation by way of efferent arterioles. Venous connections between peritubular capillaries and veins are made at every cortical level. Superficial veins drain the region near the kidney surface. These lie within the cortex and may run parallel to the capsule before descending along the interlobular axes.[10] Interlobular veins, close to the corresponding arteries, drain the bulk of the cortex. As these converge they are joined by vessels from the medullary rays and veins returning from the medulla in vascular bundles. Unlike the arterial system, which has no collateral pathways, the venous vessels anastomose at several levels. [2] [8] Convergence at the arcuate and interlobar veins gives rise to several main trunks that join to form the renal vein. The large veins of the renal hilum have no clear segmental organization, and because of the earlier anastomoses, obstruction of one large venous channel usually leads to diversion of blood flow to the others.

The pattern of the renal arterial system is similar in most of the mammals commonly used experimentally. Nomenclature is also similar. For example, the main arterial branches that lie beside the medullary pyramid are called interlobar, even in animals that have but a single lobe. The absence of arterial anastomoses seems to be a general finding.[10] In contrast to the similarity in arterial vessels, the venous pattern shows more marked species differences. The canine kidney has a major outer cortical venous system that is drained by way of the interlobular axes. [9] [10] Superficial cortical veins are also a feature of the feline kidney, but in this species these vessels are subcapsular and extend around the surface of the kidney to join with the renal vein at the hilum. [8] [11] This arrangement has permitted experiments involving separate collection of the venous drainage from the superficial and deep cortex.[12] In the ringed seal, the subcapsular system is so developed that virtually the entire venous outflow of the kidney is directed to the peripheral plexuses. This species differs from most other mammals in that no arcuate venous system exists and no major vein of consequence emerges from the renal hilum.[13] In the hamster, rat, and mouse, superficial veins are absent and blood leaves the cortex entirely by way of interlobular veins descending in a direction perpendicular to the capsule. [8] [14] Such veins can also be seen in photographs of injected rabbit kidneys.[15] Anastomoses between the arcuate vessels of the venous system appear to be a consistent finding in all species except the seal.


Hydraulic Pressure Profile of the Renal Circulation

Based on studies of the vasculature of a unique set of juxtamedullary nephrons [16] [17] most of the preglomerular pressure drop between the arcuate artery and the glomerulus occurs along the afferent arteriole ( Fig. 3-3 ). The pressure drop between the systemic vasculature and the end of the interlobular artery in both the superficial and juxtamedullary microvasculature, however, can be as much as 25 mm Hg at normal perfusion pressures, with the majority of that pressure drop occurring along the interlobular arteries (see Fig. 3-3 and Refs 17, 18 [17] [18]). Approximately 70% of the postglomerular hydraulic pressure drop takes place along the efferent arterioles with approximately 40% of the total postglomerular resistance accounted for by the early efferent arteriole (see Fig. 3-3 ). Of note, studies using this preparation now demonstrate that the very late portion of the afferent arteriole (last 50 mm–150 mm) and the very early portion of the efferent arteriole (first 50 mm–150 mm) provide a large portion of the total pre- and postglomerular resistance (see Fig. 3-3 ).



FIGURE 3-3  Hydraulic pressure profile in the renal vasculature. Filled squares and triangles denote values (mean± 2 SD) obtained from a variety of micropuncture studies in euvolemic and hydropenic rats, respectively. Values obtained from studies of the squirrel monkey are shown as open diamonds. Values shown by open inverted triangles and open squares were obtained by micropunture of juxtamedullary nephrons in the Sprague-Dawley rat. In these studies the arcuate artery ( was perfused with whole blood (at the perfusion pressures shown) and hydraulic pressures measured at downstream sites including the interlobular artery (Interlob. art.), the proximal (Early a.a.) and distal (Late a.a.) portions of the afferent arteriole, the glomerular capillaries (000736   GC), the proximal (Early e.a.) and late (Late e.a.) segments of the efferent arteriole, the peritubular capillaries (PC), and the renal vein (R.V.). (See Refs 18 and 551 for sources of data.)



Structure of the Glomerular Microcirculation

The glomerulus and glomerular filtration are discussed in detail in a later part of this chapter. Structurally, the glomerulus consists of an enlargement of the proximal end of the tubule to incorporate a vascular tuft. The vascular structure of the tuft is strikingly similar in different species and appears to be genetically defined, at least in its major divisions. For example, vascular pathways of the injected canine glomerulus, shown in Figure 3-4 , are similar to those of a human glomerulus drawn from a reconstruction by Elias ( Fig. 3-5 ). [19] [20] The efferent vessel is formed by an abrupt and distinctive convergence of the glomerular capillary pathways (see Figs. 3-4 and 3-5 [4] [5]).



FIGURE 3-4  Photomicrograph of a silicone-injected and cleared canine glomerulus. The afferent arteriole (A) enters at the bottom of the photograph. The efferent arteriole (E) extends upward. The vascular tuft has been teased apart slightly to reveal the distinctive dilation in the early part of the efferent vessel. (Magnification ×360.)  (Reprinted with permission from Barger AC, Herd JA: The renal circulation. N Engl J Med 284:482, 1971.)






FIGURE 3-5  Human glomerular capillary pathways, as reconstructed by Elias. This drawing shows the abrupt connections of capillary pathways to the efferent arteriole. Such connections are apparent in the dog glomerulus (see Fig. 3-4 ). This diagram does not indicate the details of the capillary walls or membranes. The dashed arrow indicates a short pathway between afferent and efferent arterioles.  (From Elias H, Hossmann A, Barth IB, Solmor A: Blood flow in the renal glomerulus. J Urol 83:790–798, 1960.)




Elger and co-workers[21] provided a detailed ultrastructural analysis of the vascular pole of the renal glomerulus. They described significant differences in the structure and branching patterns of the afferent and efferent arterioles as they enter and exit the tuft. Afferent arterioles lose their internal elastic layer and smooth muscle cell layer prior to entering the glomerular tuft. Smooth muscle cells are replaced by granular cells that are in close contact with the extraglomerular mesangium. Upon entering, afferent arterioles branch immediately and are distributed along the surface of the glomerular tuft. These primary branches have wide lumens and immediately acquire features of glomerular capillaries, including a fenestrated endothelium, characteristic glomerular basement membrane, and epithelial foot processes. In contrast, the efferent arteriole arises deep within the tuft, from the convergence of capillaries arising from multiple lobules. Additional tributaries join the arteriole as it travels toward the vascular pole. The structure of the capillary wall begins to change even before the vessels coalesce to form the efferent arteriole, losing fenestrae progressively until a smooth epithelial lining is formed. At its terminal portion within the tuft, endothelial cells may bulge into the lumen, reducing its internal diameter. Typically, the diameter of the efferent arteriole within the tuft is significantly less than that of the afferent arteriole. Depending on the location of the final confluence of capillaries, efferent arterioles may acquire a smooth muscle cell layer, which is observed distal to the entry point of the final capillary. The efferent arteriole is also in close contact with the glomerular mesangium as it forms inside the tuft and with the extraglomerular mesangium as it exits the tuft. This precise and close anatomic relationship between the afferent and efferent arterioles and mesangium is of uncertain physiologic significance, but is consistent with the presence of an intraglomerular signaling system that may participate in the regulation of blood flow and filtration rate.

The appearance of the vascular pathways within the glomerulus may change under different physiologic conditions. In injection studies, some glomeruli show only simple, large-diameter paths ( Fig. 3-6 ), whereas other glomeruli nearby may show a myriad of small pathways, as in Figure 3-4 . This may result from variability in the degree of filling of available intraglomerular pathways.[21] Intermittent flow within glomeruli has been reported in amphibian species,[22] and Hall[23] has suggested that variation in filling of different intraglomerular pathways is a means of regulating filtration by altering the filtration surface area and axial resistance to blood flow. For a given cross-sectional area, small channels have much higher resistance than large channels.



FIGURE 3-6  Photomicrograph of a silicone-injected and cleared glomerulus from a dog in which only relatively large-diameter channels have filled. In contrast with the glomerulus shown in Figure 3-4 , with its myriad of small pathways, the simple structure of this capillary tuft is striking. Such variability of intraglomerular perfusion may play a role in regulating filtration rate in mammals (see text).  (Reprinted with permission from Barger AC, Herd JA: The renal circulation. N Engl J Med 284:482, 1971.)




Some insight into the mechanism by which intraglomerular flow patterns might be changed has been obtained. The glomerular mesangium has been shown to contain contractile elements[24] and exhibit contractile activity when exposed to angiotensin II (AII).[25] Mesangial cells, which possess specific receptors for angiotensin II, undergo contraction when exposed to this peptide in vitro.[26] Three-dimensional reconstruction of the entire mesangium in the rat suggests that approximately 15% of capillary loops may be entirely enclosed within armlike extensions of mesangial cells that, together with the body of the mesangial cell, are anchored to the extracellular matrix.[27] Contraction of these cells might alter local blood flow and filtration rate as well as alter the intraglomerular distribution of blood flow and total filtration surface area. Many hormones and other vasoactive substances capable of altering the glomerular ultrafiltration coefficient bring about this adjustment by altering the state of contraction of mesangial cells.

Recent studies have employed newer imaging techniques to more accurately assess the three-dimensional structure of the glomerular tuft. Yu and co-workers[28] applied scanning electron microscopy to mouse glomeruli that were fixed by an in vivo cryotechnique with freeze substitution, as opposed to more conventional methods. This technique maintained open capillary lumens and may preserve the ultrastructure of the glomerulus closer to the living state. Kaczmarek[29] applied confocal microscopy of normal rats to more precisely reveal the lobular structure of glomeruli and to estimate the average length of the capillary network. He proposed that three-dimensional models based on confocal data were much easier to generate than reconstructions based on serial sections. In addition, Antiga and colleagues[30] developed an automated method to produce a three-dimensional model of the glomerular capillary network using digitized images of serial sections of a tuft. This method was used to produce a topographic map of the glomerulus and to derive data on the length, radius, and spatial configuration of capillary segments. More recently, a novel technology, termed two-photon microscopy, has been applied to optimize three-dimensional, multicolor imaging and single-cell segmentation of glo-merular components in either biopsy or intravital kidney tissue.[31]

A detailed discussion of the various driving forces and physiologic modulators of the glomerular ultrafiltration process are provided later. The sieving characteristics of the glomerular capillary wall for macromolecules are considered in Chapter 26 .

Cortical Postglomerular Microcirculation

Vascular Patterns

The precise description of efferent vascular patterns in each cortical region has been achieved through careful microscopic examination of kidneys after vascular injection with appropriate media, usually silicone rubber. [11] [32] [33] [34] [35] More recently, microcomputed tomography has allowed visualization of injected renal microvessels without sectioning the kidney.[36] From these studies, it has become clear that the appearance of efferent arterioles, and of the peritubular capillary networks arising from them, varies markedly from one cortical region to another[37] (see Fig. 3-8 ). This intracortical heterogeneity may have important physiologic consequences. Indeed, some functional characteristics of the cortical circulation suggest that at least three different circulations exist in parallel within the cortex (see “Intrarenal Blood Flow Distribution”).



FIGURE 3-8  Transmission electron micrographs of efferent arterioles. A, A vessel arising from a superficial glomerulus of a rabbit. The thick basal lamina frequently broadens to lakelike structures (*) underneath the endothelium. (Magnification ×2400.) B, A vessel derived from a juxtamedullary glomerulus in the rat. Note the many profiles of endothelial cells (*). (Magnification ×1800.)  (Adapted from Kriz W, Kaissling B: Structural organization of the mammalian kidney. In Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. New York, Raven Press, 1985, p 281.)




In the outermost, or subcapsular, region of the cortex, the efferent arterioles give rise to a dense capillary network that surrounds the convoluted tubule segments arising from the superficial glomeruli (rectangle 1 in Fig. 3-7 ). There is evidence suggesting that this arrangement is of great importance for reabsorption of water and electrolytes in proximal tubule segments of superficial nephrons (see Chapter 9 ). In contrast, the efferent arterioles originating from the comparatively fewer juxtamedullary glomeruli (rectangle 4 in Fig. 3-7 ) extend into the medulla and give rise to the medullary microcirculatory patterns: an intricate capillary network in the outer medulla and long, unbranched capillary loops, the so-called vasa recta, in the inner medulla. More localized, inner cortical capillary networks may also arise from juxtamedullary glomeruli (rectangle 4 in Fig. 3-4 ). The arrangement of the medullary microcirculation plays an important role in the process of concentration of urine (see Chapter 9 ).



FIGURE 3-7  Diagram showing the vascular and tubule organization of the kidney in the dog. In the right-hand portion of the figure, nephrons arising from glomeruli in outer, middle, and inner cortex are shown to scale. Cortex (C), outer medulla (OM), and inner medulla (IM) are indicated. The left portion of the figure illustrates the pattern of glomeruli (G) arising from afferent arterioles (AA). The efferent vessels (EV) from these glomeruli divide to form the peritubular capillaries. At the kidney surface, proximal convoluted tubules (PCT) are associated with a dense capillary network arising from division of superficial efferent arterioles (rectangle 1). In the middle and inner cortex, convoluted tubule segments are located close to interlobular arteries and are perfused by a complex peritubular capillary network, usually derived from the efferent vessels of many glomeruli (rectangles 2 and 4). Midway between interlobular vessels, loops of Henle are grouped together with collecting ducts (CD). The peritubular capillary network of this region, derived from midcortical efferent arterioles, is largely oriented parallel to the tubular structures of the medullary ray (rectangle 3). In the inner or juxtamedullary cortex, glomeruli have efferent arterioles that extend downward and divide to form outer medullary vascular bundles (rectangle 4). A dense outer medullary capillary network arises from these bundles. Only thin limbs of Henle extend with collecting ducts to the papillary tip. These are accompanied by vasa recta extending from the cores of the vascular bundles. For simplicity, venous vessels have not been shown.  (Modified from Beeuwkes R III, Bonventre JV: Tubular organization and vascular tubular relations in the dog kidney. Am J Physiol 229:F695, 1975.)




Differences in wall structure are also observed when one compares the efferent arterioles of juxtamedullary glomeruli with those of other nephrons. Superficial and midcortical efferent arterioles are smaller in diameter than juxtamedullary vessels, [10] [15] [38] [39] and usually possess only one layer of smooth muscle cells ( Fig. 3-8A ). The larger juxtamedullary efferent arterioles (see Fig. 3-8B ) characteristically display two to four layers of smooth muscle cells. The endothelial layer consists of a large number of longitudinally arranged cells. [39] [40] Kriz and Kaissling[41] have described basal lamina material filling irregular, wide spaces between the smooth muscle and endothelial cell layers in efferent arterioles of both superficial and deep nephrons.

The complex microcirculatory architecture described, with its striking “vertical” heterogeneity, is further complicated by the existence of a “horizontal” heterogeneity: near the interlobular arteries, a dense capillary network, with no definable orientation, is formed by efferent arterioles and enmeshes both proximal and distal convoluted segments (see rectangles 2 and 4 in Fig. 3-7 ). However, when one examines the central portion of the lobule, in the region of the medullary rays (see Chapter 2 ), less dense capillary networks are found, most of them oriented parallel to the tubule structures with which they are associated, namely cortical segments of loops of Henle and collecting ducts (see rectangle 3 in Fig. 3-7 ). This variability in cortical efferent arteriolar branching patterns, whose physiologic significance is unknown, is further illustrated in Fig. 3-9 .



FIGURE 3-9  Photomicrographs of glomeruli and efferent vessels as observed in silicone-injected and cleared canine kidneys. A and B, Superficial cortex. Near the kidney surface, many glomeruli have long efferent arterioles that extend to, or nearly to, the surface before dividing (A). Other glomeruli located at the same cortical level are nearly obscured by the surrounding dense peritubular capillary network (B). The glomerulus is indicated by an arrow. C, D, and E, Midcortex. In the midcortex, most glomeruli are located near the interlobular arterioles. Although the peritubular capillary network often remains close to its parent glomerulus (C), many midcortical glomeruli have efferent arterioles that extend to perfuse the tubule structures of many nephrons in the medullary ray. Such efferent arterioles are long and simply branched (D and E). F, Inner cortex. In the inner, or juxtamedullary cortex, many glomeruli are associated with long efferent arterioles that divide in the outer medulla to form characteristic vascular bundles. Here, the contribution of two such efferent vessels to a vascular bundle is shown. Typically, such bundles are formed from efferent arterioles of 10 or more glomeruli. All panels are shown at approximately the same magnification. Scale bar in A equals 0.5 mm.  (Modified from Beeuwkes R: Efferent vascular patterns and early vascular-tubular relations in the dog kidney. Am J Physiol 221:1361, 1971.)




The cortical venous circulation also shows a high degree of regional variability. The most superficial cortex is drained, at least in humans, dogs, and cats, by way of the superficial cortical veins. [8] [10] [12] In middle and inner cortex, venous drainage is achieved mainly by the interlobular veins. The dense peritubular capillary network surrounding the interlobular vessels (see rectangles 2 and 4 in Fig. 3-7 ) drains directly into the interlobular veins through multiple connections, whereas the less dense, long-meshed network of the medullary rays (see rectangle 3 in Fig. 3-7 ) appears to anastomose with the interlobular network and thus drain laterally. The medullary circulation also shows two different types of drainage: the outer medullary networks typically extend into the medullary rays before joining interlobular veins, whereas the long vascular bundles of the inner medulla (vasa recta) converge abruptly and join the arcuate veins (see later section on medullary circulation).

Vascular-Tubule Relations

Diagrams of renal vascular and tubule organization in earlier textbooks often showed nephrons that were associated throughout their entire length with the postglomerular network arising from the same glomerulus. However, given the limited spatial extent and local venous drainage of cortical efferent networks, this description is now recognized as incorrect. The development of suitable double-injection techniques permitted vascular-tubule relationships to be defined in detail. [10] [35] [42] [43] In such studies, the blood vessels are injected with a colored silicone rubber. Then, after the tissue is cleared, selected nephrons in all cortical regions are injected with silicone materials of contrasting color. Because only single nephrons are made visible, their relationships to nearby peritubular capillaries can be evaluated. Vascular-tubule relationships on the kidney surface have also been defined by techniques based on conventional micropunc-ture, and such studies have yielded additional valuable information. [33] [44]

Cortical vascular-tubule relations have been described most completely in the canine kidney. [10] [35] [45] These studies show that, except for convoluted tubule segments in the outermost region of the cortex, the efferent peritubular capillary network and the nephron arising from each glomerulus are dissociated. In addition, even though many superficial proximal and distal convoluted tubules are perfused, at least in part, by pertitubular capillaries arising from the parent glomerulus of the same nephron, the loops of Henle of such nephrons, descending in the medullary ray, are perfused successively by blood emerging from many midcortical glomeruli through efferent arterioles that extend directly into the ray (see Fig. 3-7 ). The early divisions of such efferent arterioles probably supply only a small region of tubule, because typical networks extend only about 1 mm. Nephrons originating from midcortical glomeruli have proximal and distal convoluted tubule segments lying close to the interlobular axis in the region above the glomerulus of origin. This region is perfused by capillary networks arising from the efferents of more superficial glomeruli (see Fig. 3-7 ). It is in the inner cortex, however, that this dissociation between individual tubules and the corresponding postglomerular capillary network is most apparent (see Fig. 3-7 ). The convoluted tubule segments of these nephrons lie above the glomeruli, surrounded either by the dense network close to the interlobular vessels or by capillary networks arising from other inner cortical glomeruli.

In the human kidney, efferent vessel patterns and vascular-tubule relationships are similar to those of the dog. [42] [43] Vascular-tubule relationships in the superficial cortex of the rat have also been defined in micropuncture studies. In general, a close association between the initial portions of peritubular capillaries and early and late proximal tubule segments of the same glomerulus has been shown. [34] [46] [47] However, this close association does not mean that each vessel adjacent to a given tubule necessarily arises from the same glomerulus. In fact, Briggs and Wright[44] have found that, although superficial nephron segments and stellate vessels arising from the same glomerulus are closely associated, each stellate vessel may serve segments of more than one nephron. Thus, of 142 stellate vessels studied, only one third were entirely surrounded by convoluted tubule segments arising from a single nephron.

Peritubular Capillary Dynamics

The same Starling forces that control fluid movement across all capillary beds govern the rate of fluid movement across peritubular capillary walls. Because of a large drop in hydraulic pressure along the efferent arteriole, the oncotic pressure difference across the walls of peritubular capillaries exceeds the hydraulic pressure difference, thereby favoring fluid movement into the capillaries. The absolute amount of movement resulting from this driving force also depends on the peritubular capillary surface area available for fluid uptake and the hydraulic conductivity of the capillary wall. Values for the hydraulic conductivity of the glomerular capillaries far exceed those of all other microvascular beds measured thus far, including the peritubular capillaries. This difference is offset by the much larger total surface area of the peritubular capillary network. For detailed values, the reader is referred to Chapter 7 of the 7th Edition of this book.

The electron microscope shows that the endothelium of the peritubular capillary is fenestrated. In the rat, it has been estimated that approximately 50% of the capillary surface is composed of fenestrated areas.[38] Unlike the glomerular capillaries, peritubular capillary fenestrations are bridged by a thin diaphragm[38] that is negatively charged.[48] Beneath the fenestrae of the endothelial cells lies a basement membrane that completely surrounds the capillary. Glomerular and peritubular capillaries are distinguished, however, by the absence in the latter of an epithelial structure comparable to the glomerular podocyte. For the most part, peritubular capillaries are closely apposed to cortical tubules so that the extracellular space between the tubules and capillaries constitutes only about 5% of the cortical volume.[49] The tubular epithelial cells are surrounded by the tubular basement membrane, which is distinct from and wider than the capillary basement membrane. Numerous microfibrils connect the tubular and capillary basement membranes.[50] The function of these fibrils is uncertain, but as reviewed elsewhere,[51] they may help limit expansion of the interstitium and maintain close contact between the tubular epithelial cells and peritubular capillaries during periods of high fluid flux. Thus, the pathway for fluid reabsorption from the tubular lumen to the peritubular capillary is composed in series of the epithelial cell, tubular basement membrane, a narrow interstitial region containing microfibrils, the capillary basement membrane, and the thin membrane closing the endothelial fenestrae.[51]

Like the endothelial cells, the basement membrane of the peritubular capillaries possesses anionic sites.[48] The electronegative charge density of the peritubular capillary basement membrane is significantly greater than that observed in the unfenestrated capillaries of skeletal muscle and similar to that observed in the glomerular capillary bed. Although the function of the anionic sites in the peritubular capillaries is uncertain, by analogy to the glomerulus, it is likely that they are an adaptation to compensate for the greater permeability of fenestrated capillaries, allowing free exchange of water and small molecules while restricting anionic plasma proteins to the circulation. In fact, some workers have reported that the renal peritubular capillaries are more permeable to both small and large molecules than are other beds.[52] This conclusion is based on tracer studies in which the renal artery was clamped or the kidney removed before fixation. Because normal plasma flow conditions appear necessary for the maintenance of the glomerular permeability barrier,[53] it is likely that these high stop-flow peritubular permeabilities are also due to the unfavorable experimental conditions employed. Indeed, studies by Deen and associates[54] indicate that, at least under free-flow conditions, the permeability of these vessels to dextrans and albumin is extremely low.

Because the peritubular capillary uptake process is in series with all cellular mechanisms for tubule fluid reabsorption, it is ideally situated to modulate the rate of tubule fluid reabsorption. In fact, even the diameter or total number of functioning peritubular capillaries may be important in the regulation of proximal fluid reabsorption.[55] Typically, however, alterations in peritubular capillary hydraulic pressure or intracapillary oncotic pressure lead to major alterations in proximal tubule reabsorption. During volume expansion, the correlation between physical factors and proximal tubule fluid reabsorption is sufficiently strong that it is possible to model the reabsorptive mechanism as if transcapillary exchange were the only regulatory process involved, implying that peritubular capillary uptake is rate-limiting for reabsorption. However, a number of micropuncture and microperfusion studies indicate that alterations in peritubular capillary oncotic or hydraulic pressure do not always result in parallel changes in proximal tubule fluid transfer.[56] Furthermore, significant changes in proximal reabsorption may occur in the absence of detectable variations in Starling forces (i.e., direct inhibition of ion pumps in epithelia).

In actuality, the interaction between blood vessel and tubule is undoubtedly quite complex. Ott and colleagues[57] determined that the state of hydration affected the ability of peritubular capillary oncotic pressure to alter proximal reabsorption. They found that increasing oncotic pressure increased proximal reabsorption in volume-expanded animals but not in hydropenic animals. This finding is consistent with a model of proximal tubule function that envisions the magnitude of back-leakage, into the tubule lumen, of fluid originally transported into the intercellular spaces as an important factor in the control of net proximal reabsorption.[58] During volume expansion, decreasing capillary uptake leads to increased hydraulic pressure in the interstitial space between the tubules and the peritubular capillaries. Increased renal interstitial pressure would, in turn, reduce fluid flux out of the lateral intercellular spaces. In contrast, during hydropenia, transport of solute into the lateral intercellular spaces might be reduced to the point at which changes in oncotic pressure would have little effect on proximal reabsorption. In fact, a variety of studies support an association between renal interstitial pressure and Na excretion,[59] although some investigators have suggested that the augmenting effect of increased interstitial pressure on Na excretion depends on sites distal to the proximal tubule. Haas and colleagues[60] reported that only proximal tubules of deep nephrons were sensitive to changes in renal perfusion pressure, suggesting that these nephrons may be more responsive to changes in interstitial pressure.

More recently, Granger and co-workers[61] suggested that alterations in cortical interstitial pressure may be a major determinant of capillary uptake in settings where the oncotic pressure gradient across the capillary wall is absent or low. This occurs experimentally in isolated kidneys perfused with colloid-free solutions[62] or when interstitial pressure is artificially reduced by exposing the kidney to subatmospheric pressure,[63] and in vivo in older animals in which interstitial protein concentration and oncotic pressures approach plasma levels.[64] In these settings, peritubular capillary uptake of fluid persists despite the absence of a significant oncotic pressure gradient. Evidence suggests[61] that the interstitial hydrostatic pressure rises in this setting, possibly as a result of ongoing transport of solute into the peritubular interstitium, which has limited ability to expand due to the presence of the microfilaments described above that bridge that space. Increased interstitial pressure creates a favorable hydrostatic pressure gradient for fluid movement into the capillary, which also does not collapse due to the same cytoskeletal support system.

Because the peritubular capillaries that surround a given nephron are derived from many efferent vessels, regulatory processes related to capillary factors need not be viewed as a mechanism only for balancing filtration and reabsorption in a single nephron. Instead, assuming that capillary dynamics throughout the cortex are the same as has thus far been defined for the microcirculation of the superficial cortex, we may consider that, within broad regions of the cortex, all tubule segments are surrounded by capillary vessels that are operating in a similar reabsorptive mode. Thus, the function of the cortex as a whole may reflect the average reabsorptive capacity of all cortical peritubular vessels. This is obviously a first approximation. For further discussion of the factors that regulate proximal tubule fluid reabsorption, the reader is referred to Chapter 5 .

Medullary Microcirculation

Vascular Patterns

The precise location of the boundary between the renal cortex and medulla is difficult to discern because the medullary rays of the cortex merge imperceptibly with the medulla. In general, the sites at which the interlobular arteries branch into arcuate arteries, or the arcuate arteries themselves, mark this boundary. When considering the medullary circulation, most focus on its relation to the countercurrent mechanism as facilitated by the parallel array of descending and ascending vasa recta. However, although this configuration is characteristic of the inner medulla, the medulla also contains an outer zone, which contains two morphologically distinct regions, the outer and inner stripes (Figs. 3-10 and 3-11 [10] [11]). The boundary between the outer and inner medullary zones is defined by the beginning of the thick ascending limbs of Henle.[65] In addition to the thick ascending limbs, the outer medulla contains descending straight segments of proximal tubules (pars recta), descending thin limbs, and collecting ducts (see Fig. 3-11 ). The inner stripe of the outer medulla is the region in which thick ascending limbs overlap with thin descending limbs. Each of these morphologically distinct medullary regions is supplied and drained by an independent, specific vascular system.



FIGURE 3-11  Three populations of nephrons based on location of their glomeruli are depicted schematically: superficial (SF), midcortical (MC), and juxtamedullary (JM) nephrons. The major nephron segments are labeled as follows: ATLH, ascending thin limb of Henle; CCT, cortical collecting tubule; CS, connecting segment; CTALH, cortical thick ascending limb of Henle; DCT, distal convoluted tubule; DTLH, descending thin limb of Henle; ICT, initial collecting tubule; IMCT, inner medullary collecting tubule; MTALH, medullary thick ascending limb of Henle; OMCT, outer medullary collecting tubule; PCD, papillary collecting duct; PCT, proximal convoluted tubule; PR, pars recta. Transport characteristics of these segments are discussed in the text.  (From Jacobson HR: Functional segmentation of the mammalian nephron. Am J Physiol 241:F203, 1981.)




The blood supply of the medulla is entirely derived from the efferent arterioles of the juxtamedullary glomeruli. [8] [14] [35] [66] Infrequent aglomerular vessels mark sites where corresponding glomeruli have degenerated.[67]Depending on the species and the method of evaluation, it has been estimated that from 7% to 18% of glomeruli give rise to efferents that ultimately supply the medulla. [66] [68] As already discussed, efferent arterioles of juxtamedullary nephrons are larger in diameter and possess a thicker endothelium and more prominent smooth muscle layer than arterioles originating from superficial glomeruli. [39] [40] [41] In the rat, cat, and dog, afferent arterioles supplying juxtamedullary glomeruli also differ and are distinguished by the presence, at their origins from the interlobular arteries, of intra-arterial “cushions,” smooth muscle cell-like structures that protrude into the lumen of the vessel.[69] These structures are not found in a variety of other mammalian species, including humans.[8] Although their function is unknown, these cushions are ideally located to regulate blood flow to the deeper medullary structures.

Although the vasculature of the outer medulla displays both vertical and lateral heterogeneity, in general, both the outer and inner stripes contain two distinct circulatory regions. These are the vascular bundles, formed by the coalescence of the descending and ascending vasa recta, and the interbundle capillary plexus. The descending vasa recta arise from the efferent arterioles and descend through the outer stripe of the outer medulla to supply the inner stripe of the outer medulla and the inner medulla (see Fig. 3-10 ). Within the outer stripe, the descending vasa recta also give rise, via small side branches, to a complex capillary plexus. Early studies suggested that this capillary network was limited and, therefore, not the main blood supply to this region. Instead, it was thought that nutrient flow was provided by the ascending vasa recta rising from the inner medulla and the inner stripe. This was further suggested by the large area of contact between ascending vasa recta and the descending proximal straight tubules within this zone ( Fig. 3-12 ). [38] [68] [70] Using resin casting and scanning electron microscopy, Yamamoto and co-workers[71] visualized a dense capillary network perfusing the entire outer medulla.



FIGURE 3-10  Longitudinal section of kidney of the sand rat (Psammomys obesus) after arterial injection of Microfil silicone rubber and clearing. A, The low-power magnification reveals distinct zonation of the kidney (c, cortex; OS and IS, outer and inner stripes of the outer medulla, respectively; IZ, inner medulla). The inner medulla is long and extends a short distance below the bottom of the picture. Giant vascular bundles, including a mixture of descending and ascending vasa recta, traverse the outer medulla to supply blood to the inner medulla. B, The outer medulla at a higher magnification. Between the vascular bundles (three are visible), a rich capillary plexus (asterisk) supplies the tubule segments present in this zone.  (From Bankir L, Kaissling B, de Rouffignac C, Kriz W: The vascular organization of the kidney of Psammomys obesus. Anat Embryol 155:149, 1979.)






FIGURE 3-12  Electron micrograph showing cross sections of both outer stripe and inner stripe of outer medulla and a cross section of inner medulla. C, collecting duct; P, pars recta; S and L, thin descending limbs of short and long loops, respectively; T, thick ascending limb. Triangles indicate arterial descending vasa recta; asterisks indicate venous ascending vasa recta. In the outer stripe, note the large area of contact between ascending vasa recta and pars recta and the paucity of interstitial space. In the inner stripe, part of a vascular bundle is shown in the upper right half of the photograph, and the interbundle region is shown in the lower half. Note that the thin descending limbs of short loops are surrounded by venous vasa recta ascending from the inner medulla. The wall of these vessels adapts to available space between the descending vasa recta and the thin limbs, offering a large area of contact with these descending structures. Thin limbs of long loops lie in the interbundle region and are surrounded by vessels belonging to the interbundle capillary plexus. In the inner medulla, note abundant interstitium surrounding all tubule and vascular structures. Walls of tubules and vessels are not in direct contact. (Outer stripe is from rabbit kidney; inner stripe and inner medulla are from rat kidney.) Bar is approximately 30 (mm).  (Adapted from Bankir L, de Rouffignac C: Urinary concentration ability: Insights derived from comparative anatomy. Am J Physiol 249:R643, 1985.)




Within the inner stripe, the two vascular regions are even more easily identified (see Figs. 3-11 and 3-13 [11] [13]). The exact organization of the ascending and descending vasa recta within the vascular bundles displays significant interspecies variation (discussed later). The interbundle region contains the tubules, including the metabolically active thick ascending limbs. Nutrient and O2 supply to this energy-demanding tissue is by a dense capillary plexus arising from a few descending vasa recta at the periphery of the bundles. Approximately 10% to 15% of total renal blood flow is directed to the medulla, and of this probably the largest portion perfuses this inner stripe capillary plexus. Ultrastructurally, medullary capillaries resemble their counterparts within the cortex and consist of a flattened endothelium encased in a thin basal lamina. Fenestrations, which are bridged by a thin diaphragm, are regularly and densely distributed throughout the non-nuclear regions of the endothelial cells.[41]



FIGURE 3-13  Coronal section of a human kidney after arterial silicone injection and clearing. Complete injection of the renal vascular system enables the intense vascularity of the organ to be visualized. Although the renal papilla (arrow) has often been considered to be relatively poorly vascularized, this injection study shows that capillary density of the papilla is at least as great as that found in the cortex. (Actual size.)



The rich capillary network of the inner stripe drains into numerous veins, which, for the most part, do not join the vascular bundles but ascend directly to the outer stripe. These veins subsequently rise to the cortical-medullary junction as wide, wavy channels and the majority joins with cortical veins at the level of the inner cortex. A minority of the wavy veins may extend within the medullary rays to regions near the kidney surface. [8] [10] Thus, the capillary network of the inner stripe makes no contact with the vessels draining the inner medulla.

The inner medulla contains thin descending and thin ascending limbs of Henle, together with collecting ducts (see Fig. 3-11 ). Within this region, the straight, unbranching vasa recta descend in bundles, with individual vessels leaving at every level to divide into a simple capillary network characterized by elongated links.[68] These capillaries converge to form the venous vasa recta. Within the inner medulla the descending and ascending vascular pathways remain in close apposition, although distinct vascular regions can no longer be clearly discerned. The venous vasa recta rise toward the outer medulla in parallel with the supply vessels to join the vascular bundles. Thus, the outer medullary vascular bundles include both supplying and draining vessels of the inner medulla.[40] Within the outer stripe of the outer medulla, the vascular bundles spread out and traverse the outer stripe as wide, tortuous channels that lie in close apposition to the tubules, eventually emptying into arcuate or deep intertubular veins.[68] The venous pathways within the bundles are both larger and more numerous than the arterial vessels, suggesting lower flow velocities in the ascending (venous) than in the descending (arterial) direction. [72] [73] The importance of the close apposition of the arterial and venous pathways within the vascular bundles for maintaining the hypertonicity of the inner medulla is discussed in Chapter 9 .

The number of inner medullary vessels is large; studies show that the capillary volume fraction of the inner medulla is nearly twice that of the cortex. [9] [74] However, because of the long lengths and narrow diameters of these vessels, they can be filled by arterial injection only with great difficulty. If an injection is continued long enough, the intense vascularity of the inner medulla becomes apparent, as shown in Figure 3-14 .



FIGURE 3-14  Sagittal section of rat (A) and Mongolian gerbil (Meriones shawii) (B) kidneys after arterial injection with Microfil silicone rubber, showing deep cortex, outer and inner stripes of the outer medulla, and early inner medulla (from top to bottom of each micrograph, respectively). In the inner stripe, vascular bundles (arrowheads) alternate with interbundle capillary plexuses (asterisk). The functional separation between the two adjacent compartments is present in both species but is amplified in the desert-adapted Mongolian gerbil. Bar=600 (mm) (A) and 350 (mm) (B). (From Bankir L, Bouby N, Trinh-Trang-Tan MM: Organization of the medullary circulation: Functional implications. In Robinson RR (ed): Nephrology: Proceedings of the IXth International Congress of Nephrology. New York, Springer-Verlag, 1984, pp 84-106.)




Morphologists have recognized important differences in the structure of the ascending and descending vasa recta. The descending vasa recta possess a contractile layer composed of smooth muscle cells in the early segments that evolve into pericytes by the more distal portions of the vessels. Immunohistochemical studies demonstrate that these pericytes contain smooth muscle alpha-actin, suggesting that they may serve as contractile elements and participate in the regulation of medullary blood flow.[75] These vessels also display a continuous endothelium that persists until the hairpin turn is reached and the vessels divide to form the medullary capillaries. In contrast, ascending vasa recta, like true capillaries, lack a contractile layer and are characterized by a highly fenestrated endothelium. [76] [77] Although the precise functional role of these anatomic differences is not known, it is of interest that essentially identical morphologic patterns are found in the rete mirabile of the swim bladder of fishes, a structure that serves a countercurrent exchange function (gas exchange) quite independent of urine concentration. [78] [79]

Vascular-Tubule Relations

The mechanism of urine concentration requires coordinated function of the vascular and tubule components of the medulla (see Chapter 9 ). In species capable of marked concentrating ability, medullary vascular-tubule relations show a high degree of organization with at least three functionally distinct compartments, each favoring particular exchange processes by the juxtaposition of specific tubule segments and blood vessels. In addition to anatomic proximity, the absolute magnitude of these exchanges is greatly influenced by the permeability characteristics of the structures involved, which may vary significantly among species.[80] For a further discussion of the anatomic relations and permeability characteristics of various medullary structures as they relate to mechanisms of urine concentration, the reader is referred to Chapter 9 .

Most of our detailed knowledge of vascular-tubule relations within the medulla is based on histologic studies of rodent species. [14] [40] [41] [70] [71] [75] [81] In the inner medulla, descending and ascending vasa recta are interspersed with thin limbs of the loops of Henle in a homogeneous and apparently random manner (see Fig. 3-12 ). Although the relative number of these structures varies considerably among species, this overall organization of the inner medulla is well conserved. As already discussed, the inner stripe of the outer medulla contains two distinct territories, the vascular bundles and the interbundle regions (see Figs. 3-10, 3-12, and 3-14 [10] [12] [14]). In most mammals, the vascular bundles contain only closely juxtaposed descending and ascending vasa recta running in parallel. The tubule structures of the inner stripe, including thin descending limbs, thick ascending limbs, and collecting ducts, are found in the interbundle regions and are supplied by the dense capillary bed described earlier.[40] Commonly, the interbundle territory is organized with the long loops of the juxtamedullary nephrons lying closest to the vascular bundles. The shorter loops arising from superficial glomeruli are more peripheral and, therefore, closer to the collecting ducts. The vascular bundles themselves contain no tubule structures.

Medullary Capillary Dynamics

The functional role of the medullary peritubular vasculature is basically the same as that of cortical peritubular vessels. These capillaries supply the metabolic needs of the tissues near them and are responsible for the uptake and removal of water extracted from collecting ducts during the process of urine concentration. However, because the concentration process is based on the maintenance of a hypertonic interstitium, medullary blood flow must not only avoid washing out the solute gradient but also assist in its formation. These processes are discussed in detail in Chapter 9 .


Total renal blood flow in humans typically exceeds 20% of the cardiac output. For detailed discussion of methods of measurements, the reader is referred to Chapter 7 of the previous, 7th Edition of this book. Renal blood flow in women is slightly lower than in men, even when normalized to body surface area. Early clearance measurements by Smith[82] revealed that renal blood flow in women averaged 982 ± 184 (SD) mL/minute/1.73 m2 of body surface area. The wide range of normal in these subjects is illustrated by 95% confidence intervals encompassing a range between 614 and 1350 mL/minute/1.73 m2. In men, Smith found that normalized renal blood flow averaged 1209±256 (SD) mL/minute/1.73 m2. Later studies using other methods have consistently yielded measurements with similar means and wide ranges.[82] Amith found renal plasma flow averaged 592±153 mL/minute/1.73 m2 in women and 654±163 mL/minute/1.73 m2 in men.[83] In children between 6 months and 1 year of age, normalized renal plasma flow is approximately half that of adults, but it increases progressively and reaches the adult level at about 3 years of age.[84] After age 30, renal blood flow decreases progressively with age; at 90 years it is about half that at 20 years.[85]


Cortical Blood Flow

It has long been recognized that the perfusion rate in different regions of the kidney is not uniform, especially after trauma or hemorrhage.[86] Experimentally, the existence of several compartments having different flow rates has been recognized from the dispersion of transit times and uptake rates of injected indicators and the presence of multiple components in the washout curves of radioactive tracers. Accordingly, there has been much interest in determining whether differences in flow rate are associated with definable anatomic regions and whether correlations exist between renal blood flow distribution and renal function. Because the regions of interest lie within the interior of the organ, considerable experimental ingenuity has been required, and no single technique for estimating regional flow has yet become generally accepted. Furthermore, because of differences in observations made with different methods and under different experimental conditions, results have often been difficult to interpret. To date, no clear correlation between intrarenal blood flow distribution and renal function has been established. For a detailed discussion of methods of measurements, the reader is referred to Chapter 7 of the 7th Edition of this book.

Redistribution of Cortical Blood Flow

The redistribution of renal cortical blood flow has been extensively investigated using numerous different animal models. Studies of renal blood flow distribution after hemorrhage were among the first performed. They were provoked by the report of Trueta and colleagues[11] that, in shock states, renal blood flow appeared to be shunted through the medulla. This phenomenon, observed in qualitative studies of the distribution of India ink and radiographic contrast media, was subsequently termed “cortical ischemia with maintained blood flow through the medulla.”[87] Trueta's observations suggested a medullary bypass or shunt during hemorrhage or shock, including the rapid appearance of arterially injected contrast medium in the renal vein during systemic hypotension and the visible pallor of the superficial cortex at a time when radiographs showed considerable amounts of contrast medium in the outer medullary area.[11] Although 60 years have passed since Trueta's original proposal, only the qualitative observation of relative outer cortical ischemia with hemorrhage is accepted; neither the quantitative magnitude nor the mechanism of the flow redistribution associated with hemorrhage has been established.

Medullary Blood Flow

Medullary blood flow constitutes about 10% to 15% of total renal blood flow.[86] For detailed methods of measurements, the reader is again referred to the 7th Edition of this book. In terms of flow per unit tissue mass, estimates of outer medullary flow range from 1.3 to 2.3 mL/minute/g of kidney, inner medullary flow between 0.23 and 0.7 mL/minute/g, and papillary flow between 0.22 and 0.42 mL/minute/g. Although these medullary flows are less than one fourth as high as cortical flows, medullary flow is still substantial. Thus, per gram of tissue, outer medullary flow exceeds that of liver, and inner medullary flow is comparable to that of resting muscle or brain.[83] The fact that such large flows are compatible with the existence and maintenance of the inner medullary solute concentration gradient attests to the efficiency of countercurrent mechanisms in this region. Besides, the hematocrit in the vasa recta is approximately one half that of arterial blood.[88] Autoregulatory ability has been observed[89] and is discussed in more detail later. Medullary blood flow is highest under conditions of water diuresis and declines during antidiuresis.[90] This decrease depends, at least in part, on a direct vasoconstrictive action of vasopressin on the medullary microcirculation.[91] Acetylcholine,[92] Lameire,[88] vasodilator prostaglandins, [93] [94] kinins,[95] adenosine, [96] [97]atrial peptides, [98] [99] and nitric oxide[100] may increase, and angiotensin II,[101] vasopressin, [91] [102] endothelin,[103] and increased renal nerve activity[104] may decrease, medullary flow. The role of these hormones in normal physiology is still uncertain; however, alterations in medullary blood flow may be a key determinant of medullary tonicity and, thereby, solute transport in the loops of Henle. In addition, and reviewed by Mattson,[105] the medullary circulation may play an important role in the control of sodium excretion and blood pressure.


Vasomotor Properties of the Renal Microcirculations

Whether mediated by neural, humoral, or intrarenal physical factors, the regulation of the renal circulation ultimately depends on resistance changes resulting from the constriction or relaxation of vascular smooth muscle. The vessels up to and including the interlobular arteries contain smooth muscle in many layers, enclosed within elastic intimal and adventitial sheaths. Afferent arterioles contain less smooth muscle—only one or two layers—and lack intimal and adventitial laminae.[40] Near the glomerular pole, smooth muscle cells around the entire circumference of the arteriole are modified to form the granular cells of the juxtaglomerular apparatus. [106] [107] The hydraulic pressure within glomerular capillaries depends on afferent and efferent arteriolar resistances, increasing with selective efferent constriction or afferent dilation. Flow within the glomerular capillaries, on the other hand, is reduced by an increase in resistance of either vessel. As early as 1924, Richards and Schmidt[22] recognized the potential role of contractile elements in the control of glomerular capillary flow and pressure.

Functional proof of afferent and efferent vascular reactivity has come from micropuncture studies of glomerular dynamics. Click and colleagues[108] grafted renal tissue from neonatal hamsters into the cheek pouch of adult hamsters. Such grafts developed primitive glomerular circulations with visible afferent and efferent vessels. Local application of norepinephrine or angiotensin II by means of micropipettes resulted in clearly visible constriction of both vessel types. Afferent vessels responded more strongly to norepinephrine, whereas efferent vessels were more sensitive to angiotensin II.[108] This technique has also been used to demonstrate the presence of myogenic responses to alterations in extravascular pressure in afferent arterioles whereas efferent arterioles responded passively to changes in applied pressure.[109]

Steinhausen and co-workers[110] applied epi- and transillumination microscopic techniques to the split, hydronephrotic rat kidney. At 6 to 8 weeks after unilateral ureteral ligation, the tubule system had undergone atrophy; however, the vascular system remained relatively intact. The kidney was split at its large curvature, immobilized, and placed in a tissue bath. This preparation permits the arcuate artery, interlobular artery, afferent arteriole, and efferent arteriole to be visualized and studied in situ during perfusion with systemic blood. Changes in the diameter of these vessels have been measured in response to systemically or locally applied vasoactive substance. The effect of acute, intravenous infusion of angiotensin II on the pre- and postglomerular circulation was assessed. The diameter of the large, preglomerular vessels decreased in a dose-dependent fashion, with the interlobular artery displaying the greatest percent reduction. Significant but less constriction was observed in efferent arterioles. Studies in which perfusion pressure was held constant indicated that preglomerular constriction resulted primarily from receptor-mediated effects of angiotensin II on these vessels. When angiotensin II was infused chronically, an attenuated vascular response was observed. In other studies using this technique, dilation of the preglomerular vasculature has been observed during infusion of low doses of dopamine[111] and after administration of a Ca2+ channel blocker. [112] [113] Atrial peptide infused intravenously dilated the preglomerular vessels but caused postglomerular vasoconstriction.[104] Subsequently, Gabriels and co-workers[114] examined the effects of diadenosine phosphates, which bind to A1 and P2 purinoceptors, on afferent and efferent vessels using this technique. These agents induced transient constrictions that were more prominent in intralobular arteries and afferent arterioles than in efferent arterioles.

Loutzenhiser and co-workers [112] [113] [115] employed a modification of the hydronephrotic kidney technique in which the kidney is mounted and perfused in vitro to examine the response of the afferent arteriole to various stimuli. They[112] found that low concentrations of adenosine produced a vasodilation in afferent arterioles that had been previously constricted by exposure to pressure. They[115] also observed complex responses to prostaglandin E2 in this preparation, which elicited both vasodilator and vasoconstrictor responses in the afferent arteriole via different receptors. More recently, Loutzenhiser and co-workers[113] examined the kinetic aspects of the myogenic response in afferent arterioles by examining pressure-dependent vasoconstriction and vasodilation in this model. They found that high systolic pressures elicited a contractile response even when mean arterial pressure was reduced. These data suggest that the main role of the afferent arteriolar constriction is to protect the glomerular capillary bed from increases in pulse pressure, rather than autoregulation per se.

In vitro perfusion of rat kidney has also been utilized to assess segmental vascular reactivity directly in the juxtamedullary nephrons that lie in apposition to the pelvic cavity.[116] To expose these nephrons, the perfused kidney is removed and bisected along its longitudinal axis. The intact papilla, left on one half of the kidney, is lifted back, exposing the pelvic mucosa, which is then removed to reveal the underlying vessels. Applying epifluorescence videomicroscopy to these structures, the inside diameters of the various renal vascular segments can be determined.[116] The effects of angiotensin II on segmental diameters as measured by this technique are shown in Figure 3-15(Top). Angiotensin II reversibly decreased the diameters of both pre- and postglomerular vessels. The estimated effects of the alterations in vessel caliber on segmental resistance are summarized in Figure 3-15 (Bottom). This analysis suggests that despite the large changes in arcuate and interlobular artery diameter, the majority of the increase in resistance occurs near the glomerulus. This is due to the fact that equivalent changes in diameter elicit greater effects on resistance in smaller than in larger vessels.[117]



FIGURE 3-15  Effect of angiotensin II on the blood-perfused juxtamedullary nephron microvasculature. Top, Vessel inside-diameter responses to angiotensin II (AII). Each line denotes observations of a single vessel segment during control, angiotensin II, and recovery periods. Bottom, Estimation of angiotensin II-induced changes in segmental vascular resistance, calculated from data in upper panel. **P<.01.  (From Navar LG, Gilmore JP, Joyner WL, et al: Direct assessment of renal microcirculatory dynamics. Fed Proc 45:2851, 1986.)




In fact, the exact anatomic distribution of preglomerular vascular resistance has been a matter of debate. Initially, it was assumed that resistance at the level of the afferent arteriole was responsible for the entire pressure drop from the aorta to the glomerular capillaries. However, subsequent data obtained using a variety of other techniques suggests that this is not correct. Interlobular arteries respond to changes in perfusion pressure[118] and to a broad spectrum of vasoactive substances in vivo [110] [111] and in vitro. [119] [120] [121] [122] Examination of vascular casts suggests that even interlobar arteries may be involved.[123] Direct measurements of interlobular artery pressure indicate that the afferent arteriole accounts for approximately 50% of preglomerular vascular resistance.[124] In fact, hydraulic pressure has been observed to decline in a continuous manner from the arcuate artery to the distal afferent arteriole in the split hydronephrotic kidney preparation,[125] which allows visualization and direct puncture of the entire renal vascular tree. These data are also consistent with findings in other vascular beds.[126]

Edwards developed an in vitro technique to study the reactivity of isolated segments of interlobular arteries and superficial afferent and efferent arterioles dissected from rabbit kidneys.[119] All three types of vessels responded with a dose-dependent decrease in luminal diameter when norepinephrine was added to the system. In contrast, only efferent arteriolar segments showed a similar dose-dependent vasoconstriction in response to angiotensin II. The reasons for the differences between the sites of action of angiotensin II shown by this technique and those shown by the techniques described earlier are uncertain. The isolated vessel technique has also been utilized to assess the renal vascular reactivity to a variety of vasodilator substances. [120] [121] As shown in Figure 3-16 , dopamine, acetylcholine, and prostaglandins E2 and I2 (prostacyclin) all dilate the afferent arteriole of the rabbit, whereas bradykinin, adenosine, and prostaglandins D2 and F do not. The efferent arteriole dilated in response not only to dopamine, acetylcholine, and prostacyclin but also to bradykinin and adenosine. Prostaglandins E2, D2, and F had no effect on this vessel.



FIGURE 3-16  Relaxation response of afferent (top) and efferent (bottom) arterioles to acetylcholine (ACh), dopamine (DA), bradykinin (BK), adenosine (ADO), and prostaglandins (PGE2, PGI2, PGD2, and PGF). Tone was induced with 3×107 M norepinephrine. Numbers in parentheses represent numbers of arterioles.  (From Navar LG, Gilmore JP, Joyner WL, et al: Direct assessment of renal microcirculatory dynamics. Fed Proc 45:2851, 1986.)




Ito and colleagues[127] developed an in vitro approach to study changes in preglomerular resistance using the isolated perfused afferent arteriole with its glomerulus attached. Angiotensin II and endothelin produce afferent arteriolar constriction in this preparation that is modulated by nitric oxide.[128] The afferent arteriolar response to angiotensin II was also enhanced when the NaCl concentration at the macula densa was raised.[129] In contrast to angiotensin II, Ren and co-workers[101] found that angiotensin 1-7 induced dilation in afferent arterioles that was not mediated by either angiotensin II AT1 or AT2 receptors.

Numerous studies indicate that preglomerular vessels including the arcuate artery, interlobular artery, and afferent arteriole do constrict in response to exogenous and endogenous AII. [127] [130] [131] [132] [133] [134] The efferent arteriole, however, has a 10-fold to 100-fold greater sensitivity to AII. [130] [131] [133] The vasoconstrictor effects of AII are blunted by the endogenous production of vasodilators including the endothelium-derived relaxing factor nitric oxide as well as cyclooxygenase and cytochrome P450 epoxygenase metabolites in the afferent but not the efferent arteriole. [115] [127] [130] [135] [136] [137] [138] AII-simulated release of NO in the afferent arteriole occurs through activation of the AT1 receptors.[139] AII increases the production of prostaglandins in afferent arteriolar smooth muscle cells (both PGE2 and PGI2) and PGE2, PGI2, and cAMP all blunt AII-induced calcium entry into these cells[138] potentially explaining, at least in part, the different effects of AII on vasoconstriction of the afferent and efferent arteriole. [137] [138] PGE2 was with-out effect on AII-induced vasoconstriction of the efferent arteriole.[115]The effects of PGE2 on AII-induced vasoconstriction of the afferent arteriole are concentration-dependent with low concentrations acting as a vasodilator via interaction with prostaglandin EP4 receptors whereas high concentrations of PGE2 act on prostaglandin EP3 receptors to restore the AII effects in that segment.[115] While AII infusion alone has little effect on single nephron glomerular filtration rate (SNGFR) when combined with cyclooxygenase inhibition AII causes marked reductions in SNGFR as well as glomerular plasma flow rate (QA) suggesting an important role for endogenous vasodilatory prostaglandins in ameliorating the vasoconstrictor effects of AII.[140]Because AII increases renal production of vasodilatory prostaglandin production this may serve as a feedback loop to modulate the vasoconstrictor effects on AII under chronic conditions when the renin angiotensin system is stimulated.[18]

In addition to causing renal vasoconstriction, reduced blood flow, and glomerular capillary hypertension, AII causes a decrease in the glomerular ultrafiltration coefficient (Kf). [18] [140] [141] As discussed later in “Determinants of Glomerular Ultrafiltration” Kf is the product of the surface area available for filtration (S) and hydraulic conductivity of the filtration barrier (k) and is one of the primary determinants of SNGFR. A decrease in Kf induced by AII could be the result of either a decrease in S or k. As noted earlier, glomerular AII receptors are found on the mesangial cells, glomerular capillary endothelial cells, and podocytes. Because AII causes contraction of mesangial cells[142] one possibility is that contraction of the mesangial cells reduces effective filtration area by blocking flow through some glomerular capillaries but no direct evidence has been obtained that would support this hypothesis. Alternatively the AII-induced decrease in Kf could be the result of a decrease in hydraulic conductivity rather than a reduction in the surface area available for filtration.[141] A role for glomerular epithelial cells in the effects of AII on Kf is suggested by the fact that they possess both AT1 and AT2 receptors and respond to AII by increasing cAMP production.[143] Alterations in epithelial structure or the size of the filtration slits were not detected, however, following infusion of AII at a dose sufficient to decrease glomerular filtration rate (GFR) and Kf and increase blood pressure[144] and the mechanisms by which AII causes a reduction in Kf have not yet been determined.

Just as the renal vascular effects of AII are moderated by production of vasodilator prostaglandins and nitric oxide, AII-induced changes in Kf are also be affected by such substances. Endogenous prostaglandins help to prevent the reduction in Kf caused by AII.[140] The vasoconstrictive effect of AII on glomerular mesangial cells is markedly reduced by endothelial derived relaxing factor (EDRF, now known to be nitric oxide, NO—see later).[145] Mesangial cells co-incubated with endothelial cells have increased cGMP production induced by NO release from the endothelial cells resulting in decreased vasoconstrictive effects of AII, indicating that local NO production can modify the effects of agents such as AII.[145] Whether a similar effect would be observed for glomerular epithelial cells co-incubated with endothelial cells and whether either would translate into protection from AII-induced alterations on glomerular capillary surface area or hydraulic conductivity is not known but inhibition of NO production in the normal rat does produce a marked decrease in Kf. [145] [146] [147]

Arima and co-workers[148] examined angiotensin II AT2 receptor-mediated effects on afferent arteriolar tone. When the AT1 receptor was blocked, angiotension II caused a dose-dependent dilation of the afferent arteriole that could be blocked by disruption of the endothelium or by simultaneous inhibition of the cytochrome P-450 pathway. These data suggest that AT2 receptor vasodilation in efferent arterioles is endothelium-dependent, possibly via the synthesis of epoxyeicosatrienoic acids via a cytochrome P450 pathway, partially blocking the vasoconstrictor effects of AII. [148] [149]

Role of Endothelial Factors in the Control of Renal Circulation and Glomerular Filtration

Endothelial cells were once considered to be simple cells that passively lined the vascular tree. We now recognize that these cells produce a number of substances that can profoundly alter vascular tone, including vasodilator substances such as prostacyclin and the endothelium-derived relaxing factor, NO, as well as vasoconstrictor substances such as the endothelins. These factors play an important role in the minute-to-minute regulation of renal vascular flow and resistance.

Nitric Oxide

In 1980, Furchgott and Zawadzki[150] demonstrated that the action of the vasodilator acetylcholine required the presence of an intact endothelium to be vasorelaxant. The binding of acetylcholine and many other vasodilator substances to receptors on endothelial cells leads to the formation and release of an endothelial relaxing factor subsequently determined to be NO. [151] [152] NO is formed from L-arginine[153] by a family of enzymes that are encoded by separate genes called nitric oxide synthases (NOSs) that are present in many cells, including vascular endothelial cells, macrophages, neurons,[154] glomerular mesangial cells,[155] macula densa,[156] and renal tubular cells. Once released by the endothelium, NO diffuses into adjacent and downstream vascular smooth muscle cells,[157] where it activates soluble guanylate cyclase leading to cyclic guanosine monophosphate (cGMP) accumulation.[145] [158] [159] [160] [161] [162] Cyclic GMP reduces phosphatidyl inositol hydrolysis and calcium influx and intracellular calcium release, thereby reducing the amount of calcium available for contraction hence promoting relaxation.[163] In addition to stimulation by acetylcholine, NO formation in the vascular endothelium increases in response to bradykinin, [145] [164] [165] [166] [167] thrombin,[168] platelet activating factor,[169] endothelin,[170] and calcitonin gene-related peptide. [165] [171] [172] [173] Increased flow through blood vessels with intact endothelium or across cultured endothelial cells resulting in increased shear stress, also increases NO release [159] [164] [167] [174] [175] [176] [177] [178] and elevated perfusion pressure/shear stress increased NO release from afferent arterioles.[179] Both pulse frequency and amplitude modulate flow-induced NO release.[174]

In the kidney nitric oxide (NO) has numerous important functions including the regulation of renal hemodynamics, maintenance of medullary perfusion, mediation of pressure-natriuresis, blunting of tubuloglomerular feedback, inhibition of tubular sodium reabsorption, and modulation of renal sympathetic neural activity. The net effect of NO in the kidney is to promote natriuresis and diuresis.[180] Experimental studies also support the presence of an important interaction between NO, angiotensin II, and renal nerves in the control of renal function.[181] Renal hemodynamics are continuously affected by endogenous NO production as evidenced by the fact that nonselective NOS inhibition results in marked decreases in renal plasma flow rate (RPF), an increase in mean arterial blood pressure (AP), and generally a reduction in GFR. [182] [183] [184] These effects are largely prevented by the simultaneous administration of excess L-arginine.[182] Selective inhibition of neuronal NOS (nNOS or type I NOS), which is found in the thick ascending limb of the loop of Henle, the macula densa, and efferent arterioles, [156] [185] decreases GFR without affecting blood pressure or renal blood flow (RBF).[186] Because eNOS (endothelial NOS or type II NOS) is found in the endothelium of renal blood vessels including the afferent and efferent arterioles and glomerular capillary endothelial cells,[156] differences in the effects of inhibition of NO formation on RBF from generalized NOS inhibition versus specific inhibition of nNOS appear to be related to the distinct distribution of eNOS versus nNOS in the kidney. Both acute and chronic inhibition of NO production results in systemic and glomerular capillary hypertension, an increase in preglomerular (RA) and efferent arteriolar (RE) resistance, a decrease in Kf, and decreases in both QA and SNGFR. [146] [147] [187] [188] [189] These responses to NO inhibition are largely mediated through the actions of AII and endothelin. [127] [128] [187] [190] Administration of nonpressor doses of an inhibitor of NO formation through the renal artery yielded an increase in preglomerular resistance and a decrease in SNGFR and Kf but no effect on efferent resistance was observed unless systemic blood pressure increased.[147] These studies suggested that the cortical afferent, but not efferent, arterioles were under tonic control by NO. However, others have found that the renal artery, arcuate and interlobular arteries and the afferent and efferent arterioles have all been shown to produce NO and constrict in response to inhibition of endogenous NO production. [17] [127] [128] [130] [157] [191] [192] In agreement with this finding, other investigators [193] [194] have reported that NO dilates both efferent and afferent arterioles in the perfused juxtamedullary nephron.

Controversy exists regarding the role of the renin-angiotensin system in the genesis of the increase in vascular resistance that follows blockade of NOS. Studies of in vitro perfused nephrons[191] and of anesthetized rats in vivo[195]suggest that the increase in renal vascular resistance that follows NOS blockade is blunted when angiotensin II formation or binding is blocked. NO inhibits renin release while acute AII infusion increases cortical NOS activity and protein expression and chronic AII infusion increases mRNA levels for both eNOS and nNOS. [196] [197] AII increases NO production in isolated perfused afferent arterioles via activation of the AT1 AII receptors.[198] On the other hand, Baylis and colleagues[199] reported that inhibition of NOS in the conscious rats had similar effects on renal hemodynamics in the intact and angiotensin II-blocked state. This suggests that the vasoconstrictor response of NOS blockade is not mediated by angiotensin II. In a later study, workers in this laboratory[200] showed that when the angiotensin II level was acutely raised by infusion of exogenous peptide, acute NO blockade amplified the renal vascoconstrictor actions of angiotensin II. In agreement with this finding, Ito and co-workers[127] showed that intrarenal inhibition of NO enhanced angiotensin II-induced afferent, but not efferent, arteriolar vasoconstriction in the rabbit. Similar results have also been obtained in dogs.[135] These data suggest that NO modulates the vasoconstrictor effects of angiotensin II on glomerular arterioles in vivo in settings where angiotensin II levels are elevated.


Endothelin, a potent vasoconstrictor derived primarily from vascular endothelial cells, was first described by Yanagisawa and colleagues.[201] There are three distinct genes for endothelin, each encoding distinct 21 amino acid isopeptides termed ET-1, ET-2, ET-3. [201] [202] [203] Endothelin is produced following cleavage by endothelin converting enzyme of the 38-40 amino acid proendothelin which, in turn, is produced from proteolytic cleavage of prepro-endothelin (≈212 amino acids) by furin. [204] [205] ET-1 is the primary endothelin produced in the kidney including arcuate arteries and veins, interlobular arteries, afferent and efferent arterioles, glomerular capillary endothelial cells, glomerular epithelial cells, and glomerular mesangial cells of both rat and human [206] [207] [208] [209] [210] [211] [212] [213] [214] [215] [216] and acts in an autocrine or paracrine fashion or both[217] to alter a variety of biologic processes in these cells. Endothelins are extremely potent vasoconstrictors and the renal vasculature is highly sensitive to these agents.[218] Once released from endothelial cells, endothelins bind to specific receptors on vascular smooth muscle, the ETA receptors, that bind both ET-1 and ET-2. [217] [219] [220] [221] [222] ETB receptors are expressed in the glomerulus on mesangial cells and podocytes with equal affinity for ET-1, ET-2, or ET-3. [217] [219] [220] [223] [224] [225] There are two subtypes of ETB receptors, the ETB1 linked to vasodilation and the ETB2 linked to vasoconstriction.[226] An endothelin-specific protease modulates endothelin levels in the kidney.[227]

Endothelin production is stimulated by physical factors including increased shear stress and vascular stretch. [228] [229] In addition a variety of hormones, growth factors, and vasoactive peptides increase endothelin production including transforming growth factor-β, platelet-derived growth factor, tumor necrosis factor-α, angiotensin II, arginine vasopressin, insulin, bradykinin, thromboxane A2, and thrombin. [206] [207] [211] [213] [216] [230] [231] [232] [233]Endothelin production is inhibited by atrial and brain natriuretic peptides acting through a cyclic GMP-dependent process[227] and by factors that increase intracellular cyclic AMP and protein kinase A activation such as β-adrenergic agonists.[211]

Typically, intravenous infusion of ET-1 induces a marked, prolonged pressor response [201] [234] accompanied by increases in preglomerular and efferent arteriolar resistances and a decrease in renal blood flow and GFR.[234]Infusion of subpressor doses of ET-1 also decreases whole kidney and single nephron GFR and blood flow, [235] [236] [237] [238] [239] again accompanied by increases in both preglomerular and postglomerular resistances and filtration fraction. [235] [239] [240] Vasoconstriction of afferent and efferent arterioles by endothelin has been confirmed in the split, hydronephrotic rat kidney preparation [241] [242] and in isolated perfused arterioles. [128] [131] [243] In both micropuncture[239] and isolated arteriole[131] studies, the sensitivity and response of the efferent arteriole exceeded those of the afferent vessel. Endothelin also causes mesangial cell contraction. [244] [245] Finally, other studies have suggested that the vasoconstrictor effects of the endothelins can be modulated by a number of factors [221] [246] including endothelium-derived relaxing factor,[128] bradykinin,[247] and prostaglandin E2[248] and prostacyclin. [248] [249]

There are multiple endothelin receptors; most is known about the ETA and ETB receptors, which have been cloned and characterized. [220] [250] [251] According to the traditional view, ETA receptors, abundant on vascular smooth muscle, have a high affinity for ET-1 and play a prominent role in the pressor response to endothelin.[252] ETB receptors are present on endothelial cells where they may mediate NO release and endothelial-dependent relaxation.[251]However, the distribution and function of ETA and ETB receptors vary greatly among species and, in the rat, even according to strain. In the normal rat, both ETA and ETB receptors are expressed in the media of interlobular arteries, afferent and efferent arterioles. In interlobar and arcuate arteries only ETA receptors were present on vascular smooth muscle cells.[253] ETB receptor immunoreactivity is sparse on endothelial cells of renal arteries, while there is strong labeling of peritubular and glomerular capillaries as well as vasa recta endothelium.[253] ETA receptors are evident on glomerular mesangial cells and pericytes of descending vasa recta bundles.[253] In the rat, endogenous endothelin may actually tonically dilate the afferent arteriole and lower Kf via ETB receptors.[254] However, ETB receptors on vascular smooth muscle also mediate vasoconstriction in the rat and this is potentiated in hypertensive animals.[255]

Endothelin stimulates the production of vasodilatory prostaglandins [238] [249] [256] [257] [258] yielding a feedback loop to modify the vasoconstrictor effects of endothelin. ET-1, ET-2, and ET-3 also stimulate NO production in the arteriole and glomerular mesangium via activation of the ETB receptor. [128] [168] [170] [257] [259] Resistance in the renal and systemic vasculature are markedly increased during inhibition of nitric oxide production and these effects can be partially reversed by ETA blockade or inhibition of endothelin-converting enzyme, indicating the dynamic interrelationship between nitric oxide and endothelin effects. [260] [261] The vasoconstrictive effects of AII may be mediated, in part, by a stimulation of endothelin-1 production that acts on endothelin type A (ETA) receptors to produce vasoconstriction. [231] [232] Indeed chronic administration reduces renal blood flow, an effect prevented by administration of a mixed ETA/ETB receptor antagonist suggesting that endothelin contributes importantly to the renal vasoconstrictive effects of AII.[232]

Tubuloglomerular Feedback Control of Renal Blood Flow and Glomerular Filtration

The nephron is organized in a manner such that each tubule that leaves the glomerulus returns again to come in contact with it in a specialized nephron segment lying between the end of the thick ascending limb of the loop of Henle and the distal convoluted tubule. The specialized cells in this region are the known as the macula densa cells and they sit adjacent to the cells of the extraglomerular mesangium, which fill the space in the angle formed by the afferent and efferent arterioles of the glomerulus of the same nephron. This anatomical arrangement of macula densa cells, extraglomerular mesangial cells, vascular smooth muscle cells, and renin-secreting cells of the afferent arteriole, is known as the juxtaglomerular apparatus (JGA). The JGA is ideally suited for a feedback system whereby a stimulus received at the macula densa might be transmitted to the arterioles of the same nephron to alter renal blood flow and glomerular filtration rate. Changes in the delivery and composition of the fluid flowing past the macula densa have now been shown to elicit rapid changes in glomerular filtration of the same nephron with increases in delivery of fluid out of the proximal tubule resulting in decreases in SNGFR and glomerular capillary hydraulic pressure (PGC) of the same nephron. [262] [263] This feedback between delivery of fluid to the macula densa and filtration rate, termed tubuloglomerular feedback, provides a powerful mechanism to regulate the pressures and flows that govern glomerular filtration rate in response to acute perturbations in delivery of fluid out of the proximal tubule.

Changes in delivery of Na+, Cl-, and K+ are thought to be sensed by the macula densa through the Na+/2Cl-/K+ cotransporter on the luminal cell membrane of the macula densa cells.[263] Alterations in Na+, K+, and Cl-reabsorption result in inverse changes in SNGFR and renal vascular resistance, primarily in the preglomerular vessels.[263] Agents such as furosemide that interfere with the Na+/2Cl-/K+ cotransporter in the macula densa cells inhibit the feedback response.[262] Evidence now indicates that adenosine and possibly ATP play a central role in mediating the relationship between Na+, Cl-, K+ transport at the luminal cell membrane of the macula densa and glomerular filtration rate of the same nephron. This is illustrated in Figure 3-17 adapted from Vallon.[264] According to this scheme increased delivery of solute to the macula densa results in concentration-dependent increases in solute uptake by the Na+/2Cl-/K+ cotransporter. This, in turn, stimulates Na+/K+-ATPase activity on the basolateral side of the cells leading to the formation of ADP and subsequent formation of adenosine monophosphate (AMP). Dephosphorylation of AMP by cytosolic 5′ nucleotidase or endo-5′ nucleotidase bound to the cell membrane yields the formation of adenosine.[264] AMP might also be be extruded into the interstium where it is converted to adenosine by ecto-5′ nucleotidases. According to the scheme shown in Figure 3-17 once adenosine leaves the macula densa cells or is formed in the adjacent interstitum it interacts with adenosine A1 receptors on the extraglomerular mesangial cells resulting in an increase in [Ca2+]i.[265] The increase in [Ca2+]i may occur via in part basolateral membrane depolarization through Cl- channel followed by Ca2+ entry into the cells via voltage-gated Ca2+ channels.[266] As indicated in Figure 3-17 gap junctions then transmit the calcium transient to the adjacent afferent arteriole leading to vasoconstriction and renin release.[264] Macula densa cells respond to an increase in luminal [NaCl] by releasing ATP at the basolateral cell membrane through ATP-permeable large conductance anion channels, possibly providing a communication link between macula densa cells and adjacent mesangial cells via purinoceptors receptors on the latter.[267]



FIGURE 3-17  Proposed mechanism of tubuloglomerular feedback (TGF). The sequence of events (numbers in circles) are (1) uptake of Na+, Cl-, and K+ by the Na+/2Cl-/K+ cotransporter on the luminal cell membrane of the macula densa cells; (2) intracellular or extracellular production of adenosine (ADO); (3) ADO activation of adenosine A1 receptors triggering an increase in cytosolic Ca2+ in extraglomerular mesangial cells (MC); (4) coupling between extraglomerular MC and granular cells (containing renin) and smooth muscle cells of the afferent arteriole (VSMC) by gap junctions allowing propagation of the increased [Ca2+]i resulting in afferent arteriolar vasoconstriction and inhibition of renin release. Local angiotensin II and nNOS activity modulate the response.  (Figure reproduced by permission from Vallon V: Tubuloglomerular feedback and the control of glomerular filtration rate. News Physiol Sci 18:169–174, 2003.)




Several lines of evidence support the role for adenosine in mediating tubuloglomerular feedback. Intraluminal administration of an adenosine A1 receptor agonist enhances the TGF response.[268] In addition tubuloglomerular feedback is completely absent in adenosine A1 receptor-deficient mice despite the fact that the animals had plasma renin activities that were twice normal. [269] [270] Blocking adenosine A1 receptors or by inhibition of 5′-nucleotidase reduce tubuloglomerular feedback efficiency and combining the two inhibitors nearly completely blocked tubuloglomerular feedback.[271] Addition of adenosine to the afferent arteriole causes vasoconstriction via activation of the adenosine A1 receptor and addition of an A1 receptor antagonist blocked both the effects of adenosine and of high macula densa [NaCl].[272] Of note, the effects only occur when adenosine is added to the extravascular space and do not occur when adenosine is added to the lumen of the macula densa.[272] These results are consistent with the proposed scheme in Figure 3-17 , which suggests that an increase in [NaCl] to the macula densa stimulates Na+/K+-ATPase activity leading to increased adenosine synthesis followed by constriction of the afferent arterioles via A1 receptor activation.[272]

Efferent arterioles preconstricted with norepinephrine vasodilate in response to an increase in [NaCl] at the macula densa, an effect blocked with adenosine A2 receptor antagonists but not by blocking the A1 receptor.[273] The changes in efferent arteriolar resistance are in opposite direction to that of the afferent arterioles, which vasoconstrict in response to increased [NaCl] at the macula densa. [272] [274] The net result would be decreased glomerular blood flow, decreased glomerular hydraulic pressure, and a reduction in SNGFR. Extracellular ATP attenuates the TGF system.[275]

The tubuloglomerular feedback (TGF) response is blunted by AII antagonists and AII synthesis inhibitors and is absent in knockout mice lacking either the AT1A angiotensin II receptor or angiotensin converting enzyme (ACE) and systemic infusion of AII in ACE knockout mice restores tubuloglomerular feedback. [276] [277] [278] [279] [280] AII enhances tubuloglomerular feedback via activation of AT1 receptors on the luminal membrane of the macula densa.[281] Acute inhibition of the AT1 receptor in normal mice blocked tubuloglomerular feedback and reduced autoregulatory efficiency.[278] These results indicate that AII plays a central role in modulating tubuloglomerular feedback and that this response is mediated through the AT1 receptor.

The macula densa is a site of immunocytochemical localization of neuronal nitric oxide synthase (nNOS or NOS 1).[282] Nitric oxide derived from nNOS in the macula densa provides a vasodilatory influence on tubuloglomerular feedback, decreasing the amount of vasoconstriction of the afferent arteriole than otherwise would occur. [282] [283] Increased distal sodium chloride delivery to the macula densa stimulates nNOS activity and also increases activity of the inducible form of cyclooxygenase (COX-2) to generate metabolites that also participate in counteracting TGF-mediated constriction of the afferent arteriole. [282] [284] Macula densa cell pH increases in response to increased luminal sodium concentration and may be related to the stimulation of nNOS.[285] Inhibition of macula densa guanylate cyclase increases the TGF response to high luminal [NaCl] further indicating the importance of NO in modulating TGF.[274] Ito and Ren, using an isolated perfused complete JGA preparation, found that microperfusion of the macula densa with an inhibitor of nitric oxide production led to constriction of the adjacent afferent arteriole.[286] When the macula densa was perfused with a low sodium solution, however, the response was blocked, indicating that solute reabsorption is required.[286] Microperfusion of the macula densa with the precursor of nitric oxide, L-arginine, blunts tubuloglomerular feedback, especially in salt depleted animals. [287] [288] [289] Thus it appears that the afferent arteriole acutely vasodilates in response to NO, blunting TGF. An increase in NO production may also inhibit renin release by increasing cGMP in the granular cells of the afferent arteriole,[290] thereby accentuating its vasodilatory effects. Of note, however, Schnermann and co-workers reported that when nitric oxide production is chronically blocked in knockout mice lacking nNOS tubuloglomerular feedback in response to acute perturbations in distal sodium delivery is normal.[276] They did observe, however, that the presence of intact nNOS in the JGA is required for sodium chloride-dependent renin secretion.[276] The tubuloglomerular feedback system, which elicits vasoconstriction and a reduction in SNGFR in response to acute increases in delivery to the macula densa, appears to secondarily activate a vasodilatory response. Stimulation of NO production in response to increased distal salt delivery under conditions of volume expansion would be advantageous by resetting tubuloglomerular feedback and limiting TGF-mediated vasoconstrictor responses.

Tubuloglomerular feedback responses might be temporally divided into two opposing events. The initial, rapid (seconds) tubuloglomerular feedback response would yield vasoconstriction and a decrease in GFR and PGC when sodium delivery out of the proximal tubule is acutely increased. The same increase in delivery would be expected with time (minutes) to decrease renin secretion, which in the face of a continued stimulus such as volume expansion, would reduce AII production and allow filtration rate to increase, thereby helping to increase urinary excretion rates. The rapid tubuloglomerular feedback system would prevent large changes in GFR under such conditions as spontaneous fluctuations in blood pressure that might otherwise occur, thereby maintaining tight control of distal sodium delivery in the short term.[276] Schnermann and co-workers hypothesized that the juxtaglomerular apparatus functions to maintain tight control of distal sodium delivery only for the short term.[276] Over the long term, renin secretion is controlled by the JGA in accordance with the requirements for sodium balance and the TGF system resets at a new sodium delivery rate.[276] The TGF system then continues to operate around this new setpoint. The resetting of the TGF system may thus be the result of sustained increases in GFR and distal delivery rather than the cause of the resetting. [276] [291] [292]

Renal Autoregulation

Many organs are capable of maintaining relative constancy of blood flow in the face of major changes in perfusion pressure. Although the efficiency with which blood flow is maintained differs from organ to organ (being most efficient in brain and kidney), virtually all organs and tissues, including skeletal muscle and intestine, exhibit this property, termed autoregulation. The ability of the kidney to autoregulate renal blood flow and glomerular filtration rate over a wide range of renal perfusion pressures was first demonstrated by Forster and Maes[293] and subsequently confirmed by others. [294] [295] Figure 3-18 shows typical patterns of autoregulation for the dog and rat kidney.



FIGURE 3-18  Autoregulatory response of total renal blood flow to changes in renal perfusion pressure in the dog and rat. In general, the normal anesthetized dog exhibits greater autoregulatory capability to lower arterial pressure than does the rat.  (From Navar LG, Bell PD, Burke TJ: Role of a macula densa feedback mechanism as a mediator of renal autoregulation. Kidney Int 22:S157, 1982.)




Autoregulation of blood flow requires parallel changes in resistance with changes in perfusion pressure. However, if efferent arteriolar resistance declined significantly when perfusion pressure was reduced, glomerular capillary pressure and GFR would also fall. Therefore, the finding that both renal plasma flow and GFR are autoregulated suggests that the principal resistance change is in the preglomerular vasculature. In support of this hypothesis, early micropuncture studies in the rat indicate that pressures in postglomerular surface microvessels remain relatively constant despite variations in perfusion pressure throughout the autoregulatory range. [296] [297] [298] [299] Subsequent studies using the Munich-Wistar rat, which has glomeruli on the renal cortical surface that are readily accessible to micropuncture, afforded an opportunity to observe the renal cortical microvascular adjust-ments that take place in response to variations in renal arterial perfusion pressure. Figure 3-19 summarizes the effects in the normal hydropenic rat of graded reductions in renal perfusion pressure on glomerular capillary blood flow rate, mean glomerular capillary hydraulic pressure (PGC), and preglomerular (RA) and efferent arteriolar (RE) resistance.[300] As shown in Figure 3-19 , graded reduction in renal perfusion pressure from 120 mm Hg to 80 mm Hg resulted in only a modest decline in glomerular capillary blood flow, whereas further reduction in perfusion pressure to 60 mm Hg led to a more pronounced decline. Despite the decline in perfu-sion pressure from 120 mm Hg to 80 mm Hg, values of PGC fell only modestly on average, from 45 mm Hg to 40 mm Hg. Further reduction in perfusion pressure from 80 mm Hg to 60 mm Hg resulted in a further fall in PGC (from 40 mm Hg to 35 mm Hg). Calculated values for RA and RE are shown in Figure 3-19 . The better autoregulation of glomerular capillary blood flow in the perfusion pressure range 80 mm Hg to 120 mm Hg was due to the more pronounced fall in RA than occurred in the lower range of perfusion pressure. Over the range of renal perfusion pressure from 120 mm Hg to 60 mm Hg, RE tended to increase slightly. In that study when plasma volume was expanded, RA declined while RE increased as renal perfusion pressure was lowered so that PGC and ΔP were virtually unchanged over the entire range of renal perfusion pressures.[300] In plasma-expanded animals, the mean glomerular transcapillary hydraulic pressure differ-ence (DP) exhibited nearly perfect autoregulation over the entire range of perfusion pressures because of concomitant increases in RE as RA fell.[300] These results indicate that autoregulation of GFR is the consequence of the autoregulation of both glomerular blood flow and glomerular capillary pressure.



FIGURE 3-19  Glomerular dynamics in response to reduction of renal arterial perfusion pressure in the normal hydropenic rat. As can be seen, glomerular blood flow (GBF) and glomerular capillary hydraulic pressure (000736   GC) remained relatively constant over the range of perfusion pressure examined, primarily as a result of a marked decrease in afferent arteriolar resistance (RA). RE, efferent arteriolar resistance.  (Adapted from Robertson CR, Deen WM, Troy JL, Brenner BM: Dynamics of glomerular ultrafiltration in the rat. III. Hemodynamics and autoregulation. Am J Physiol 223:1191, 1972.)




The medullary circulation has also been shown to possess autoregulatory capacity. [301] [302] Cohen and co-workers[89] demonstrated that vasa recta blood flow remained relatively constant for the pressure range 85 mm Hg to 125 mm Hg. Mattson and associates[303] reported that outer and inner medullary blood flow in rats decreased when perfusion pressure was reduced below 100 mm Hg. In contrast, simultaneously measured superficial and deep cortical blood flows were well autoregulated in this range. Thus, the autoregulatory range of the medulla may be narrower than that of the cortex and altered responses of the postglomerular circulation of deep nephrons to changes in perfusion pressure might account for this difference.

Preglomerular vessels including the afferent arterioles and vessels as large as the arcuate and interlobular arteries participate in the autoregulatory response. In the split, hydronephrotic rat kidney preparation, Steinhausen and co-workers[118] observed dilation of all preglomerular vessels from the arcuate to interlobular arteries in response to reductions in perfusion pressure from 120 mm Hg to 95 mm Hg. The proximal afferent arteriole did not respond to pressure changes in this range but did dilate when perfusion pressure was reduced to 70 mm Hg. The diameter of the distal afferent arteriole did not change at any pressure. Also consistent with an important role of large, preglomerular vessels in the autoregulatory response, Heyeraas and Aukland[304] reported that interlobular arterial pressure remained constant when renal perfusion pressure was reduced by 20 mm Hg, again suggesting that these vessels contribute importantly to the constancy of outer cortical blood flow in the upper autoregulatory range. A number of observations suggest that the major preglomerular resistor is located close to the glomerulus, at the level of the afferent arteriole. [99] [305] [306] [307] As in superficial nephrons, direct observations of perfused juxtamedullary nephrons revealed parallel reductions in the luminal diameters of arcuate, interlobular, and afferent arterioles in response to elevation in perfusion pressure. However, because quantitatively similar reductions in vessel diameter produce much greater elevations in resistance in small than in large vessels, the predominant effect of these changes is an increase in afferent arteriolar resistance.[308]

Renal Autoregulatory Mechanisms

Cellular Mechanisms Involved in Renal Autoregulation

Autoregulation of the afferent arteriole and interlobular artery is blocked by administration of L-type calcium channel blockers, inhibition of mechanosensitive cation channels, and a calcium-free perfusate. [309] [310] [311] [312] The autoregulatory response thus involves gating of mechanosensitive channels producing membrane depolarization and activation of voltage-dependent calcium channels leading to an increase in intracellular calcium concentration and vasoconstriction. [309] [313] [314] Indeed calcium channel blockade almost completely blocks autoregulation of renal blood flow. [315] [316] The autoregulatory capacity of the afferent arteriole is attenuated by intrinsic metabolites of the cytochrome P450 epoxygenase pathway while metabolites of the cytochrome P450 hydroxylase pathway enhance autoregulatory responsiveness.[317]

Autoregulation of both GFR and RBF occur in the presence of inhibition of nitric oxide but values for RBF were reduced at any given renal perfusion pressure as compared with control values. [183] [318] [319] [320] In the isolated perfused juxtamedullary afferent arteriole the initial vasodilatation observed when pressure was increased was of shorter duration when endogenous nitric oxide formation was blocked but the autoregulatory response was unaffected.[313] Cortical and juxtamedullary preglomerular vessels in the split hydronephrotic kidney also autoregulate in the presence of NO inhibition.[192] The majority of evidence therefore suggests that NO is not essential at least for the myogenic component of renal autoregulation, though nitric oxide may play a role in tubuloglomerular feedback (see later discussion).[193]

Several other vasoactive substances have been implicated in the autoregulation of renal blood flow, including various vasoactive eicosanoids, [321] [322] [323] kinins,[324] and the renin-angiotensin system [323] [325] but definitive evidence in favor of any of these is lacking. Kaloyanides and co-workers[326] found that autoregulation of renal blood flow and GFR persists when prostaglandin synthesis is inhibited. On the other hand, Schnermann and co-workers[323] have shown renal autoregulatory ability to be severely impaired by indomethacin infusion. Suppression of renin release by high-salt diets and administration of desoxycorticosterone also yielded conflicting results.[327]Although many studies have shown that angiotensin II plays an important role in regulating TGF mechanism, [280] [322] [328] intrarenal administration of angiotensin II antagonists has not been associated with impairment of renal blood flow autoregulation. [329] [330] [331] [332] [333]

As noted previously, autoregulation of renal blood flow is demonstrable in denervated and isolated organ preparations and is therefore thought to be independent of circulating humoral or neurogenic factors but governed instead by a mechanism or mechanisms intrinsic to the kidney. [299] [334] Several hypotheses have been proposed to account for this phenomenon including (1) a role for an intrinsic myogenic mechanism first proposed by Bayliss,[335] (2) a role for the tubuloglomerular feedback system, and (3) a role for a metabolic mechanism.

The Myogenic Mechanism for Autoregulation

According to the myogenic theory arterial smooth muscle contracts and relaxes in response to increases and decreases in vascular wall tension.[335] Thus, an increase in perfusion pressure, which initially distends the vascular wall, is followed by a contraction of resistance vessels, resulting in a recovery of blood flow from an initial elevation to a value comparable to the control level. Renal blood flow thus tends to remain relatively constant. This autoregulatory mechanism has also been proposed for other organs. [336] [337] Lush and co-workers [338] [339] presented a model of myogenic control of renal blood flow based on the assumption that flow remains constant when the distending force and the constricting forces, determined by the properties of the vessel wall, are equal. The constricting force is envisioned to have both a passive and an active component, the latter sensitive to stretch in the vessel.

Several lines of evidence indicate that such a myogenic mechanism is important in renal autoregulation. Autoregulation of renal blood flow is observed even when tubuloglomerular feedback is inhibited by furosemide suggesting an important role for a myogenic mechanism.[134] This myogenic mechanism of autoregulation occurs very rapidly, reaching a full response in 3 to 10 seconds.[134] Autoregulation occurs in all of the preglomerular resistance vessels of the in vitro blood-perfused juxtamedullary nephron preparation. [317] [340] [341] [342] [343] Of note the afferent arteriole in this preparation was able to constrict in response to rapid changes in perfusion pressure even when all flow to the macula densa was stopped by resection of the papilla indicating an important role for a myogenic mechanism in autoregulation.[340] Isolated perfused rabbit afferent arterioles respond to step increases of intraluminal pressure with a decrease in luminal diameter.[119] In contrast, efferent arteriolar segments showed vasodilation when submitted to the same procedure, probably reflecting simple passive physical properties. Autoregulation is also observed in the afferent arteriole and arcuate and interlobular artery of the split hydronephrotic kidney, [192] [309] [310] [311] [312] [313] [314] [315] [316] [317] [318] [319] [320] [321] [322] [344] but again the efferent arteriole did not autoregulate in this model.[192] Further evidence that the renal vasculature is indeed intrinsically responsive to variations in the transmural hydraulic pressure difference was obtained by Gilmore and co-workers[109] who provided direct evidence for myogenic autoregulation in renal vessels transplanted into a cheek pouch of the hamster. In this nonfiltering system, contraction of afferent but not efferent arterioles was observed in response to increased interstitial pressure in the pouch. However, it should be noted that, in vivo, efferent arteriolar resistance may increase in response to decreases in arterial pressure, [300] [345] and this may result from increased activity of the renin-angiotensin system. These data may also explain why autoregulation of GFR is more efficient than autoregulation of renal blood flow.

The autoregulatory threshold can be reset in response to a variety of perturbations. Autoregulation in the afferent arteriole is greatly attenuated in diabetic kidneys and may contribute to the hyperfiltration seen in this disease.[344]Autoregulation is partially restored by insulin treatment or by inhibition of endogenous prostaglandin production (or both).[344] Autoregulation in the remnant kidney is markedly attenuated 24 hours after the reduction in renal mass and is again restored by cyclooxygenase inhibition, suggesting that release of vasodilatory prostaglandins may be involved in the initial response to increase SNGFR in the remaining nephrons after acute partial nephrectomy.[346]Much higher pressures than normal are required to evoke a vasoconstrictor response in the afferent arteriole during the development of spontaneous hypertension.[347] The intermediate portion of the interlobular artery of the spontaneously hypertensive rat exhibits an enhanced myogenic response, with a lower threshold pressure and a greater maximal response.[310] Both the afferent arterioles and the interlobular arteries of the Dahl salt-sensitive hypertensive rat exhibit a reduced myogenic responsiveness to increases in perfusion pressure in rats fed a high-salt diet.[348] Thus, alterations in autoregulatory responses of the renal vasculature occur in a variety of disease states for the control of renal blood flow and glomerular ultrafiltration.

Autoregulation Mediated by Tubuloglomerular Feedback

The tubuloglomerular feedback (TGF) mechanism has been suggested as an alternative to the myogenic response to explain the autoregulation of renal blood flow and GFR. This system is envisioned to operate through the following sequence as described in detail later. Increased arterial pressure augments renal blood flow and glomerular capillary hydraulic pressure. These alterations cause GFR and therefore delivery of solute to the distal tubule to rise. Increased distal delivery is sensed by the macula densa, which activates effector mechanisms that increase preglomerular resistance, reducing renal blood flow, glomerular pressure, and GFR. A number of observations support this hypothesis. Perfusion of the renal distal tubule at increasing flows causes reduction in glomerular blood flow and GFR.[349] Furthermore, as reviewed by Navar and colleagues, [193] [307] a variety of experimental maneuvers that cause distal tubule fluid flow to decline or cease induce afferent arteriolar vasodilation and interfere with the normal autoregulatory response. In addition, Moore and Casellas[350] found that infusion of furosemide into the macula densa segment of juxtamedullary nephrons significantly abrogated the normal constrictor response of afferent arterioles to increased perfusion pressure. A similar observation was made by Takenaka and co-workers.[343] These studies suggested that the autoregulatory response in juxtamedullary nephrons was mainly dependent on the TGF mechanism.

To examine the mechanisms responsible for autoregulation, investigators have studied spontaneous oscillations in proximal tubule pressure and renal blood flow and the response of the renal circulation to high-frequency oscillations in tubule flow rates or renal perfusion pressure.[351] Oscillations in tubule pressure have been observed in anesthetized rats at a rate of about three cycles per minute.[352] These spontaneous oscillations do not correlate with changes in blood pressure,[352] can be induced by maneuvers that alter NaCl delivery to the macula densa,[352] vary from nephron to nephron, [353] [354] and are eliminated by loop diuretics,[355] findings consistent with the hypothesis that they are mediated by the TGF response. To examine this hypothesis, Holstein-Rathlou[351] induced sinusoidal oscillations in distal tubule flow in rats at a frequency similar to that of the spontaneous fluctuations in tubule pressure. Varying distal delivery at this rate caused parallel fluctuations in stop-flow pressure (an index of glomerular capillary pressure), probably mediated by alterations in afferent resistance, again consistent with dynamic regulation of glomerular blood flow by the TGF system. To investigate the role of this system in autoregulation, Holstein-Rathlou and colleagues[356] examined the effects of sinusoidal variations in arterial pressure at varying frequencies on renal blood flow in rats. Two separate components of autoregulation were identified, one operating at about the same frequency as the spontaneous fluctuations in tubule pressure (the TGF component) and one operating at a much higher frequency consistent with spontaneous fluctuations in vascular smooth muscle tone (the myogenic component). Subsequently, Flemming and co-workers[357] reported that renal vascular responses to alterations in renal perfusion pressure varied considerably depending on the dynamics of the change and that rapid and slow changes in perfusion pressure could have opposite effects. They suggested that slow pressure changes elicited a predominant TGF response, whereas rapid changes invoked the myogenic mechanism. Despite these observations, the conclusion that the TGF system plays a central role in autoregulation is complicated by several factors. First, there is the process of glomerulotubular balance, by which proximal tubule reabsorption increases as GFR rises. This mechanism would tend to blunt the effects of alterations in GFR on distal delivery. In addition, the persistence of autoregulatory behavior in nonfiltering kidneys[358] and in isolated blood vessels suggests that the delivery of filtrate to the distal tubule is not absolutely required for constancy of blood flow, at least in superficial nephrons. Consistent with this view, Just and colleagues [134] [359] demonstrated in the conscious dog that although TGF contributes to maximum autoregulatory capacity of renal blood flow, autoregulation is observed even when tubuloglomerular feedback is inhibited by furosemide suggesting an important role for a myogenic mechanism. Finally, it should be noted that the myogenic and TGF mechanisms are not mutually exclusive and Aukland and Hien[360] have proposed a model of renal autoregulation that incorporates both systems. Because the myogenic and TGF responses share the same effector site, the afferent arteriole, interactions between these two systems are unavoidable and each response is capable of modulating the other. The prevailing view is that these two mechanisms act in concert to accomplish the same end, a stabilization of renal function when blood pressure is altered.[361]

Autoregulation Mediated by Metabolic Mechanisms

The metabolic theory predicts that, given the relative constancy of tissue metabolism, a decrease in organ blood flow leads to local accumulation of a vasodilator metabolite, maintaining blood flow at or near its previous level. [360] [361] [362] [363] [364] Some investigators believe this mechanism is valid for the kidney as well.[362] A strong objection to this theory is related to the unique relationship between renal blood flow and renal metabolism.[365] The latter is determined mainly by Na reabsorption (see Chapter 4 ), which in turn is roughly proportional to GFR (glomerulotubular balance). Because it has been demonstrated in many species that GFR varies in proportion to renal blood flow under physiologic conditions, it follows that renal metabolism should also vary directly with renal blood flow. If it is true that some vasodilator metabolite plays a major role in the autoregulation of renal blood flow, then elevation in the latter would increase the production of the putative vasodilator, leading to further elevation in renal blood flow and rendering autoregulation of this parameter impossible.[365] Recent evidence indicates, however, that adenosine triphosphate (ATP) and its metabolites adenosine diphosphate (ADP) and adenosine have important effects on renal vascular smooth muscle and thus may provide a metabolic link to autoregulation.

Role of Purine Nucleotides in Autoregulation and Renal Hemodynamics

Adenosine Triphosphate

Navar[193] proposed that adenosine triphosphate (ATP) may function as a metabolic regulator tubuloglomerular feedback and autoregulation of renal blood flow. ATP is present in and required for the function of all cells. ATP is released from vascular smooth muscle cells and endothelial cells[366] as well as from ATP-releasing nerve fibers or “purinergic” nerve fibers. [366] [367] [368] When ATP is released from the nerves or other types of cells into the extracellular space it activates two types of purinoceptors, the P2X and the P2Y receptors, resulting in vasoconstriction. [322] [369] [370] [371] [372] Activation of P2X purinoceptors by ATP leads to increases in intracellular calcium concentration ([Ca2+]i) through an initial rapid influx through nonselective ligand-gated cation channels followed by sustained entry through opening of voltage-dependent L-type calcium channels. [369] [370] [373] [374] ATP also activates P2Y receptors lead-ing to activation of phospholipase C, formation of 1,4,5-trisphosphate, and mobilization of intracellular calcium stores promoting vasoconstriction. [369] [370] [373] [375] Superfusion with ATP leads to vasoconstriction of arcuate arteries, interlobular arteries, and the afferent arteriole with effects on the afferent arteriole being stronger and lasting longer than in the other vessels, but ATP does not constrict the efferent arteriole. [369] [371] [372] [374] [376] ATP promotes a transient vasoconstriction in the arcuate and interlobular arteries followed by a gradual return to control diameter.[374] In the afferent arteriole ATP induces a rapid initial vasoconstriction (vessel diameter ≈70% smaller than control) followed by a gradual relaxation to a final diameter still at least 10% smaller than control.[374] This suggests that the vasoconstrictor effects of ATP may be more prolonged in the afferent arteriole than in other preglomerular vessels. These results indicate a unique role for ATP in the selective control of preglomerular resistance.

Despite the ability of ATP to promote vasoconstriction when applied from the extravascular side of the blood vessel, [369] [371] [372] [374] [376] intrarenal infusion of ATP leads to renal vasodilatation rather than vasoconstriction. [162] [319] ATP from the luminal side of the blood vessel activates P2Y purinoceptors on vascular endothelial cells leading to increased synthesis and release of nitric oxide as well as stimulation of the production of prostacyclin resulting in vasodilatation. [162] [319] The net effect of ATP on renal vascular resistance in vivo may depend on whether the ATP is delivered from the blood side or the interstitial side, and NO and prostacyclin production stimulated by ATP in the endothelium may modulate any direct vasoconstrictive effects of this compound on the renal circulation. [369] [371] [372] [374] [376] Thus ATP serves as a metabolic regulator of renal blood flow and glomerular filtration rate. Majid and co-workers[318] found that infusion of ATP in large enough amounts to saturate the P2 purinergic receptors completely blocked autoregulation that was then fully restored adjustments in renal blood flow. Interstitial levels of ATP decrease with reductions in perfusion pressure, which would decrease ATP-induced preglomerular vasoconstriction.[377] These results thus suggest that ATP-mediated effects on autoregulation are significant.

Adenosine Diphosphate

Adenosine diphosphate (ADP) acts as a vasodilator by activating ATP-sensitive potassium (KATP) channels resulting in membrane hyperpolarization whereas ATP closes the channel leading to membrane depolarization. [378] [379] [380] When intracellular ATP levels are decreased and ADP concentrations are increased (such as inhibition of glycolysis) vasodilatation occurs [380] [381] suggesting that [ADP] and/or the ATP/ADP ratio plays a significant role in regulating renal vascular tone. Exogenous ADP does not affect the renal vasculature[380] but alterations in intracellular ADP concentrations may play an important role in modulating renal vascular resistance and glomerular ultrafiltration by its effects on the KATP channel. The vasodilatation induced by ADP is, at least in part, endothelium-dependent.[379] These data suggest a potential role for ADP in the metabolic control of renal hemodynamics and autoregulation but further studies are needed.


The metabolism of ATP generates the purinergic agonist adenosine, which binds to the P1 class of purinergic receptors that preferentially bind adenosine over ATP, ADP, or AMP. [366] [382] Four subtypes of membrane bound G protein-coupled adenosine receptors of the P1 class have been identified; the A1, the A, the A, and the A3 receptor. [366] [383] [384] Low levels of adenosine (nanomolar concentrations) activate A1 receptors resulting in inhibition of adenylate cyclase activity, mobilization of intracellular Ca2+, and vasoconstriction whereas activation of either type of A2 receptors by higher adenosine levels (micromolar concentrations) stimulates adenylate cyclase activity and promotes vasorelaxation. [384] [385] [386] [387] Adenosine-induced vasodilation of afferent arterioles occurs via activation of adenosine A2A receptors.[387] Intracellular adenosine formation is an important component in the macula densa cells for tubuloglomerular feedback control of glomerular filtration rate (see later) and thus is involved in that component of autoregulation. Delivery of solute to the macula densa cells increases Na+/2Cl-/K+ transport at the luminal cell membrane leading to increased basolateral Na+/K+-ATPase activity and the formation of ADP. Conversion of ADP to AMP by intracellular phosphodiesterase and subsequently to adenosine by intracellular 5′nucleotidase results in adenosine formation with subsequent effects on vascular tone and renin production of the adjacent arterioles as presented in the earlier discussion of tubuloglormerular feedback. An additional pathway leading to adenosine production is the transport of intracellular cAMP to the extracellular compartment leading to the production of adenosine by membrane bound ectophosphodiesterase and ecto-5′-nucleotidase. [384] [388] This extracellular adenosine may then directly regulate vascular tone through interaction with vascular adenosine receptors and indirectly affect tone by inhibition of renin release from juxtaglomerular cells via activation of A1 receptors,[389] the adenosine brake hypothesis, to block production of the vasoconstrictor AII. [384] [388] [390]

Intravenous infusion of adenosine results in a transient renal vasoconstriction followed by vasodilatation and an increase in RBF. [391] [392] The initial vasoconstriction is potentiated and the duration of the contraction prolonged by NO inhibition suggesting that at least a portion of the recovery from adenosine-induced renal vasoconstriction is mediated by increases in NO production[392] and indeed adenosine stimulates NO production in vascular endothelial cells.[386] Both A1 and A adenosine receptors are present in afferent and efferent arterioles and activation of the A1 receptor by low concentrations of adenosine results in vasoconstriction of these vessels whereas activation of the A receptors by high concentrations of adenosine results in vasodilatation. [112] [376] [393] [394] Selective blockade of the A receptors significantly augmented the vasoconstrictor response of the arterioles to adenosine indicating that adenosine-mediated vasoconstriction is modified by vasodilatory influences of adenosine A receptor activation.[393]

A1 adenosine receptors in the afferent arteriole are selectively activated from the interstitial side resulting in vasoconstriction suggesting a paracrine role for adenosine in the control of GFR.[391] Vasoconstriction of the afferent and efferent arterioles in response to addition of adenosine to the bathing solution is prevented by adenosine receptor blockade.[395] Adenosine concentrations in cortical and medullary interstitial fluid averaged 23 nm and 55 nm, respectively, in animals on a low (0.15%) sodium diet and increased markedly to 418 nm and 1040 nm in the cortex and medulla, respectively for rats on a high-salt (4%) diet.[396] High adenosine levels under conditions of a high-salt diet may contribute to a decrease in macula densa-mediated reductions in renin secretion.[397] Intravenous infusion of adenosine in conscious, healthy humans results in a decrease in GFR with only slight (non-significant) declines in renal plasma flow[398] whereas administration of a selective A1 antagonist produces increases in GFR[399] suggesting that under normal circumstances adenosine concentrations are low enough to activate the vasoconstrictor response via A1 receptors but activation of A2A receptors provides counteracting vasodilatation. Glomerular mesangial cells constrict in response to adenosine via A1 receptors.[265] Based on the effects of adenosine on the mesangial cell, an adenosine-induced decrease in GFR may be related, in part, to a decrease in the glomerular ultrafiltration coefficient (Kf). Specific adenosine A1 receptor antagonists block tubuloglomerular feedback-mediated reductions in glomerular pressure in response to increases in delivery of fluid out of the proximal tubule suggesting that at least part of the vasoconstrictor effect of adenosine is mediated through the tubuloglomerular feedback loop and thus might affect autoregulation.[400] Because of the link between local adenosine concentrations and the divergent hemodynamic responses that can result, adenosine plays an important role in the control of renal blood flow and glomerular filtration rate.

Other Factors Involved in Autoregulation

Studies have shown that endothelium-dependent factors might play a role in the myogenic response of renal arteries and arterioles to changes in perfusion pressure. For example, in 1992 Hishikawa and co-workers[401] reported that increased transmural pressure increased NO release by cultured endothelial cells. In addition, Tojo and co-workers[402] used histochemical techniques to demonstrate the presence of NOS in the macula densa, suggesting that NO also participates in the TGF response. More recent studies suggest that NO produced by the macula densa can dampen the TGF response.[287] In fact, studies have examined the role of this endothelial factor in the autoregulatory response. In dogs, inhibition of produc-tion of endothelium-dependent relaxing factor leads to an increase in blood pressure and a decline in basal renal vascular resistance; however, autoregulatory ability is unimpaired.[183] On the other hand, Salom and co-workers[403] reported that inhibition of NO production causes a greater decline in renal blood flow in the kidneys of rats perfused at hypertensive compared with normotensive pressure. This suggests that increased NO production might modulate the vasoconstrictor response to an increase in perfusion pressure. Consistent with this view are the data of Imig and co-workers,[404] who utilized the isolated perfused juxtamedullary nephron technique to examine the response of the preglomerular circulation to an increase in perfusion pressure in the presence and absence of NOS blockade. They found that pressure-induced contraction of the interlobular artery and afferent arteriole was enhanced when NO production was inhibited.

Elevations in transmural pressure also increase endothelin release by cultured endothelial cells and this was not altered by the presence of a calcium channel blocker, nifedipine, or a channel activator, gadolinium.[405] These findings suggest that endothelin, via a mechanism other than extracellular Ca2 influx, may play a role in pressure-induced control of renal blood flow. Of note, endothelin production is also stimulated by a rise in sheer stress.[229] However, infusions of endothelin produce a prolonged constrictor response that is ill suited to an autoregulatory role, [224] [225] [239] and there is little or no evidence linking this factor to the minute-to-minute control of renal vascular resistance in normal animals.

Other Hormones and Vasoactive Substances Controlling Renal Blood Flow and Glomerular Filtration


Processing of linoleic acid (an essential polyunsaturated fatty acid in the diet) by the liver yields arachidonic acid (AA) that is then stored in membrane phospholipids. Following interaction of a variety of hormones and vasoactive substances with their membrane receptors phospholipase A2 (PLA2) is activated resulting in the release of AA from the cell membranes, allowing the enzymatic action of cyclooxygenase to process arachidonic acid into prostaglandins (PG) PGG2 and subsequently PGH2. PGH2 is then converted into a number of biologically active prostaglandins including PGE2, prostacyclin (PGI2), PGF, PGE1, PGD2, and thromboxane (TxA2) (see Chapter 11 ).

PGE1, PGE2, and PGI2 are vasodilator prostaglandins that generally increase renal plasma flow yet produce little or no increase in GFR and SNGFR, in part due to a large decline in Kf. [406] [407] [408] PGE1 infusion yields little or no increase in SNGFR despite an increase in QA due to a large decline in Kf, with little or no change in 000736   or φA.[408] During blockade of endogenous prostaglandin production infusion of PGE2 or PGI2 induce large declines in SNGFR and QA accompanied by an increase in renal vascular resistance (particularly RE), increases in 000736   GC and 000736   , and a decline in Kf.[409] Additional blockade of AII receptors during cyclooxygenase inhibition yielded marked vasodilatation in response to PGE2 or PGI2 resulting in a return of SNGFR and QA equal to or greater than control values, a fall in PGC below control values, and a return of Kf to normal.[409] Thus, the renal vasoconstriction induced by exogenous PGE2 or PGI2 appears to be mediated by induction of renin and AII production. Vasodilatation at the whole kidney level resulting from PGI2 infusion during cyclooxygenase and AII inhibition has not always been observed.[410] Topical application (but not luminal) of PGE2 to the afferent arteriole increased the vasoconstrictive effect of AII and norepinephrine whereas PGI2 only attenuated norepinephrine-induced vasoconstriction.[411]PGE2 also constricted interlobular arteries but neither prostaglandin produced vasodilatation of vessels preconstricted by AII.[411] Indomethacin alone induced vasoconstriction of all pre- and postglomerular resistance vessels of superficial and juxtamedullary nephrons suggesting that vasodilatory prostaglandins normally modulate endogenous vasoconstrictors.[412] The combination of cyclooxygenase inhibition with an ACE inhibitor caused vasodilatation of pre- but not postglomerular vessels of the cortical nephrons due to the effects of continued NO production on preglomerular vessels.[412] These data taken together indicate that there could indeed be differences in the response to vasoactive prostaglandins between superficial and deep nephrons.


Systemic infusion of norepinephrine increases arterial blood pressure and induces vasoconstriction of the preglomerular vessels and the efferent arteriole, resulting in a decrease in QA but with unknown effects on Kf.[413] 000736   GCand 000736   increase with norepinephrine infusion, however, so that SNGFR is relatively unchanged.[413] Like angiotensin II, norepinephrine constricts the arcuate artery, the interlobular arteries, and the afferent and efferent arterioles as well as mesangial cells. [130] [133] [313] [411] [423] [414] Vasoconstriction of the afferent and efferent arterioles occurs via activation of α1 receptors.[415] This is partially counterbalanced, however, by activation of cycloxygensase-2 (COX-2) to increase production of the prostaglandins PGE2 and PGF.[414]

Antidiuretic Hormone

Antidiuretic hormone (ADH or arginine vasopressin, AVP) at low doses causes renal vasodilatation in the dog[416] whereas acute intravenous infusion of AVP in Munich-Wistar rats undergoing a chronic water diuresis does not change SNGFR or QA but markedly decreases Kf.[417] SNGFR was maintained despite the fall in Kf because of a decline in proximal tubule hydraulic pressure that resulted in a rise in ΔP. By contrast chronic administration of AVP or the V2 agonist dDAVP causes a large increase in GFR in the conscious rat in direct relationship with increases in urine osmolality suggesting possible renal vasodilatation, but glomerular dynamics were not studied in this model.[418] [419] [420] AVP-induced renal vasodilatation appears to be mediated by increased nitric oxide production [421] [422] and vasodilatory prostaglandins and a vasoconstrictor effect is unmasked when prostaglandin production is blocked.[423]

Arginine vasopressin has been shown to constrict afferent and efferent arterioles and mesangial cells by activating V1 subtype vasopressin receptors. [424] [425] [426] However, when afferent arterioles were pretreated with a V1receptor antagonist and constricted with norepinephrine, AVP caused vasodilatation, an effect blocked by a V2 receptor antagonist.[426] This suggests that AVP causes vasoconstriction through interaction with V1 receptors and causes vasodilatation through interaction with V2 receptors and both are present on the same vessel.[426]

Leukotrienes and Lipoxins

Leukotrienes are a class of lipid products formed from arachidonic acid following activation of the 5-lipoxygenase enzymes glutathione-S-alkyl-transferase and glutamyl transpeptidase.[427] Leukotrienes known to affect glomerular filtration and renal blood flow are leukotrienes C4 (LTC4), leukotriene D4 (LTD4), and leukotriene B4 (LTB4). LTC4 and LTD4 are potent vasoconstrictors[428] whereas LTB4 produces moderate renal vasodilatation and an increase in renal blood flow with no change in GFR in the normal rat.[429] Intravenous infusion of LTC4 increases renal vascular resistance leading to a fall in renal blood flow and GFR as well as a decrease in plasma volume and cardiac output. [430] [431] The decline in renal blood flow is partially but not completely reversed by saralasin (AII receptor antagonist) and indomethacin (inhibitor of cyclooxygenase), indicating (1) involvement of angiotensin II and cyclooxygenase products in the response to LTC4 and (2) an additional direct effect of LTC4 on the renal resistance vessels.[431] Similarly LTD4 induced a marked decrease in Kf, a rise in renal vascular resistance, particularly in RE, a fall in QA and SNGFR, and a rise in 000736   GC and 000736   during blockade of AII and control of renal perfusion pressure demonstrating a direct effect of this leukotriene on renal hemodynamics.[432]

Inflammatory injury also activates the 5-, 12-, and 15-lipoxygenase pathways in neutorphils and platelets to form acyclic eicosanoids called lipoxins (LX) of which there are two main types, LXA4 and LXB4.[433] The lipoxins produce diverse effects on renal hemodynamics. LXB4 and 7-cis-11-trans-LXA4 produce renal vasoconstriction.[434] By contrast intrarenal infusion of LXA4 induces a marked reduction in preglomerular hydraulic resistance (RA) without affecting RE, thereby resulting in an increase in 000736   GC and 000736   .[435] The specific vasodilatation of the preglomerular vessels by LXA4 was blocked by cyclooxygenase inhibition indicating that vasodilatory prostaglandins were responsible for this effect. [434] [435] Unique to this compound, LXA4 produced vasodilatation while simultaneously causing a reduction in Kf.[434] Because 000736   GC000736   , and QA were increased, however, SNGFR also increased.[435]

Platelet-Activating Factor

Platelet-activating factor (PAF) (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a phospholipid involved in allergic reactions and inflammatory processes.[436] In the kidney PAF is both produced and metabolized by glomerular mesangial cells.[437] Intrarenal infusion of low dose PAF results in renal vasodilatation and an increase in renal blood flow mediated through enhanced nitric oxide production. [169] [438] Higher intrarenal doses of PAF, by contrast, result in AII-independent renal vasoconstriction and a decrease in Kf resulting in declines in both SNGFR and QA. [437] [439] [440] These effects were blocked by inhibition of cyclooxygenase suggesting that PAF stimulates production of vasoconstrictor cyclooxygenase products such as thromboxane A2. Indeed concomitant administration of a thromboxane A2 receptor antagonist resulted in a PAF-induced increase in renal plasma flow and GFR.[439]PAF in picomolar concentrations causes vasodilatation of afferent arteriole through stimulation of NO production whereas nanomolar doses result in vasoconstriction.[440] PAF in nanomolar concentrations also constricts the efferent arteriole, an effect that is attenuated by pretreatment with indomethecin.[441] Possibly related to the PAF-induced decrease in Kf, PAF constricts mesangial cells, probably through increased production of thromboxane A2.[439]Endothelin increases PAF production by isolated glomeruli and blockade of PAF receptor binding prevents endothelin-induced renal vasoconstriction as well as endothelin-induced contraction of isolated glomeruli and mesangial cells, suggesting that PAF may be a mediator of the effects of endothelin.[442]


Acetylcholine is a potent vasodilator that increases renal blood flow without changing SNGFR. [403] [408] [443] The interlobular arteries and afferent and efferent arterioles vasodilate in response to acetylcholine and the effects can be prevented by muscarinic receptor antagonists. [120] [408] [443] As a consequence of the decrease in renal vascular resistance QA increased in response to acetylcholine in the rat as did ΔP (RA decreased more than RE so that 000736   GCand 000736   increased), yet SNGFR remained unchanged because of a marked decline in Kf.[408]

Acetylcholine-induced renal and systemic vasodilatation is mediated in part through the stimulation of NO production, [150] [172] [191] [313] [403] [444] [445] [446] enhanced production of vasodilatory prostaglandins, [166] [403] [447] and production of a putative endothelium-derived hyperpolarizing factor (EDHF) that hyperpolarizes adjacent vascular smooth muscle. [447] [448] [449] [450] [451] [452] [453] Figure 3-20 summarizes the mechanisms by which a number of vasodilators including acetylcholine and bradykinin might lead to vasodilatation. Acetylcholine acts on muscarinic receptors of the endothelium to increase endothelial intracellular [Ca2+]i leading to opening of Ca2+-activated K+channels and endothelial membrane hyperpolarization.[453] By way of myoendothelial gap junctions hyperpolarization of adjacent smooth muscle cells results in closure of voltage-gated Ca2+ channels, a decrease in [Ca2+]i, and vasodilatation. [452] [453] The increase in endothelial [Ca2+]i following stimulation of the muscarinic receptors also triggers the production of nitric oxide and prostanoids in the endothelium, which hyperpolarize the underlying smooth muscle by activation of ATP-sensitive K+ channels.[451] Thus acetylcholine can stimulate three endothelium-dependent vasodilatation pathways, the production of vasodilatory prostaglandins, the production of nitric oxide, and the production of EDHF.[454]



FIGURE 3-20  Potential mechanisms involved in endothelium-dependent vasodilatation in response to agonists such as acetylcholine, bradykinin, or ATP. Coupling of agonists to G-protein coupled receptors activates the beta isoform of protein kinase C (PKC-β) leading to the production of inositol 3,4,5, trisphosphate (IP3) with subsequent rapid release of intracellular calcium stores followed by increased calcium influx through store-operated calcium channels (SOC). Increased [Ca2+]i opens intermediate or small Ca2+-activated K+ channels (IKCa and/or sKCa, respectively) leading to endothelial cell membrane hyperpolarization. The hyperpolarization may activate K+IR channels, contributing to the hyperpolarization. Endothleial shear stress may also active these channels. Coupling of endothelial cell hyperpolarization to adjacent vascular smooth muscle cells through gap junctions may then close voltage-gated calcium channels (VGCC) leading to a fall in smooth muscle intracellular calcium concentration and vasodilatation. Agonist-induced increases in endothelial cell [Ca2+]i also increases production of NO and cyclooxygenase and epoxygenase-derived vasodilator compounds, which when combined with hyperpolarization, yields smooth muscle vasodilatation.  (Figure reproduced by permission from Jackson WF: Silent inward rectifier K+ channels in hypercholesterolemia. Circ Res 98:982–984, 2006.)





Bradykinin is a potent vasodilator that produces large increases in renal blood flow due to dilation of both the preglomerular blood vessels and the efferent arteriole mediated through the bradykinin B2 receptor. [408] [455] [456] [457]Although in the rat bradykinin had no significant effects on 000736   , the increase in QA that might be expected to increase SNGFR failed to do so because Kf fell to levels half of those seen in normal rats.[408] Figure 3-20 summarizes potential mechanisms of bradykinin-induced vasodilatation. Bradykinin stimulates inositol (1,4,5)-trisphosphate production and increased cytosolic free [Ca2+] in cultured mesangial cells, glomerular epithelial cells, and vascular endothelial cells. [314] [412] [458] [459] Subsequent activation of Ca2+-dependent potassium channels and activation of chloride channels leads to membrane depolarization and relaxation. [166] [460] [461] [462] Low concentrations of bradykinin induce vasodilatation of isolated afferent and efferent arterioles in the rat[120] mediated via bradykinin B2 receptors.[412] In the rabbit low concentrations of bradykinin (10-12 mol/L to 10-10 mol/L) dilate the afferent arteriole via B2 receptor activation while high concentrations (10-9 mol/L to 10-8 mol/L) result in vasoconstriction.[456] By contrast, high concentrations of bradykinin cause vasodilatation of the efferent arteriole in that species.[456]Vasoconstriction of the afferent arteriole to high concentrations of bradykinin appears to be mediated through vasoconstrictor prostanoids.[463] Bradykinin-induced vasodilatation of the afferent arteriole is mediated by cyclooxygenase vasodilator products including PGE2 and epoxyeicosatrienoic acids (EETs) via increased epoxygenase activity.[464] When the efferent arteriole is perfused in a retrograde fashion with bradykinin the response, acting through B2 receptors, is a dose-dependent vasodilatation that is independent of either NO or cyclooxygenase metabolites.[463] Instead the vasodilator effects in that segment under such conditions are mediated by cytochrome P450 metabolites, probably EETs.[463] In the absence of cyclooxygenase inhibitors bradykinin infused orthograde through the afferent arteriole induces the glomerular release of a vasoconstrictor (20-hydroxyeicosatetraenoic acid, 20-HETE) that blunts the vasodilator effects of bradykinin-induced release of EETs from the efferent arteriole and glomerulus.[465]


Chronic administration of glucocorticoid hormones increases glomerular filtration rate as a direct consequence of an increase in plasma flow since Kf, φA, and 000736   are unaffected. [466] [467] For cortisol renal vasodilatation involves stimulation of NO production.[467] Volume retention, tubuloglomerular feedback, and alterations in eicosanoid production do not appear to be involved in the renal response to glucocorticoids.[466]


Insulin, necessary for tissue glucose metabolism, is also a vasoactive hormone important in the regulation of blood pressure and glomerular filtration rate.[468] Insulin is a vasodilator in the systemic and renal vasculature, acting in part through a stimulation of nitric oxide formation. [469] [470] [471] [472] Vasodilatation in response to insulin can still take place during inhibition of nitric oxide synthesis, however and this effect is mediated in part through increased production of the metabolite adenosine.[473] In normal rats acute insulin infusion (during euglycoemic clamp) decreases preglomerular and efferent arteriolar resistance resulting in increases in QA, SNGFR, and 000736   .[474]

Early insulin-dependent diabetes is characterized by high rates of renal blood flow and glomerular filtration due, in part, to elevations in atrial natriuretic peptide and vasodilatory prostaglandins. [474] [475] Insulin administration in diabetic animals produces preglomerular vasoconstriction rather than the vasodilatation seen in normal animals resulting in decreases in QA000736   GC and 000736   , and SNGFR.[474] The increase in preglomerular resistance observed following insulin infusion in the diabetic animal could be related to a stimulation of vasoconstrictor prostaglandin (thromboxane A2) and endothelin production that might obviate any vasodilatory effects of insulin. [206] [474]

Insulin-Like Growth Factor

Insulin-like growth factor (IGF) is produced as two peptides hormones, IGF-I and IGF-II, which upon secretion, are >99% bound to IGF-binding proteins that regulate the bioavailability of IGFs.[476] IGF-1 is produced in several portions of the nephron including mesangial cells that also contain IGF-1 receptors. [476] [477] High dietary protein intake (which increases GFR) increases IGF-1 production and increases the bioavailability of the peptide, whereas decreased protein intake or fasting decrease IGF-1 production and increase binding protein levels.[476] The response to acute IGF-1 administration is vasodilatation of preglomerular blood vessels and the efferent arteriole leading to increases in GFR and RPF. [478] [479] [480] [481] [482] [483] Administration of IGF-1 to either non-starved (12h food restriction) or in rats with short-term starvation (60–72 h food restriction), which would have low levels of circulating IGF-1, resulted in increases in SNGFR and QA.[478] The increase in SNGFR was a consequence of the large increases in QA and a near doubling of Kf because 000736   GC and 000736   were unaffected by IGF-1.[478] Increases in vasodilatory prostaglandins and nitric oxide production combined with stimulation of the renal kalikrein/kinin system are largely responsible for the renal vasodilatation induced by IGF-1. [479] [481] [484] Inhibition of the effects of AII by IGF-1[149] may be responsible for the increase in Kf observed with IGF-I infusions.[478]

Calcitonin Gene-Related Peptide (CGRP)

Calcitonin-gene related peptide (CGRP) is a 37-amino acid peptide that is an important cardiovascular vasodilator that also causes renal vasodilatation yielding an increase in renal blood flow and GFR while decreasing systemic blood pressure.[485] Atrial natriuretic peptide (ANP) and two other peptides, long-acting natriuretic peptide and vessel dilator, all increase circulating CGRP threefold to fourfold with the effects of ANP on CGRP being of shorter duration than with the other two peptides.[486] Immunohistochemical staining of CGRP-containing nerves and nerve terminals are observed in the main renal artery, arcuate arteries, interlobular arteries, afferent arterioles including the juxtaglomerular apparatus, and the veins, with some staining of the efferent arterioles.[487] CGRP by itself does not affect the diameter of isolated afferent or efferent arterioles,[488] but CGRP produced a dose-dependent inhibition of myogenic reactivity in the afferent arteriole and vasodilatation of both afferent and efferent arterioles preconstricted by AII. [488] [489] [490] CGRP can also induce vasodilatation in norepinephrine-contracted afferent, but not efferent, arterioles. [488] [489] CGRP reverses renal vasoconstriction and the accompanying reduction in GFR in the kidney induced by endothelin[485] as well as norepinephrine-induced constriction in the isolated perfused kidney.[491] Calcitonin, by contrast, had no vasodilatory effects on either the afferent or efferent arteriole.[489]

The renal vasodilatory effects of CGRP are mediated at least in part through stimulation of the production of NO. [171] [172] [173] [485] [492] CGRP also increases the production of cAMP in isolated glomeruli[489] as well as in the whole kidney[493] suggesting a role for cAMP in the vasodilatation produced by CGRP. Pretreatment with indomethacin does not block the renal vasodilatation and increase in GFR observed with CGRP administration indicating that prostaglandins are not involved in the response to CGRP.[485]


Relaxin, an ovarian hormone secreted by the corpus luteum in pregnancy, appears to be involved in the endothelin-nitric oxide-cGMP pathway responsible for the renal vasodilatation seen in the first two trimesters. [494] [495] [496]Relaxin is a potent vasodilator and chronic administration of relaxin to virgin females increases in GFR and RPF and produces a decrease in plasma osmolality and hematocrit suggesting plasma volume expansion [494] [496] similar to that seen in pregnancy.[497] Relaxin antibodies block the gestational elevation of GFR and RPF and prevent the reduction in myogenic activity of small renal arteries.[498] In addition chronic administration of relaxin to either overiectomized rats or to male rats results in an increase in GFR and RPF indicating that estrogen and progesterone are not necessary for the vasodilatory effects of relaxin. [494] [496] Acute blockade of NO production completely reverses chronic relaxin-induced hyperfiltration and hyperperfusion indicating that relaxin stimulates NO production.[496] The vasodilatory effects of chronic relaxin administration are completely reversed by a specific ETB receptor antagonist or a NOS inhibitor. [494] [498] Pressure-induced myogenic reactivity is reduced in small renal and mesenteric arteries isolated from mid-gestational rats leading to a greater increase in diameter in response to a greater increase in pressure than normal.[499] Myogenic reactivity of these vessels was restored to levels seen in vessels obtained from virgin rats when the vessels from the pregnant animals were incubated with NOS inhibitors, a selective ETB receptor antagonist, or had the endothelium removed.[499] Thus plasma volume expansion and the renal vasodilatation and glomerular hyperfiltration observed in pregnancy appear to be largely mediated through the release of relaxin leading to activation of ETB receptors, increased NO production, and increased GFR and RPF.

Natriuretic Peptides

Increased left atrial pressure such as that induced by blood volume expansion leads to natriuresis and diuresis [500] [501] caused by release of an atrial natriuretic peptide (ANP).[502] ANP is synthesized as part of a larger (151 amino acid) preprohormone (preproANP) and is stored in the atria as a high molecular weight 126 amino acid precursor, proANP.[503] Upon release from the atria proANP is cleaved yielding two polypeptides including the 28 amino acid active form of the peptide, ANP.[503] Other ANP-like natriuretic compounds include brain natriuretic peptide (BNP) and two ANP-like natriuretic peptides produced by the kidney, one a natriuretic peptide containing 32 amino acids known as urodilatin (URO) [460] [504] [505] and a C-type natriuretic peptide (C-ANP). [506] [507] Receptors for ANP have been identified in the glomerulus,[508] the arcuate and interlobular arteries, and the afferent and efferent arterioles.[509] ANP A-Type receptors mediate the vascular response to ANP in the afferent and efferent arterioles but ANP binds to both ANP Type-A and ANP Type-C receptors.[509] The biological effects of URO are mediated by cGMP following interaction with an ANP A-type receptor whereas C-ANP binds to both C-ANP type and B-ANP type receptors but only exerts its effects through the ANP B-Type receptor located primarily in the glomerulus, the afferent arteriole, and distal portions of the nephron. [149] [506] [507] [509] [510] The C-ANP dilates afferent arterioles via a prostaglandin/nitric oxide pathway. A third type of ANP receptor, the ANP C-type receptor, serves to clear natriuretic peptides with no vasoactive effects.[509] ANP stimulates secretion of URO resulting in large increases in circulating URO.[511] Glomerular ANP receptor density is down-regulated in rats on a high-salt diet and up-regulated in rats on a low-salt diet. [508] [512] ANP stimulates NO production and increases guanylate cyclase activity and cyclic GMP production in the kidney.[446]

Acute and chronic blood volume expansion and increased atrial pressure increase plasma levels of ANP and BNP. [513] [514] [515] [516] Systemic blood pressure decreases and GFR, filtration fraction, and salt and water excretion increase in response to exogenous ANP. [98] [513] [516] [517] Studies in the hydronephrotic kidney preparation demonstrated increased glomerular blood flow in a dose-dependent manner in response to both ANP and urodilantin.[412]In the euvolemic rat, pretreatment with an ANP receptor antagonist resulted in a significantly lower GFR during subsequent ANP infusion than was observed in control rats receiving vehicle prior to the ANP infusion, [475] [518] again suggesting a role for ANP in the control of GFR in the normal rat. Renal hemodynamics are not altered by ANP antibody administration or ANP receptor antagonists in rats with myocardial infarction or congestive heart failure. [516] [519] ANP receptor antagonists decreased GFR in DOCA-salt hypertension, a model associated with elevated ANP and BNP levels.[515] Infusion of ANP antibodies into diabetic animals that already had elevated baseline values of GFR and RPF reduced GFR toward normal animal levels, indicating that high endogenous ANP contributes to hyperfiltration in early diabetes. [475] [514] The effect of natriuretic peptide inhibition on GFR and RPF is greatest under conditions of high levels of endogenous natriuretic peptides such as chronic high sodium intake.[520] Elevated prostacyclin and PGE2 production also contribute to the hyperfiltration seen in diabetes. [514] [521]

Atrial natriuretic peptide increases SNGFR without altering QA in the rat resulting in an increase in filtration fraction.[98] Unique among vasoactive agents, ANP induces preglomerular vasodilatation (arcuate arteries, interlobular arteries, and afferent aterioles) but efferent arteriolar vasoconstriction. [98] [412] [506] [509] As a consequence 000736   GC and 000736   increased with little effect on Kf indicating that the increase in SNGFR was almost entirely the consequence of the increase in ΔP.[98] The preglomerular vasodilatation and efferent arteriolar constriction occurred even when AII receptors were blocked or renal perfusion pressure was controlled.[98]

Similar to the effects of ANP, urodilatin also produces dose-dependent vasodilatation of the arcuate and interlobular arteries and afferent arteriole, vasoconstriction of the efferent arteriole, and a net increase in glomerular blood flow in both cortical and juxtamedullary nephrons.[412] Low-dose URO inhibits the renin-angiotensin system whereas high concentrations of URO activate it leading to variable effects on RPF and GFR depending on the dose used. [412] [518] [522] [523] Angiotensin converting enzyme inhibition (ACEI) combined ACEI and cyclooxygenase inhibition (CYOI), and endothelin receptor blockade reduced the URO-induced vasodilatation of the preglomerular vessels.[412]URO-induced vasoconstriction of the efferent arteriole is exaggerated by NO blockade and was completely blocked by combined AII and cyclooxygenase inhibition, by bradykinin receptor blockade, and by endothelin blockade.[412]C-ANP induces dose-dependent vasodilatation of both the preglomerular and postglomerular vessels and a large increase in renal blood flow.[509]

Parathyroid Hormone

Parathyroid hormone (PTH) has renal hemodynamic effects in addition to regulating calcium and phosphate transport in the kidney. Intrarenal infusion of PTH (1–34) produces a dose-dependent increase in RBF when given at low enough doses to prevent a fall in blood pressure.[524] Low-dose PTH administered intravenously to thyroparathyroidectomized (TPTX) animals or high-dose PTH to normal animals causes a marked reduction in Kf.[525] PTH in the rat caused a decline in SNGFR without affecting QA000736   GC, or 000736   owing to the reduction in Kf.[525] In the dog SNGFR did not decrease despite the decline in Kf because of a small increase in 000736   .[526] Intravenous administration of PTH in some studies increases renal blood flow in the intact animal.[527] Trizna and Edwards observed relaxation of isolated norepinephrine-contracted afferent and efferent arterioles in response to PTH that was completely blocked by a specific PTH antagonist.[528] These data indicate that PTH is a vasodilator, but in vivo administration of PTH can secondarily lead to the release of counteracting vasoconstrictor substances.

Parathyroid hormone increases cAMP production in glomeruli, vascular endothelial cells, mesangial cells, and proximal tubules. [528] [529] [530] [531] If prostaglandin synthesis is inhibited, subsequent administration of PTH results in reductions in both SNGFR and QA and a decrease in Kf.[409] When prostaglandin synthesis inhibition and AII receptor blockade are combined, the effects of PTH on glomerular hemodynamics are completely abolished and Kfreturns to normal.[409] PTH also stimulates NO and cGMP production.[531] Thus the effects of PTH appear to be mediated through stimulation of cAMP production leading to enhanced renin/AII production[532] and a reduction in Kf. The hemodynamic effects of AII, in turn, are modulated by enhanced production of nitric oxide and vasodilatory prostaglandins.

Parathyroid Hormone-Related Protein (PTHrP)

PTH-related protein (PTHrP) has an amino acid sequence at the N-terminus that is similar to PTH and binds to and acts through a common PTH/PTHrP receptor.[533] PTHrP is found in the media of smooth muscle cells and in endothelial cells of all renal microvessels including the afferent and efferent arterioles, the interlobular and arcuate arteries, and the macula densa as well as in the visceral and parietal cells of the glomerulus and the tubules.[534]Intrarenal infusion of PTHrP in the rat at low doses increased RBF and GFR in the absence of changes in heart rate or mean arterial pressure similar to effects seen with PTH. [524] [535] Both PTH and PTHrP cause renal vasodilatation in the isolated kidney ruling out a role for the renal nerves or stimulation of other extrarenal hormones in producing the effects.[536] Preglomerular vessels vasodilate in response to either PTH or PTHrP in almost an identical fashion[535] and both PTH and PTHrP stimulate renin release.[531] This may account for the failure of the efferent arteriole in the intact animal to vasodilate in response to PTH or PTHrP in the absence of angtiotensin II inhibition[535] because that segment is more sensitive to AII. In accord with that hypothesis isolated perfused afferent and efferent arterioles both vasodilate in response to PTHrP as well as PTH.[528] PTHrP as well as PTH stimulates adenylate cyclase activity and cAMP formation in isolated glomeruli, vascular endothelial cells, and cultured mesangial cells as well as in the isolated kidney. [529] [530] [531] Both PTH and PTHrP stimulate activation of endothelial-derived NO production via PTH/PTHrP receptors and mediated by the calcium/calmodulin pathway,[530] and inhibition of NOS markedly reduces PTHrP-induced vasorelaxation. [534] [537] PTHrP also inhibits endothelin-1 production in cultured endothelial cells, possibly mediated through increased NO and cGMP production. [537] [538] Thus PTHrP may play an important role in the local regulation of renal blood flow and glomerular filtration rate.


Adrenomedullin (ADM) is a 52 amino acid peptide that was isolated from human pheochromocytoma in the adrenal medulla that induces hypotension.[539] Messenger RNA for ADM is found in a number of organs including the kidney. [540] [541] ADM induces arterial vasodilatation via interaction with CGRP1 receptors[542] and both ADM and CGRP stimulate cAMP formation in glomeruli and glomerular mesangial cells, but ADM is more potent. [543] [544] Intrarenal administration of ADM increases renal blood flow and GFR whereas intravenous infusion decreases RBF in the absence of changes in GFR. [543] [545] [546] [547] The increase in RBF induced by ADM occurs even in the presence of a CGRP antagonist and both the renal artery and outer cortical glomeruli have high affinity ADM binding sites specific to ADM and have a very low or no affinity for CGRP. [543] [547] ADM inhibits PDGF-induced ET-1 production in mesangial cells suggesting that its vasodilatory capability is mediated, in part, through reduced vasoconstrictor production.[544] This peptide may therefore play a role, indirectly or directly, in the control of glomerular filtration rate and renal blood flow.

Neural Regulation of Glomerular Filtration Rate

The renal vasculature including the afferent arteriole and the efferent arteriole, the macula densa cells of the distal tubule, and the glomerular mesangium are richly innervated. [18] [548] Innervation includes renal efferent sympathetic adrenergic nerves [548] [549] and renal afferent sensory fibers containing peptides such as calcitonin gene-related peptide (CGRP) and substance P. [18] [548] Acetylcholine is a potent vasodilator of the renal vasculature (discussed previously), suggesting a role for this neurotransmitter in the control of the renal circulation. Sympathetic efferent nerves are found in all segments of the vascular tree from the main renal artery to the afferent arteriole (including the renin-containing juxtaglomerular cells) and the efferent arteriole [548] [549] and play an important role in the regulation of renal hemodynamics, sodium transport, and renin secretion.[550] Afferent nerves containing CGRP and substance P are localized primarily in the main renal artery and interlobar arteries, with some innervation also observed in the arcuate artery, the interlobular artery, and the afferent arteriole including the juxtaglomerular apparatus.[548] [549] Peptidergic nerve fibers immunoreactive for neuropeptide Y (NPY), neurotensin, vasoactive intestinal polypeptide, and somatostatin are also found in the kidney.[551] Neuronal nitric oxide synthase-immunoreactive neurons have now been identified in the kidney. [548] [552] The NOS-containing neuronal somata are seen in the wall of the renal pelvis, at the renal hilus close to the renal artery, along the interlobar arteries, the arcuate arteries, and extending to the afferent arteriole suggesting they have a role in the control of renal blood flow. [548] [552] They were also present in nerve bundles having vasomotor and sensory fibers suggesting they might modulate renal neural function. [548] [552]

In micropuncture studies of the effects of renal nerve stimulation (RNS), RNS alone increased RA and RE resulting in a fall in QA and SNGFR without any effect on Kf.[553] When prostaglandin production was inhibited by indomethacin, however, the same level of RNS produced even greater increases in RA and RE accompanied by very large declines in QA and SNGFR and decreases in Kf000736   GC, and 000736   .[553] When saralasin was administered as a competitive inhibitor of endogenous AII in conjunction with indomethacin, RNS had no effect on Kf, but both RA and RE were still increased, and 000736   was slightly reduced.[553] The release of norepinephrine by RNS enhances AII production to yield arteriolar vasoconstriction and reduction in Kf. The increase in AII production may then enhance vasodilator prostaglandin production, [553] [554] which partially ameliorates the constriction. Continued vasoconstriction by RNS during blockade of endogenous prostaglandins and AII suggests that norepinephrine has separate vasoconstrictive properties by itself. In agreement with this suggestion are the findings that norepinephrine causes constriction of preglomerular vessels.[137] Inhibition of nitric oxide synthase results in a decline in SNGFR in normal rats but not in rats with surgical renal denervation suggesting that nitric oxide normally modulates the effects of renal adrenergic activity.[555] This modulation does not appear, however, to be related to sympathetic modulation of renin secretion.[556]

Renal denervation in animals undergoing acute water deprivation (48 h duration) or with congestive heart failure produces increases in SNGFR, QA, and Kf.[557] This suggests that the natural activity of the renal nerves in these settings plays an important role in the constriction of the arterioles and reduction in Kf that were observed.[557] The vasoconstrictive effects of the renal nerves in both settings were mediated in part by a stimulatory effect on AII release, together with a direct vasoconstrictive effect on the preglomerular and postglomerular blood vessels.[557] These studies demonstrate the important role of the renal nerves in pathophysiological settings.


The filtration of a nearly protein-free fluid from the glomerular capillaries into Bowman space represents the first step in the process of urine formation. Electrolytes, amino acids, glucose, and other endogenous or exogenous compounds with molecular radii smaller than 20 Å are freely filtered while molecules larger than ≈50 Å are virtually excluded from filtration. [551] [558] [559] [560] [561] [562] This process of ultrafiltration of fluid is governed by the net balance between the transcapillary hydraulic pressure gradient (DP), the transcapillary colloid osmotic pressure gradient (Dp), and the hydraulic permeability of the filtration barrier (k), which determine the rate of fluid movement (Jv) across any given point of a capillary wall based on the expression:(1)  000780

where PGC and PT are the hydraulic pressures in the glomerular capillaries and Bowman space, respectively, and φGC and φT are the corresponding colloid osmotic pressures. The protein concentration of the fluid in Bowman space is essentially zero and thus φT is also zero. Total glomerular filtration rate for a single nephron (SNGFR) is equal to the product of the surface area for filtration (S) and average values along the length of the glomerular capillaries of the right-hand terms in Equation 1, yielding the expression:(2)  000787

Kf, the glomerular ultrafiltration coefficient, is the product of S and k while 000736   UF, the mean net ultrafiltration pressure, is the difference between the mean transcapillary and colloid osmotic pressure differences, 000790   and 000219   , respectively.

The barrier for ultrafiltration consists of the glomerular capillary endothelium with its fenestrations, the glomerular basement membrane, the filtration slits between glomerular epithelial cell foot processes, and ultimately the filtration slit diaphragm within the filtration slits. Mathematical modeling based on known ultrastructural detail and the hydrodynamic properties of the individual components of the filtration barrier suggests that only ≈2% of the total hydraulic resistance is accounted for by the fenestrated capillary endothelium whereas the basement membrane accounts for nearly 50%. [563] [564] [565] The filtration slits between the glomerular epithelial foot processes account for the remaining hydraulic resistance with the majority of that resistance residing in the filtration slit diaphragm. [563] [564] A reduction in the frequency of the filtration slits is an important factor in controlling filtration in some disease states. [564] [566]

Hydraulic Pressures in the Glomerular Capillaries and Bowman Space

The first direct measurements of PGC in the Munich-Wistar rat were obtained 36 years ago by Brenner and co-workers[560] who found that 000736   GC[*] averaged 46 mm Hg. Many studies subsequently confirmed the original observations demonstrating that values for 000736   GC average 43 mm Hg to 49 mm Hg ( Fig. 3-21 ) with similar values found in the squirrel monkey.[567] Because PGC is nearly constant along the length of the capillary bed the transcapillary hydraulic pressure difference averages 34 mm Hg in the hydropenic Munich-Wistar rat (see Fig. 3-21 ). Coupling these hydraulic pressure measurements with direct determinations of efferent arteriolar protein concentrations of superficial nephrons[568] permits direct determination of all of hydraulic and oncotic pressures that govern glomerular ultrafiltration at the beginning and end of the capillary network.



FIGURE 3-21  Glomerular ultrafiltration in the Munich-Wistar rat. Each point represents the mean value reported for studies in hydropenic and euvolemic rats provided food and water ad libitum until the time of study. Only studies using male or a mix of male and female rats are shown. Values of the ultrafiltration coefficient, Kf, shown by filled circles in panel D denote minimum values because the animals were in filtration pressure equilibrium. Open circles represent unique values of Kf calculated under conditions of filtration pressure disequilibrium φE/000736   ≤0.95). (See Refs 18 and 551 for data sources.)



The early direct measurements of 000736   GC were obtained in the hydropenic rats that exhibit a surgically induced reduction in plasma volume and glomerular filtration rate.[569] As shown in Figure 3-21 , following restoration of plasma volume to the “euvolemic” state by infusion of isooncotic plasma yields single nephron glomerular filtration rates (SNGFR) substantially higher in euvolemic animals than in hydropenic rats primarily as a consequence of a marked increase in glomerular plasma flow (QA) associated with a fall in preglomerular (RA) and efferent arteriolar (RE) resistance values. Because surface glomeruli are not available in most experimental animals the stop-flow technique has been used by a number of investigators to estimate 000736   GC and comparisons of glomerular capillary pressure calculated using the stop-flow technique (PGCSF) with direct determinations of 000736   GC generally indicate that PGCSF provides a reasonable estimate of 000736   GC with PGCSF generally being ≈2 mm Hg greater than that for 000736   GC measured directly.[18]

*  000736   GC represents the average value for the mean pulsatile glomerular capillary hydraulic pressure as measured along the whole glomerulus.[551]

Glomerular Capillary Hydraulic and Colloid Osmotic Pressure Profiles

Figure 3-22 depicts the glomerular capillary hydraulic and oncotic pressure profiles for hydropenic and euvolemic Munich-Wistar rats using the mean values determined from the studies shown in Figure 3-21 . Plasma oncotic pressure at the efferent end of the glomerular capillary (φE) rises to a value that, on average, equals ΔP yielding a reduction in net local ultrafiltration pressure, PUF, [PGC-(PTGC)] from approximately 17 mm Hg at the afferent end of the glomerular capillary network to essentially zero by the efferent end in hydropenic animals. The equality between φE and 000736   is referred to as filtration pressure equilibrium. As seen in Figure 3-21 , panel D, filtration pressure equilibrium (φE/ΔP≅1.00) is almost always observed in the hydropenic Munich-Wistar but is present in only ≈40% of the studies in the euvolemic Munich-Wistar rat, suggesting that the normal condition in the glomerulus of the conscious animal is poised on the verge of disequilibrium.



FIGURE 3-22  Hydraulic and colloid osmotic pressure profiles along idealized glomerular capillaries in hydropenic and euvolemic rats. Values shown are mean values derived from the studies shown in Figure 3-21 . ΔP=PGC - PT and Δπ=φGC - φT, where PGC and PT are the hydraulic pressures in the glomerular capillary and Bowman space, respectively, and φGC and φT are the corresponding colloid osmotic pressures. Because the value of φT is negligible, ΔP essentially equals φGC. PUF is the ultrafiltration pressure at any point. The area between the ΔP and Δπ curves represents the net ultrafiltration pressure, PUF. Curves A and B in the left panel represent two of the many possible profiles under conditions of filtration pressure equilibrium whereas Line D represents disequilibrium. Line C represents the hypothetical linear Δπ profile.



PUF declines between the afferent end and efferent ends of the glomerular capillary network in the hydropenic animal primarily due to the rise in φGC because ΔP remains nearly constant along the glomerular capillaries (see Fig. 3-22). The decline in PUF depicted by Curve A in Figure 3-22 shows that this decline in PUF (the difference between ΔP and ΔP curves) is nonlinear. This is because (1) filtration is more rapid at the afferent end where PUF is greatest, and (2) the relationship between plasma protein concentration and colloid osmotic pressure is nonlinear (see refs 18, 551). The exact profile of ΔP along the capillary network cannot be determined under conditions of filtration pressure disequilibrium and Curves A and B in Figure 3-22 are only two of many possibilities.

Determination of the Ultrafiltration Coefficient

Single nephron glomerular filtration rates equals the ultrafiltration coefficient (Kf) times the net driving force for ultrafiltration averaged over the length of the glomerular capillaries (000736   UF) (Equation 2). Under conditions of filtration pressure equilibrium determination of a unique value of 000736   UF is not possible because an exact ΔP profile cannot be defined but if a linear rise in ΔP between the afferent and efferent ends of the glomerular capillaries is assumed a maximum value for 000736   UF can be determined (curve C, dashed line in Fig. 3-22 ). Using this maximum value for PUF and measured values of SNGFR, a minimum estimate of Kf can be obtained. This minimum estimate of Kf in the hydropenic Munich-Wistar rat averages 3.5 ± 0.2 nl/(min·mm Hg) ( Fig. 3-21 , panel D). In the euvolemic Munich-Wistar rat Kf increases with age with little differences noted between sexes when body mass is taken into account ( Fig. 3-23 ).



FIGURE 3-23  Maturational alterations in the determinants of glomerular ultrafiltration in the euvolemic Munich-Wister rat. In panels A, B, C, and D filled symbols denote values obtained from female rats whereas open symbols were from studies of male or male plus female rats. In panel E the filled symbols denote values of RA whereas open symbols are values of RE. In panel E the circles were from studies of male or male plus female rats whereas squares were from studies of female animals. Each point represents the mean value for a given study. (See Refs 18 and 551 for sources of data.)



Under conditions of filtration pressure equilibrium changes in glomerular plasma flow rate (QA) (in the absence of significant changes in φA or ΔP) are predicted to result in proportional changes in SNGFR.[570] This occurs because in the absence of changes in any other determinants of SNGFR an increase in QA slows the rate of increase of plasma protein concentration and therefore ΔP along the glomerular capillary network. This shifts the point at which filtration equilibrium is achieved toward the efferent end of the glomerular capillary network, effectively increasing the total capillary surface area exposed to a positive net ultrafiltration pressure and increases the magnitude of the local PUF at any point along the glomerular capillary network. This is illustrated in Figure 3-22 , which shows that even in the absence of changes in 000736   or plasma protein concentration an increase in QA can result in a change in the profile from that seen with curve A to that of curve B while still achieving filtration pressure equilibrium. For curve B, however, 000736   UF is significantly greater than with curve A, and hence SNGFR will increase proportionately.

If QA increases enough, ΔP no longer rises to an extent that φE equals 000736   , and filtration pressure disequilibrium is obtained.[570] Under these conditions a unique profile of ΔP can be derived, 000736   UF can be accurately determined, and a unique value of Kf can be calculated.[570] The first unique determinations of Kf in the Munich-Wistar rat were obtained by Deen and colleagues using iso-oncotic plasma volume expansion to increase QAsufficiently to produce filtration pressure disequilibrium.[570] Under these conditions Kf was found to exceed the minimum estimate obtained in hydropenic rats by 37%, averaging 4.8 nl/(min·mm Hg). This value remained essentially unchanged over a twofold range of changes in QA, however, suggesting that changes in QA per se did not affect Kf.[570]

Filtration pressure equilibrium is generally achieved when QA is less than 130 nl/min whereas QA values greater than 130 nl/min generally yield filtration pressure disequilibrium.[18] The values of Kf for all of the studies in euvolemic Munich-Wistar rats shown in Figure 3-21 averaged 5.0±0.3 nl/(min·mm Hg) and are similar to those obtained in plasma expanded Munich Wistar rats in which only unique values of Kf were obtained (4.8±0.3 nl/(min·mm Hg)). [551] [570] Measured values of 000736   are slightly higher in euvolemic rats than in hydropenic animals (see Fig. 3-21 ), but this is offset by higher plasma protein concentrations (CA and hence φA), so that PUF at the afferent end of the glomerular capillary network is nearly identical in euvolemia versus hydropenia. Thus SNGFR euvolemic rats is higher primarily as a result of increases in QA (see Fig. 3-21 ), yielding a greater value of 000736   UF (see Fig. 3-22 ).

Kf is the product of the total surface area available for filtration and the hydraulic conductivity of the filtration barrier (k). Total capillary basement membrane area per glomerulus (As) in the rat has been determined to be equal to ≈0.003 cm2 in superficial nephrons and 0.004 cm2 in the deep nephrons.[571] Only the peripheral area of the capillaries surrounded by podocytes participates in filtration and that peripheral area available for filtration (Ap) has been estimated to be 0.0016–0.0018 and 0.0019–0.0022 cm2 in the superficial and deep glomeruli, respectively, or about half that of the total.[571] Using these estimates of Ap and a value of Kf of ≈5 nl/(min·mm Hg) as determined by micropuncture techniques, then k=45–48 nl/(s·mm Hg·cm2). These estimates of k for the rat glomerulus are all 1 to 2 orders in magnitude higher than those reported for capillary networks in mesentery, skeletal muscle, omentum, or in peritubular capillaries of the kidney. [18] [551] This very high glomerular hydraulic permeability permits very rapid rates of filtration across glomerular capillaries despite mean net ultrafiltration pressures (PUF) of only 5 mm Hg to 6 mm Hg in hydropenia and 8 mm Hg to 9 mm Hg in euvolemia.

Selective Alterations in the Primary Determinants of Glomerular Ultrafiltration

Alterations in any of the four primary determinants of ultrafiltration, QA000736   , Kf, and φA, will affect glomerular filtration rate. The degree to which selective alterations will modify SNGFR has been examined by mathematical modeling[570] and compared with values obtained experimentally.[18]

Glomerular Plasma Flow Rate (QA)

Because protein is normally excluded from the glomerular ultrafiltrate, conservation of mass dictates that the total amount of protein entering the the glomerular capillary network from the afferent arteriole equals the total amount leaving at the efferent arteriole:(3)  000797

For Equation 3, QE = efferent arteriolar plasma flow rate, and CA and CE are the afferent and efferent arteriolar plasma concentrations of protein, respectively. This can be expressed as:(4)  000808

Rearranging Equation 4 yields(5)  000811(6)  000315

where SNFF is the single nephron filtration fraction. Although the relationship between colloid osmotic pressure (p) and protein concentration deviates from linearity,[572] Equation 4 can be approximated as:(7)  000326

Because at filtration pressure equilibrium φE = ΔP,(8)  000818

Under conditions of filtration pressure equilibrium, filtration fraction [≅(1-(φA/ΔP)] is constant if φA and ΔP are unchanged. SNGFR will then vary directly with changes in QA (Equation 8). Increases in QA great enough to produce disequilibrium (φE less than 000736   ) yields a fall in CE, a decrease in SNFF (Equation 5), and SNGFR no longer varies linearly with QA. Brenner and colleagues first demonstrated the plasma flow dependence of GFR[573] and as shown in Figure 3-24 increases in glomerular plasma flow are associated with increases in SNGFR in studies of rats, dogs, nonhuman primates, and humans. Because filtration pressure equilibrium occurs in most studies at plasma flow rates less than 100 nl/min to 150 nl/min, increases in QA result in proportional increases in SNGFR, and SNFF remains constant. Further increases in QA are associated with proportionately lower increases in SNGFR resulting in decreased SNFF as filtration pressure disequilibrium is achieved.



FIGURE 3-24  Relationship between SNGFR and glomerular plasma flow rate. Values from studies in rats are denoted by open circles whereas data from dogs are presented as filled squares. Also shown are values from primates including the squirrel monkey (filled circle) and humans (filled triangles). The values for SNGFR and QA for humans were calculated by dividing whole kidney GFR and renal plasma flow by the estimated total number of nephrons/kidney (one million). Each point represents the mean value for a given study. (See Refs 18 and 551 for sources of data.)



Transcapillary Hydraulic Pressure Difference (ΔP)

Isolated changes in the glomerular transcapillary hydraulic pressure gradient are also predicted to affect SNGFR.[570] Until ΔP exceeds the colloid osmotic pressure at the afferent end of the glomerular capillary there is no filtration. Once that point is reached SNGFR increases as ΔP increases, but the rate of increase is nonlinear because the rise in SNGFR at any given fixed value of QA results in a concurrent (but smaller) increase in ΔP. Because 000736   is normally 30 mm Hg to 40 mm Hg (see Fig. 3-21 ), changes in 000736   generally result in relatively minor variations in SNGFR.

Glomerular Capillary Ultrafiltration Coefficient (Kf)

The glomerular ultrafiltration coefficient is reduced in a variety of kidney diseases, in part as a consequence of a reduction in surface area available for filtration as glomerulosclerosis progresses. In addition, the hydraulic permeability of the glomerular basement membrane is inversely related to 000736   , indicating that Kf, the product of surface area and hydraulic conductivity, may be directly affected by 000736   .[574] The hydraulic conductivity of the GBM and Kf, are also affected by the plasma protein concentration (see later discussion). Because filtration pressure equilibrium is generally observed at low values of QA, reductions in Kf do not affect SNGFR until Kf is reduced enough to produce filtration pressure disequilibrium. At low QA values increases in Kf above normal values move the point of equilibrium closer to the afferent end of the capillaries but have little affect on SNGFR. [18] [570] For high QA values filtration pressure disequilibrium occurs and there is a more direct relationship between Kf and SNGFR.[570]

Colloid Osmotic Pressure (φA)

Single nephron glomerular filtration rate and SNFF are predicted to vary reciprocally as a function of φA.[570] This is because changes in φA are associated with alterations in Kf, thereby offsetting variations in PUF that occur with changes in φA.[18] These divergent results can be partially explained by the results from studies of isolated glomerular basement membranes by Daniels and co-workers, who observed a biphasic relationship between albumin concentration and hydraulic permeability.[574] They observed lower values of hydraulic permeability at albumin concentrations of 4 g/dl than at either 0 or 8 g/dl, but they did not study the effects of extremely high protein concentrations (e.g., 11 g/dl).[574] Their studies suggest a primary effect on hydraulic conductivity,[574] but the mechanism is unknown.


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