SECTION I Essential Renal Anatomy and Physiology
1 Renal Anatomy Wilhelm Kriz, Marlies Elger
The complex structure of the mammalian kidney is best understood in the unipapillary form that is common to all small species. Fig. 1.1 is a schematic coronal section through a unipapillary kidney, with a cortex enclosing a pyramid-shaped medulla, the tip (papilla) of which protrudes into the renal pelvis. The medulla is divided into an outer and an inner medulla; the outer medulla is further subdivided into an outer and an inner stripe.
STRUCTURE OF THE KIDNEY The specific components of the kidney are the nephrons, the collecting ducts (CDs), and a unique microvasculature.1 The multipapillary kidney of humans contains approximately 1 million nephrons, although this number varies considerably. The number of nephrons is already established during prenatal development; after birth, new nephrons cannot be developed and a lost nephron cannot be replaced.
Nephrons A nephron consists of a renal corpuscle (glomerulus) connected to a complicated and twisted tubule that finally drains into a CD (Fig. 1.2 and Table 1.1). Three types of nephron can be distinguished by the location of renal corpuscles within the cortex: superficial, midcortical, and juxtamedullary nephrons. The tubular part of the nephron consists of a proximal tubule and a distal tubule connected by a loop of Henle2 (see later discussion). There are two types of nephrons: those with long loops of Henle and those with short loops. Short loops turn back in the outer medulla or even in the cortex (cortical loops). Long loops turn back at successive levels of the inner medulla.
Collecting Ducts A CD is formed in the renal cortex when several nephrons join. A connecting tubule (CNT) is interposed between a nephron and a cortical CD. Cortical CDs descend within the medullary rays of the cortex. Then they traverse the outer medulla as unbranched tubes. On entering the inner medulla, they fuse successively and open finally as papillary ducts into the renal pelvis (see Fig. 1.2 and Table 1.1).
Microvasculature The microvascular pattern of the kidney is similarly organized in mammalian species1,3 (Fig. 1.3; see also Fig. 1.1). The renal artery, after entering
the renal sinus, finally divides into the interlobar arteries, which extend toward the cortex in the space between the wall of the pelvis (or calyx) and the adjacent cortical tissue. At the junction between cortex and medulla, the interlobar arteries divide and pass over into the arcuate arteries, which also branch. The arcuate arteries give rise to the cortical radial arteries (interlobular arteries), which ascend radially through the cortex. No arteries penetrate the medulla. Afferent arterioles supply the glomerular tufts and generally arise from cortical radial arteries. As a result, the blood supply of the peritubular capillaries of the cortex and the medulla is exclusively postglomerular. Glomeruli are drained by efferent arterioles. Two basic types of efferent arterioles can be distinguished: cortical and juxtamedullary. Cortical efferent arterioles, which derive from superficial and midcortical glomeruli, supply the capillary plexus of the cortex. The efferent arterioles of juxtamedullary glomeruli represent the supplying vessels of the renal medulla. Within the outer stripe of the medulla, these vessels divide into the descending vasa recta and then penetrate the inner stripe in cone-shaped vascular bundles. At intervals, individual vessels leave the bundles to supply the capillary plexus at the adjacent medullary level. Ascending vasa recta drain the renal medulla. In the inner medulla, the vasa recta arise at every level, ascending as unbranched vessels, and traverse the inner stripe within the vascular bundles. The ascending vasa recta that drain the inner stripe may join the vascular bundles or may ascend directly to the outer stripe between the bundles. All the ascending vasa recta traverse the outer stripe as individual wavy vessels with wide lumina interspersed among the tubules. Because true capillaries derived from direct branches of efferent arterioles are relatively scarce, the ascending vasa recta form the capillary plexus of the outer stripe. The ascending vasa recta empty into arcuate veins. The vascular bundles represent a countercurrent exchanger between the blood entering and that leaving the medulla. In addition, the organization of the vascular bundles results in a separation of the blood flow to the inner stripe from that to the inner medulla. Descending vasa recta supplying the inner medulla traverse the inner stripe within the vascular bundles. Therefore blood flowing to the inner medulla has not been exposed previously to tubules of the inner or outer stripe. All ascending vasa recta originating from the inner medulla traverse the inner stripe within the vascular bundles. Thus blood that has perfused tubules of the inner medulla does not subsequently perfuse tubules of
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SECTION I Essential Renal Anatomy and Physiology Coronal Section Through a Unipapillary Kidney Short-looped nephron
Long-looped nephron
Glomeruli
Nephrons and the Collecting Duct System
Renal artery
9
8 1
9
Cortex Outer medulla
Cortex
Inner medulla
7
2
8 1
7
2
Medullary ray
10 3
Collecting duct
Renal vein
Outer stripe
Fig. 1.1 Coronal section through a unipapillary kidney.
TABLE 1.1 Subdivisions of the Nephron and Collecting Duct System Section
Outer medulla
3
6 6
Inner stripe
11 4
Subsections
Nephron Renal corpuscle
Glomerulus: term used most frequently to refer to entire renal corpuscle Bowman capsule Convoluted part Straight part (pars recta), or thick descending limb of Henle loop Descending part, or thin descending limb of Henle loop Ascending part, or thin ascending limb of Henle loop Straight part, or thick ascending limb of Henle loop: subdivided into medullary and cortical parts; the cortical part contains the macula densa in its terminal portion Convoluted part
Proximal tubule
Intermediate tubule
Distal tubule
Collecting Duct System Connecting tubule Collecting duct
Includes the arcades in most species Cortical collecting duct Outer medullary collecting duct: subdivided into an outer stripe and an inner stripe portion Inner medullary collecting duct: subdivided into basal, middle, and papillary portions
Inner medulla
1. 2. 3. 4. 5. 6.
4
Renal corpuscle Proximal convoluted tubule Proximal straight tubule Descending thin limb Ascending thin limb Distal straight tubule (thick ascending limb)
5
12
7. Macula densa 8. Distal convoluted tubule 9. Connecting tubule 10. Cortical collecting duct 11. Outer medullary collecting duct 12. Inner medullary collecting duct
Fig. 1.2 Nephrons and the collecting duct system. Shown are short-looped and long-looped nephrons, together with a collecting duct (not drawn to scale). Arrows denote confluence of further nephrons.
The intrarenal arteries and the afferent and efferent glomerular arterioles are accompanied by sympathetic nerve fibers and terminal axons representing the efferent nerves of the kidney.1 Tubules have direct contact to terminal axons only when the tubules are located around the arteries or the arterioles. Tubular innervation consists of “occasional fibers adjacent to perivascular tubules.”4 The density of nerve contacts to convoluted proximal tubules is low; contacts to straight proximal tubules, thick ascending limbs of Henle loops, and CDs have never been encountered. Afferent nerves of the kidney are believed to be sparse.5
Glomerulus (Renal Corpuscle) the inner stripe. However, the blood returning from either the inner medulla or the inner stripe afterward does perfuse the tubules of the outer stripe. The intrarenal veins accompany the arteries. Central to the renal drainage of the kidney are the arcuate veins, which, in contrast to arcuate arteries, do form real anastomosing arches at the corticomedullary border.
The glomerulus comprises a tuft of specialized capillaries attached to the mesangium, both of which are enclosed in a pouch-like extension of the tubule that represents the Bowman capsule (Figs. 1.4 and 1.5). The capillaries together with the mesangium are covered by epithelial cells (podocytes) forming the visceral epithelium of the Bowman capsule. At the vascular pole, this is reflected to become the parietal epithelium of the Bowman capsule. At the interface between the glomerular capillaries and the mesangium on one side and the podocyte layer on the
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CHAPTER 1 Renal Anatomy Microvasculature of the Kidney Arterial vessels and capillaries
Venous vessels Cortical radial artery Afferent arteriole
Cortex
Outer stripe
Outer medulla Inner stripe
Renal Corpuscle and Juxtaglomerular Apparatus
Cortical radial vein Arcuate vein
Juxtaglomerular AA apparatus
MD
EGM EA
N Vascular pole
SMC
GC
PE
To intrarenal vein Efferent arteriole
PO Bowman capsule
E
M
Arcuate artery Descending vasa recta Ascending vasa recta
US Urinary pole Proximal tubule
AA MD EGM EA N GC SMC
Inner medulla
F GBM
Afferent arteriole Macula densa Extraglomerular mesangium Efferent arteriole Sympathetic nerve terminals Granular cells Vascular smooth muscle cells
PE PO M E F GBM US
Parietal epithelium Podocyte Mesangium Endothelium Foot process Glomerular basement membrane Urinary space
Fig. 1.4 Glomerulus and juxtaglomerular apparatus. (Modified with permission from reference 1.)
Fig. 1.3 Microvasculature of the Kidney. Afferent arterioles supply the glomeruli, and efferent arterioles leave the glomeruli and divide into the descending vasa recta, which together with the ascending vasa recta form the vascular bundles of the renal medulla. The vasa recta ascending from the inner medulla all traverse the inner stripe within the vascular bundles, whereas most of the vasa recta from the inner stripe of the outer medulla ascend outside the bundles. Both types traverse the outer stripe as wide, tortuous channels.
other side, the glomerular basement membrane (GBM) is developed. The space between both layers of the Bowman capsule represents the urinary space, which at the urinary pole continues as the tubule lumen. On entering the tuft, the afferent arteriole immediately divides into several primary capillary branches, each of which gives rise to an anastomosing capillary network representing a glomerular lobule. In contrast, the efferent arteriole is already established inside the tuft by confluence of capillaries from each lobule.6 Thus the efferent arteriole has a significant intraglomerular segment located within the glomerular stalk. Glomerular capillaries are a unique type of blood vessel composed of nothing but an endothelial tube (Figs. 1.6 and 1.7). A small stripe of the outer aspect of this tube directly abuts the mesangium; the major part bulges toward the urinary space and is covered by the GBM and
the podocyte layer. This peripheral portion of the capillary wall represents the filtration area.
Glomerular Basement Membrane The GBM serves as the skeleton of the glomerular tuft. This membrane is a complexly folded sack with an opening at the glomerular hilum (see Fig. 1.4). The outer aspect of this GBM sack is completely covered with podocytes. The interior of the sack is filled with the capillaries and the mesangium. As a result, on its inner aspect, the GBM is in contact with either capillaries or the mesangium. At any transition between these two locations, the GBM changes from a convex pericapillary to a concave perimesangial course; the turning points are called mesangial angles. In electron micrographs of traditionally fixed tissue, the GBM appears as a trilaminar structure, with a lamina densa bounded by two less dense layers, the lamina rara interna and lamina rara externa (see Fig. 1.7). Studies with freeze techniques reveal only one thick, dense layer directly attached to the bases of the epithelium and endothelium.7 The major components of the GBM include type IV collagen, laminin, and heparan sulfate proteoglycans, as in basement membranes at other sites. However, the GBM has several unique properties, notably a distinct spectrum of type IV collagen and laminin isoforms. The mature GBM consists of type IV collagen made of α3, α4, and α5 chains and laminin 11, made of α5, β2, and γ1 chains.8 Type IV collagen is the antigenic target in Goodpasture disease (see Chapter 16), and mutations in the
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SECTION I Essential Renal Anatomy and Physiology Peripheral Portion of a Glomerular Lobule
MD
EA
AA
Podocyte
EGM
Glomerular basement membrane
Foot processes Capillary
Mesangial angle
Capillary endothelium
PO PE
Microfilaments Mesangium P
Fig. 1.5 Longitudinal section through a glomerulus (rat). At the vascular pole, the afferent arteriole (AA), the efferent arteriole (EA), the extraglomerular mesangium (EGM), and the macula densa (MD) are seen; PO, podocyte. At the urinary pole, the parietal epithelium (PE) transforms into the proximal tubule (P). (Light microscopy; magnification ×390.)
genes of the α3, α4, and α5 chains are responsible for Alport syndrome (see Chapter 46). Current models depict the basic structure of the GBM as a threedimensional network of type IV collagen.7 The type IV collagen monomer consists of a triple helix that is 400 nm in length, with a large, noncollagenous globular domain at its C-terminal end called NC1. At the N terminus, the helix possesses a triple helical rod 60 nm long: the 7S domain. Interactions between the 7S domains of two triple helices or the NC1 domains of four triple helices allow type IV collagen monomers to form dimers and tetramers. In addition, triple helical strands interconnect by lateral associations through binding of NC1 domains to sites along the collagenous region. This network is complemented by an interconnected network of laminin 11, resulting in a flexible, nonfibrillar polygonal assembly that provides mechanical strength and elasticity to the basement membrane and serves as a scaffold for alignment of other matrix components.9,10 The electronegative charge of the GBM mainly results from the presence of polyanionic proteoglycans. The major proteoglycans of the GBM are heparan sulfate proteoglycans, including perlecan and agrin. Proteoglycan molecules aggregate to form a meshwork that is kept well hydrated by water molecules trapped in the interstices of the matrix.
Mesangium Three major cell types occur within the glomerular tuft, all of which are in close contact with the GBM: mesangial cells, endothelial cells, and podocytes. The mesangial/endothelial/podocyte cell ratio is 2 : 3 : 1 in the rat. The mesangial cells and mesangial matrix establish the glomerular mesangium.
Mesangial matrix
Fig. 1.6 Peripheral portion of a glomerular lobule. This part shows a capillary, the axial position of the mesangium, and the visceral epithelium (podocytes). At the capillary-mesangial interface, the capillary endothelium directly abuts the mesangium.
Mesangial cells. Mesangial cells are irregular in shape, with many processes extending from the cell body toward the GBM (see Figs. 1.6 and 1.7). In these processes, dense assemblies of microfilaments are found, containing α-smooth muscle actin, myosin, and α-actinin.11 The processes are attached to the GBM directly or through the interposition of microfibrils The GBM represents the effector structure of mesangial contractility. Mesangial cell–GBM connections are found throughout the mesangium-GBM interface but are especially prominent at the turning points of the GBM infoldings (mesangial angles). The folding pattern of the GBM is permanently challenged by the expansile forces of the high intraglomerular perfusion pressure. Centripetal mesangial cell contraction balances the expansile forces. Thus the folding pattern of the GBM, including the complex convolutions of glomerular capillaries, are maintained by mesangial cells. Mesangial cells possess a great variety of receptors, including those for angiotensin II (Ang II), vasopressin, atrial natriuretic factor, prostaglandins, transforming growth factor β (TGF-β), and other growth factors (platelet-derived growth factor [PDGF], epidermal growth factor [EGF], connective tissue growth factor [CTGF]).12 Mesangial matrix. The mesangial matrix fills the highly irregular spaces between the mesangial cells and the perimesangial GBM, anchoring the mesangial cells to the GBM.6 Many common extracellular matrix proteins have been demonstrated within the mesangial matrix, including collagen types IV, V, and VI and microfibrillar protein components such as fibrillin and the 31-kilodalton microfibril-associated glycoprotein. The matrix also contains several glycoproteins, most abundantly fibronectin.
Endothelium Glomerular endothelial cells consist of cell bodies and peripherally located, attenuated, and highly fenestrated cytoplasmic sheets (see Figs.
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CHAPTER 1 Renal Anatomy
5
GBM
MF
A
B Fig. 1.7 Glomerular capillary. (A)The layer of interdigitating podocyte processes and the glomerular basement membrane (GBM) do not completely encircle the capillary. At the mesangial angles (arrows), both deviate from a pericapillary course and cover the mesangium. Mesangial cell processes containing dense bundles of microfilaments (MF), interconnect the GBM, and bridge the distance between the two mesangial angles. (B) Filtration barrier. The peripheral part of the glomerular capillary wall comprises the endothelium with open pores (arrowheads), the GBM, and the interdigitating foot processes (FPs). The GBM shows a lamina densa bounded by the lamina rara interna and externa. The FPs are separated by filtration slits bridged by thin diaphragms (arrows). (Transmission electron microscopy [TEM]; magnification: A, [×8770]; B, [×50,440].)
1.6 and 1.7). Glomerular endothelial pores lack diaphragms, which are encountered only in the endothelium of the final tributaries to the efferent arteriole.6 The round to oval pores have a diameter of 50 to 100 nm. A negatively charged layer of membrane-bound and loosely attached molecules (glycocalyx) covers the entire luminal surface, including, as sieve plugs, the endothelial pores.13 Endothelial cells are active participants in processes controlling coagulation and inflammation. Endothelial cells have receptors for vascular endothelial growth factor (VEGF), angiopoietins, and TGFβ-1, among others. They synthesize and release PDGF-B, endothelin-1, and endothelium-derived relaxing factor (EDRF), among others.14
Visceral Epithelium (Podocytes) The visceral epithelium of the Bowman capsule comprises highly differentiated cells, the podocytes (Fig. 1.8; see also Fig. 1.6). Differentiated podocytes are unable to replicate; therefore lost podocytes cannot be replaced in the adult. All efforts of the last decade to find progenitor cells that might migrate into the tuft and replace lost podocytes have failed. Podocytes have a voluminous cell body that floats within the urinary space, separated from the GBM by a subpodocyte space.15 The cell bodies give rise to primary processes that fall apart into foot processes (FPs) that fix the cells to the capillaries, i.e. to the GBM. Sporadic FPs also may arise directly from the cell body. The FPs of neighboring podocytes regularly interdigitate with each other, leaving meandering slits (filtration slits) between them that are bridged by a complex extracellular structure, the slit diaphragm (SD) that may be seen as a modified adherens junction (Fig. 1.9; see also Figs. 1.6 to 1.8). Traditional scanning electron micrograph (SEM) pictures (see Fig.1.8A) do not convey the correct pattern of how FPs interdigitate and adhere to the GBM. As seen by block-face SEM (see Fig. 1.8B), individual FPs may terminate with a final branching and primary processes fall off into basal ridges
that actually are also FPs.16 Thus the interdigitating FP pattern as it adheres to the GBM is completely homogeneous, forming a uniform cover of interdigitating filopodia. In contrast to the cell body, which harbors a prominent endoplasmic reticulum and Golgi system and has well-developed endocytotic and autophagic machinery, the cell processes apart from endocytotic elements contain only a few organelles. A sophisticated cytoskeleton accounts for the complex shape of the cells. In the cell body and the primary processes, microtubules and intermediate filaments (vimentin, desmin) dominate. Within the FPs, microfilaments (β-actin) form prominent U-shaped bundles arranged in the longitudinal axis of two successive FPs in an overlapping pattern. Above, the bends of these bundles are linked to the microtubules of the primary processes; peripherally, these bundles terminate in the dense cytoplasm associated with the sole plates, being part of the anchoring system of the FPs to the GBM (see later discussion). In addition, FPs have well developed sub-plasmalemmal actin network that has intimate contact to the anchor line of the SD and diffusely to the actin bundles. Multiple actin-associated proteins, including α-actinin-4 and synaptopodin myosin (myo-1e), among many others, establish the specific cytoskeleton in podocytes.19 The luminal membrane contains a great variety of receptors (see later discussion), and together with the luminal surface of the SD it is covered by a thick surface coat that is rich in sialoglycoproteins, including podocalyxin and podoendin, accounting for the high negative surface charge of the podocytes. The abluminal cell membrane comprises a narrow band of lateral cell membrane extending from the SD to the GBM and, most important, the soles of the FPs abutting to the GBM. A complex anchoring system connects the cytoskeleton of the FPs to the GBM. Two systems are known: (1) α3β1 integrin dimers interconnect the cytoplasmic focal adhesion proteins vinculin, paxillin, and talin with the α3, α4, and α5
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SECTION I Essential Renal Anatomy and Physiology
FP PP
A
adenosine monophosphate (cAMP) signaling stimulated by prostaglandin E2 (PGE2), dopamine, VEGF, isoproterenol, parathyroid hormone (PTH), PTH-related peptide; and receptors for Ca2+ signaling stimulated by numerous ligands, including angiotensin II, acetylcholine, PGF2, arginine vasopressin (AVP), adenosine triphosphate (ATP), endothelin, and histamine.20 Among the transient receptor potential (TRP) cation channels, TRPC5 and TRPC6 have received much attention.21-23 The major target of this signaling orchestra is the cytoskeleton (see later discussion). Other receptors, such as for TGF-β, fibroblast growth factor (FGF-2), and other cytokines/chemokines, have been shown to be involved in synthesis functions (GBM components) or in development of podocyte diseases.20 Megalin is a multiligand endocytotic receptor and the major antigen of Heymann nephritis in the rat,24 but is not present in humans.12 On the other hand, podocytes, by paracrine and autocrine signaling, regulate the interplay with endothelial and mesangial cells; during development they are responsible for building a glomerulus. VEGF, angiopoietins, and PDGF, among others, are of crucial importance for the homeostatic maintenance of the tuft.25
Function and Maintenance of the Filtration Barrier
B Fig. 1.8 Branching pattern of podocyte foot processes (rat). (A) Scanning electron micrograph (SEM) showing the urinary side of the podocyte cover of a glomerular capillary consisting of cell bodies, large primary processes (PP) and interdigitating foot processes (FP) separated by the filtration slits. (B) Drawing of the basal aspect of the FP-branching pattern as seen by block-face SEM. A fully homogeneous branching pattern of FPs attaches to the glomerular basement membrane (GBM) that may be compared with a pattern of interdigitating filopodia connected by adherens junctions. The high degree of branching (not seen from the luminal aspect) provides a high degree of adaptability to area changes of the underlying GBM. (B, From reference 45, with permission.)
chains of type IV collagen and laminin 521; and (2) β-α-dystroglycans interconnect the cytoplasmic adapter protein utrophin with agrin and laminin α5 chains in the GBM.9 The junctional connection of podocyte FPs by the SD bridging the filtration slits is complex and unique. The filtration slits have a constant width of approximately 30 to 40 nm: thus the SD has to connect the FPs over a considerable distance. By transmission electron microscopy (TEM), in routinely glutaraldehyde-fixed material, the SD shows up as a single dark line in cross sections and in an en-face view as a homogenous network of fibrillar structures interconnecting both membranes. Combined tannic acid and glutaraldehyde–fixed tissue reveals, in en-face view, a zipper-like structure with a row of pores approximately 14 × 2 nm on either side of a central bar. The transmembrane proteins that establish the slit diaphragm (SD) and its connection to the actin cytoskeleton of the FPs include nephrin, P-cadherin, FAT1, NEPH 1-3, podocin, and CD2AP, among others20 (see Fig. 1.9). Podocytes contain a great variety of surface receptors and ion channels, many of which accumulate close to the SD; the schematic in Fig. 1.9 shows some of them. They include receptors for cyclic guanosine monophosphate (cGMP) signaling, stimulated by natriuretic peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]) and nitric oxide; receptors for cyclic
Most glomerular diseases start in the glomerulus, beginning with the breakdown of the filtration barrier. It is commonly accepted that the physical forces associated with filtration represent crucial challenges that account for the break down; they comprise filtration pressure and filtrate flow. Filtration pressure and expansion. Traditionally, the high transmural hydrostatic pressure gradients necessary for filtration have been considered the main challenge to the filtration barrier. Podocyte FPs were considered a kind of pericyte process counteracting variations and derailments in perfusion pressures. This view has been challenged since we learned that the major way podocytes are lost (under any circumstances) is by detachment from the GBM as viable cells. It seems self-contradictory that FPs, which need their cytoskeleton to continually adapt their pattern of attachment to the GBM (see later discussion), would simultaneously function as contractile pericyte-like processes, counteracting the expansion of the GBM by increasing their tone. Consequently, it may be concluded that the principal burden for counteracting transmural pressure gradients (i.e., for developing wall tension) falls instead on the GBM.26 As described earlier, the GBM is an elastic membrane that expands or shrinks in surface area with increasing or decreasing transmural hydrostatic pressure, respectively. Its expansion decreases with increasing pressure and is limited. Expansion of the GBM affords the immediate coordinated increase in the cover by interdigitated FPs; thus the FPs and the SD have to increase correspondingly (and vice versa when pressure decreases). The ability for such acute adaptions has been previously shown in the isolated perfused kidney. It is suggested that the changes in FP length occur by actin polymerization/depolymerization and the changes in SD length by coordinated exocytotic and endocytotic processes of SD components.26,27 An orchestrated connection between the mobility of the actin cytoskeleton and the dynamics of the SD has been uncovered in great depth by innumerable studies during the past two decades.28,29 Filtrate flow and shear stress. The flow of the filtrate through the filtration barrier represents by far the highest extravascular fluid flow in the body. It consists of the outflow from glomerular capillaries, through the GBM, and into the Bowman space. This latter step creates a problem: in contrast to the exit of filtrate from capillaries, where flow presses the endothelium against the basement membrane, its entry into the Bowman space tends to separate the podocytes from
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CHAPTER 1 Renal Anatomy
7
Glomerular Filtration Barrier Cl− Actin N
NSCC
Ca2+
M
AT1
PC
S Ez
Ang II
TRPC6 Podocin
CD
α-Actinin 4 Laminin11 Agrin
Nephrin NEPH 1-3 P-Cadherin FAT1
Ca2+ Z Cat
U
Cas FAK TPV
β
ILK TPV β1
α
α3
Dystroglycan Integrin
COLLAGEN IV (α3, α4, α5)
Capillary endothelium
Capillary endothelium
Fig. 1.9 Glomerular filtration barrier. Two podocyte foot processes (FPs) bridged by the slit membrane (SM), the glomerular basement membrane (GBM) and the porous capillary endothelium, are shown. The surfaces of podocytes and of the endothelium are covered by a negatively charged glycocalyx containing the sialoprotein podocalyxin (PC). The GBM is mainly composed of type IV collagen (α3, α4, and α5), laminin 11 (α5, β2, and γ1 chains), and the heparan sulfate proteoglycan agrin. The SM represents a porous proteinaceous membrane composed of (as far as is known) nephrin, NEPH 1-3, P-cadherin, and FAT1. The actinbased cytoskeleton of the FPs connects to both the GBM and the SM. Regarding the connections to the GBM, β1α3 integrin dimers specifically interconnect the talin, paxillin, vinculin (TPV) complex to laminin 11; the β- and α-dystroglycans interconnect utrophin to agrin. The SM proteins are joined to the cytoskeleton by various adapter proteins, including podocin, Zonula Occludens protein 1 (ZO-1; Z), CD2-associated protein (CD), and catenins (Cat). Among the nonselective cation channels (NSCC), TRPC6 associates with podocin (and nephrin, not shown) at the SM. Only the angiotensin II (Ang II) type 1 receptor (AT1) is shown as an example of the many surface receptors. Cas, p130Cas; Ez, ezrin; FAK, focal adhesion kinase; ILK, integrinlinked kinase; M, myosin; N, Na+-H+ exchanger regulatory factor (NHERF2); S, synaptopodin. (Modified from reference 17.)
the GBM. The insight that the major way of losing podocytes in disease is by detachment has brought the shear stress created by the filtrate flow into discussion. The strength of the shear stress depends on the flow rate and the geometry of the channel; the narrower the channel or the higher the flow velocity, the higher is the shear stress. In rats the filtrate flow amounts to 30 nl/min, creating a shear stress to the FPs within the filtration slit as high as 8 Pa.30 Much lower values of shear stress to the podocyte cell bodies may lead to detachment when podocytes come to lie within the urinary orifice.27 Moreover, a high sensitivity of podocytes to shear stress has been shown in cell culture studies. This led to a new view of the relevance of the SM (in addition to its barrier function; see later discussion). Shear stress tends to lead to deformations of the lateral walls of FPs, and thus widens the slit. The interconnection of both opposite FPs by the SD at the narrowest site of the slit is ideally positioned to counteract these destabilizing forces. The SD uses the shear stress against one side of the slit to balance the shear stress against the opposite side. This means that during filtrate
flow the SD is permanently under tension that counteracts the shear stress to both sides of the slit.27 Barrier function. Filtrate flow through the barrier occurs along an extracellular route, including the endothelial pores, GBM, and SD (see Figs. 1.7 and 1.9). The barrier shows a high permeability for water, small solutes, and ions, whereas the barrier is fairly tight for macromolecules, selective for size, shape, and charge.20 The charge selectivity of the barrier results from the dense accumulation of negatively charged molecules throughout the entire depth of the filtration barrier, most importantly the surface coat of endothelial cells, and from the high content of negatively charged heparan sulfate proteoglycans in the GBM. Most plasma proteins, including albumin, are negatively charged, and thus their repulsion is dominantly charge dependent. The size/shape selectivity seems to be established by the SD.13 Uncharged macromolecules up to an effective radius of 1.8 nm pass freely through the filter. Larger components are increasingly restricted (indicated by their fractional clearances, which progressively decrease) and are totally restricted at effective radii of more than 4 nm. Plasma
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SECTION I Essential Renal Anatomy and Physiology
albumin has an effective radius of 3.6 nm; without the repulsion from the negative charge, plasma albumin would pass through the filter in considerable amounts. Studies by the group of Marcus Moeller proposed an electrophoretic mechanism for the repulsion and exclusion of plasma proteins from the glomerular filter.31,32 According to their hypothesis, the flow of the filtrate through the charged filter creates a streaming potential. This electrical field is negatively charged on the urinary side of the glomerular filter compared with the capillary side by approximately −0.05 mV/10 mm Hg filtration pressure. Thus the negatively charged molecules (albumin) that approach the filter will be exposed to an electrophoretic force that drives them back toward the capillary lumen. The charm of this hypothesis consists of being independent of any structural pore preventing their passage. The barrier actually consists of a strictly filtration-dependent potential difference; without sufficient convective flow of filtrate, the barrier will become permeable.31,32 Pathology. The hypothesis that the mechanical interconnection of the FPs by the SD is the most vulnerable structure to the physical challenges of filtration is supported by the pathologic changes. The loss of the SD connection between adjacent FPs represents the earliest failure that starts the detachment of podocytes.27 This can be interpreted as the loss of local control of filtrate flow. Unchanneled filtrate flow through such leaks will exert unbalanced shear stress to the FPs, initiating locally the detachment of FPs. Repair of such leaks seems impossible in the face of ongoing filtrate flow, accounting for the observation that the damage will proceed. Taken together, the layer of interdigitating FPs interconnected by the SD regulates the entry of the filtrate flow into the Bowman space by channeling the flow through the filtration slits. The geometry of the slits is maintained against the shear forces to both opposite FPs through the interconnection of opposing FPs by the SD. Loss of the junctional connection is detrimental because it opens leaks for uncontrolled filtrate flow with the tendency to increase the leaks.33
Parietal Epithelium The parietal epithelium of the Bowman capsule consists of squamous epithelial cells resting on a basement membrane (see Figs. 1.4 and 1.5). The flat cells are filled with bundles of actin filaments running in all directions. In contrast to the GBM, the parietal basement membrane comprises several proteoglycan-dense layers that, in addition to type IV, contain type XIV collagen. The predominant proteoglycan of the parietal basement membrane is a chondroitin sulfate proteoglycan.34
Renal Tubule The renal tubule is subdivided into several distinct segments: a proximal tubule (convoluted and straight portions), an intermediate tubule, a distal tubule (straight and convoluted portion), a CNT, and the CD (see Figs. 1.1 and 1.3).1,2,34 The loop of Henle comprises the straight part of the proximal tubule (representing the thick descending limb), the thin descending and the thin ascending limbs (both thin limbs together represent the intermediate tubule), and the thick ascending limb (representing the straight portion of the distal tubule), which includes the macula densa. The CNT connects the nephron to the CD system. The renal tubules are outlined by an epithelium that comprises a single layer of cells anchored to a basement membrane. The epithelial cells have multiple transport functions and show numerous structural adaptations to their special roles. They are connected apically by a junctional complex consisting of a tight junction (zonula occludens), an adherens junction, and, at some sites, a desmosome. As a result of this organization, two different pathways through the epithelium exist (Fig. 1.10): a transcellular pathway, including the transport across the
Tubular Epithelia Luminal Paracellular Transcellular membrane transport transport
Tight junction Basolateral membrane
Lateral intercellular space
Basement membrane
Fig. 1.10 Tubular epithelia. Transport across the epithelium may follow two routes: transcellular, across luminal and basolateral membranes, and paracellular, through the tight junction and intercellular spaces.
luminal and basolateral cell membrane and through the cytoplasm and a paracellular pathway through the junctional complex and the lateral intercellular spaces. The functional characteristics of paracellular transport are determined by the tight junction, which differs markedly in its elaboration in the various tubular segments. The transcellular transport is determined by the specific channels, carriers, and transporters included in the apical and basolateral cell membranes. The various nephron segments differ markedly in function, distribution of transport proteins, and responsiveness to hormones and drugs such as diuretics. The cell surface area of the plasmalemmal compartments carrying the transport systems is extensively enlarged in many tubule cells, that is, by microvilli at the luminal membrane domain, by lamellar folds of the basolateral membrane interdigitating with those of the neighboring cells (interdigitations), or by lamellar folds of the basal cell membrane invaginating into its own cells (invaginations).
Proximal Tubule The proximal tubule reabsorbs the bulk of filtered water and solutes (Fig. 1.11). The proximal tubule is generally subdivided into three segments (known as S1, S2, and S3) that differ considerably in cellular organization and, consequently, also in function.35 Generally, the proximal tubule has a prominent brush border and e xtensive interdigitation by basolateral cell processes. This lateral cell interdigitation extends up to the leaky tight junction, thus increasing the tight junctional belt in length and providing a greatly increased passage for the passive transport of ions. Proximal tubule cells have large prominent mitochondria intimately associated with the basolateral cell membrane where the Na+,K+– adenosine triphosphatase (Na+,K+-ATPase) is located; this machinery is the molecular mechanism initiating numerous secondary transcellular transport processes. The luminal transporter for Na+ reabsorption specific for the proximal tubule is the Na+-H+ exchanger (NHE3) located in the plasma membrane of the apical microvilli and accounts for reabsorption of most of the filtered sodium. Further, sodium-coupled transporters in the microvillous membrane are the sodium-glucose cotransporters SGLT2 and SGLT1 and several sodium-phosphate cotransporters. The abundance of channel protein aquaporin 1 in the apical microvillous membrane and the basolateral cell membrane accounts for the high hydraulic permeability for water of this epithelium. An apical tubulovesicular compartment is part of the prominent
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CHAPTER 1 Renal Anatomy
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B
A
Fig. 1.11 Tubules of the renal cortex. (A) Proximal convoluted tubule is equipped with a brush border and a prominent vacuolar apparatus in the apical cytoplasm. The rest of the cytoplasm is occupied by a basal labyrinth consisting of large mitochondria associated with basolateral cell membranes. (B) Distal convoluted tubule also has interdigitated basolateral cell membranes intimately associated with large mitochondria. In contrast to the proximal tubule, however, the apical surface is amplified only by some stubby microvilli. (TEM; A, ×1530; B, ×1830.)
endosomal-lysosomal system and is responsible for the reabsorption of macromolecules (polypeptides and proteins such as albumin) that have passed the glomerular filter. The proximal tubule segment S3, including portions of S2, in addition, are engaged in many secretory processes of toxic substances and drugs via organic anion transporters and anorganic cation transporters. Proximal tubule cells are electrically coupled by gap junctions.
Intermediate Tubule The intermediate tubule comprises the thin portion of the loop of Henle displaying a flat epithelium and consists of a thin descending and (only in long loops) a thin ascending limb (Fig. 1.12; see also Fig. 1.2). The thin descending limb, like the proximal tubule, is highly permeable for water (the channels are of aquaporin 1), whereas, beginning at the turning point, the thin ascending limb is impermeable to water. The latter has a highly interdigitated epithelium also along the tight junction, which is highly permeable to ions.
Distal Straight Tubule (Thick Ascending Limb of the Loop of Henle) The thick ascending limb of the loop of Henle is often called the diluting segment. It is water impermeable but reabsorbs considerable amounts of sodium and chloride, resulting in the separation of salt from water. The salt is trapped in the medulla (see Fig. 1.12), whereas the water is carried away into the cortex, where it may return into the systemic circulation. The specific transporter for Na+ reabsorption in this segment is the Na2+K2+2Cl− symporter (NKCC2), which is specifically inhibited by loop diuretics such as furosemide. This transporter is inserted in the luminal membrane, which is amplified by only solitary microvilli. The tight junctions of the thick ascending limb are elongated by lateral interdigitation of the cells. They have a comparatively low overall permeability; however, they contain the protein Claudin 16 for paracellular
reabsorption of divalent ions, notably of magnesium. The cells are heavily interdigitated by basolateral cell processes, associated with large mitochondria supplying the energy for the transepithelial transport. The cells synthesize a specific protein, the Tamm-Horsfall protein, and release it into the tubular lumen. This protein is thought to be important for preventing the formation of kidney stones. A short distance before the transition to the distal convoluted tubule, the thick ascending limb contains the macula densa, which adheres to the glomerulus of the same nephron (see Juxtaglomerular Apparatus).
Distal Convoluted Tubule The epithelium exhibits the most extensive basolateral interdigitation of the cells and the greatest numerical density of mitochondria compared with all other nephron portions (see Fig. 1.11). Apically, the cells are equipped with numerous solitary microvilli. The specific Na+ transporter of the distal convoluted tubule is the luminal Na2+Cl− cotransport system (NCC), which can be inhibited by the thiazide diuretics. Magnesium is reabsorbed via the transient receptor potential channel melastatin subtype 6 (TRPM6) in the luminal membrane and, along the paracellular route, through the tight junctional proteins Claudin 16 and 19.
COLLECTING DUCT SYSTEM The CD system (see Fig. 1.2) includes the CNT and the cortical and medullary CDs. The embryologic origin of the CNT, which is interposed between the distal convoluted tubule and the CD, is unclear in whether it derives from the nephron anlage or the ureteral bud. Two nephrons may join at the level of the CNT, forming an arcade. Two types of cell establish the CNT: the CNT cell, which is specific to the CNT, and the intercalated (IC) cell, which is also present in varying amounts in the distal convoluted tubule and in the CD. The CNT cells are similar to the CD cells in cellular organization. Both cell types share sensitivity
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SECTION I Essential Renal Anatomy and Physiology
P
IC
CD
F CD
VR AL
TL F C
DL
TL
C
A
VR
B
Fig. 1.12 Tubules in the medulla. (A) Cross section through the inner stripe of the outer medulla shows a descending thin limb of a long Henle loop (DL), the medullary thick ascending limbs of Henle (AL), and a collecting duct (CD) with principal (P) cells and intercalated (IC) cells. C, Peritubular capillaries; F, fibroblast. (B) In the inner medulla cross section, thin descending and ascending limbs (TL), a collecting duct (CD), and vasa recta (VR) are seen. (TEM; A, ×990; B, ×1120.)
to vasopressin (antidiuretic hormone [ADH]; see later discussion). The amiloride-sensitive epithelial sodium channel (ENaC) and the epithelial calcium channel (TRPV5) are located in the apical membrane beginning in the distal convoluted tubule and extending into the CNT.
Collecting Ducts The CDs (see Fig. 1.12) may be subdivided into cortical and medullary ducts, and the medullary ducts into an outer and inner portion; the transitions are gradual. Like the CNT, the CDs are lined by two types of cell: CD cells (principal cells) and IC cells. The IC cells decrease in number as the CD descends into the medulla and are absent from the inner medullary CDs. The CD cells (Fig. 1.13A) increase in size toward the tip of the papilla. The basal cell membrane amplifies by lamellar invaginations into the cell (basal infoldings). The tight junctions have a large apicobasal depth, and the apical cell surface has a prominent glycocalyx. Along the entire CD, these cells contain an apical shuttle system for aquaporin 2 under the control of vasopressin, providing the potential to switch the water permeability of the CDs from zero to very low levels to permeable.36 A luminal amiloride-sensitive Na+ channel is involved in the responsiveness of cortical CDs to aldosterone. The terminal portions of the CD in the inner medulla express the urea transport system UTB1, which, in an antidiuretic hormone (ADH)-dependent fashion, accounts for the recycling of urea, a process that is crucial in the urineconcentrating mechanism.37,38 The second cell type, the IC cell (see Fig. 1.13B), is present in both the CNT and the CD. There are at least two types of IC cells, designated
A and B cells, distinguished on the basis of structural, immunocytochemical, and functional characteristics. Type A cells have been defined as expressing an H+-ATPase at their luminal membrane; they secrete protons. Type B cells express H+-ATPase at their basolateral membrane; they secrete bicarbonate ions and reabsorb protons.38 With these different cell types, the CDs are the final regulators of fluid and electrolyte balance, playing important roles in the handling of Na+, Cl−, and K+ and in acid-base homeostasis. The responsiveness of the CDs to vasopressin enables an organism to live in arid conditions, allowing production of concentrated urine and, if necessary, dilute urine.
JUXTAGLOMERULAR APPARATUS The juxtaglomerular apparatus comprises the macula densa, the extraglomerular mesangium, the terminal portion of the afferent arteriole with its renin-producing granular cells (also often termed juxtaglomerular cells), and the beginning portions of the efferent arteriole (see Fig. 1.4). The macula densa is a plaque of specialized cells in the wall of the thick ascending limb of Henle at the site where the limb attaches to the extraglomerular mesangium of the parent glomerulus (Fig. 1.14A; see also Fig. 1.5). The most obvious structural feature is the narrowly packed cells with large nuclei, which account for the name macula densa. The cells are anchored to a basement membrane, which blends with the matrix of the extraglomerular mesangium. The cells are joined by tight junctions with very low permeability and have prominent lateral
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CHAPTER 1 Renal Anatomy
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B
A
Fig. 1.13 Collecting duct cells. (A) Principal cell (CD cell) of a medullary collecting duct. The apical cell membrane bears some stubby microvilli covered by a prominent glycocalyx; the basal cell membrane forms invaginations. Note the deep tight junction. (B) Intercalated cells, type A. Note the dark cytoplasm (dark cells) with many mitochondria and apical microfolds; the basal membrane forms invaginations. (TEM; A, ×8720; B, ×6970.)
GC
EGM
A
B Fig. 1.14 Juxtaglomerular apparatus. (A) Macula densa of a thick ascending limb of Henle. The cells have prominent nuclei and lateral intercellular spaces. Basally, they attach to the extraglomerular mesangium (EGM). (B) Afferent arteriole near the vascular pole. Several smooth muscle cells are replaced by granular cells (GC) containing accumulations of renin granules. (TEM; A, ×1730; B, ×1310.)
intercellular spaces. The width of these spaces varies under different functional conditions.1 The most conspicuous immunocytochemical difference between macula densa cells and other epithelial cells of the nephron is the high content of neuronal nitric oxide synthase and cyclooxygenase-2 in macula densa cells.39,40 The basal aspect of the macula densa is firmly attached to the extraglomerular mesangium, a solid complex of cells and matrix penetrated by neither blood vessels nor lymphatic capillaries. As with the mesangial cells proper, extraglomerular mesangial cells are heavily branched. Their processes are interconnected by gap junctions, contain prominent bundles of microfilaments, and are connected to the basement membrane of
the Bowman capsule and the walls of both glomerular arterioles. As a whole, the extraglomerular mesangium interconnects all structures of the glomerular entrance.6 The granular cells are assembled in clusters within the terminal portion of the afferent glomerular arteriole (see Fig. 1.14B), replacing ordinary smooth muscle cells. Granular refers to the specific cytoplasmic granules in which renin, the major secretion product of these cells, is stored. Granular cells are the main site of the body where renin is secreted. Renin release occurs by exocytosis into the surrounding interstitium. Granular cells are connected to extraglomerular mesangial cells, adjacent smooth muscle cells, and endothelial cells by gap junctions
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SECTION I Essential Renal Anatomy and Physiology
and are densely innervated by sympathetic nerve terminals. Granular cells are modified smooth muscle cells; under conditions requiring enhanced renin synthesis (e.g., volume depletion, renal artery stenosis), additional smooth muscle cells of the afferent arteriole may transform into granular cells.
RENAL INTERSTITIUM The interstitium of the kidney is comparatively sparse. Its fractional volume in the cortex ranges from 5% to 7%, with a tendency to increase with age. Renal interstitium increases across the medulla from cortex to papilla. In the outer stripe, it is 3% to 4%, the lowest value of all kidney zones; this is interpreted as forming a barrier to prevent loss of solutes from a hyperosmolar medulla into the cortex. Renal interstitium is 10% in the inner stripe and up to about 30% in the inner medulla. The cellular constituents of the interstitium include resident fibroblasts, which establish the scaffold frame for renal corpuscles, tubules, and blood vessels, as well as varying numbers of migrating cells of the immune system, especially dendritic cells. The space between the cells is filled with extracellular matrix, that is, ground substance (proteoglycans, glycoproteins), fibrils, and interstitial fluid.41 Morphologically, fibroblasts are the central cells in the renal interstitium. Fibroblasts are interconnected by specialized contacts and adhere by specific attachments to the basement membranes surrounding the tubules, renal corpuscles, capillaries, and lymphatics. Renal fibroblasts are difficult to distinguish from interstitial dendritic cells on a morphologic basis, because both may show a stellate cellular shape and both display substantial amounts of mitochondria and endoplasmic reticulum. However, renal fibroblasts may be easily distinguished by immunocytochemical techniques. Dendritic cells constitutively express the major histocompatibility complex class II antigen and may express antigens such as CD11c. Dendritic cells may have an important role in maintaining peripheral tolerance in the kidney (Fig. 1.15).42 In contrast, fibroblasts in the renal cortex (not in the medulla) contain the enzyme ecto-5′-nucleotidase (5′-NT). A subset of 5′-NT–positive fibroblasts of the renal cortex synthesizes epoetin.43 Under normal conditions, these fibroblasts are exclusively found within the juxtamedullary portions of the cortical labyrinth. When there is an increasing demand for epoetin, the synthesizing cells extend to more superficial portions of the cortical labyrinth.44 Fibroblasts within the medulla, especially within the inner medulla, have a particular phenotype known as lipid-laden interstitial cells. The cells are oriented strictly perpendicularly toward the longitudinal axis of the tubules and vessels (running all in parallel) and contain conspicuous lipid droplets. These fibroblasts of the inner medulla produce large amounts of glycosaminoglycans and, possibly related to the lipid droplets, vasoactive lipids, in particular PGE2.42
Fig. 1.15 Renal dendritic cells. Dendritic cells (CX3CR1+ cells, green) surrounding tubular segments in the medulla of mice (three-dimensional reconstruction). (Reprinted with permission from reference 18.)
REFERENCES 1. Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: Seldin DW, Giebisch G, eds. The Kidney. 3rd ed. Philadelphia: Lippincott Williams & Wilkens; 2000:587–654. 2. Kriz W, Bankir L. A standard nomenclature for structure of the kidney. The Renal Commission of the International Union of Physiological Sciences (IUPS). Pflügers Arch. 1988;411:113–120. 3. Rollhäuser H, Kriz W, Heinke W. Das Gefässsystem der Rattenniere. Z Zellforsch Mikrosk Anat. 1964;64:381–403. 4. Barajas L. Innervation of the renal cortex. Fed Proc. 1978;37:1192–1201. 5. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197. 6. Elger M, Sakai T, Kriz W. The vascular pole of the renal glomerulus of rat. Adv Anat Embryol Cell Biol. 1998;139:1–98. 7. Inoue S. Ultrastructural architecture of basement membranes. Contrib Nephrol. 1994;107:21–28. 8. Miner JH. Renal basement membrane components. Kidney Int. 1999;56:2016–2024. 9. Abrahamson DR. Role of the podocyte (and glomerular epithelium) in building the GBM. Semin Nephrol. 2012;32:342–349. 10. Miner JH. Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol. 2011;26:1413–1417. 11. Kriz W, Elger M, Lemley KV, Sakai T. Structure of the glomerular mesangium: a biomechanical interpretation. Kidney Int. 1990;38:S2–S9. 12. Schlöndorff D, Banas B. The mesangial cell revisited: no cell is an island. J Am Soc Nephrol. 2009;20:1179–1187. 13. Haraldsson B, Jeansson M. Glomerular filtration barrier. Curr Opin Nephrol Hypertens. 2009;18:331–335. 14. Obeidat M, Obeidat M, Ballermann BJ. Glomerular endothelium: A porous sieve and formidable barrier. Exp Cell Res. 2012;318:964–972. 15. Neal CR, Crook H, Bell E, et al. Three-dimensional reconstruction of glomeruli by electron microscopy reveals a distinct restrictive urinary subpodocyte space. J Am Soc Nephrol. 2005;16:1223–1235. 16. Ichimura K, Miyazaki N, Sadayama S, et al. Three-dimensional architecture of podocytes revealed by block-face scanning electron microscopy. Sci Rep. 2015;5:8993. 17. Endlich KH, Kriz W, Witzgall R. Update in podocyte biology. Curr Opin Nephrol Hypertens. 2001;10:331–340. 18. Soos TJ, Sims TN, Barisoni L, et al. CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int. 2006;70:591–596. 19. Faul C. The podocyte cytoskeleton: Key to a functioning glomerulus in health and disease. Contrib Nephrol. 2014;183:22–53. 20. Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83:253–307. 21. Reiser J, Polu KR, Moller CC, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37:739–744. 22. Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308:1801–1804. 23. Greka A, Mundel P. Calcium regulates podocyte actin dynamics. Semin Nephrol. 2012;32:319–326. 24. Kerjaschki D, Farquhar MG. Immunocytochemical localization of the Heymann antigen (gp 330) in glomerular epithelial cells of normal Lewis rats. J Exp Med. 1983;157:667–686. 25. Bartlett CS, Jeansson M, Quaggin SE. Vascular growth factors and glomerular disease. Annu Rev Physiol. 2016;78:437–461. 26. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. 2015;26:258–269. 27. Kriz W, Lemley KV. Mechanical challenges to the glomerular filtration barrier: adaptations and pathway to sclerosis. Pediatr Nephrol. 2016;32:405–417. 28. Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14:211–216.
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CHAPTER 1 Renal Anatomy 29. George B, Holzman LB. Signaling from the podocyte intercellular junction to the actin cytoskeleton. Semin Nephrol. 2012;32: 307–318. 30. Endlich N, Endlich KH. The challenge and response of podocytes to glomerular hypertension. Semin Nephrol. 2012;32:327–341. 31. Hausmann R, Kuppe C, Egger H, et al. Electrical forces determine glomerular permeability. J Am Soc Nephrol. 2010;21:2053–2058. 32. Moeller MJ, Tenten V. Renal albumin filtration: alternative models to the standard physical barriers. Nat Rev Nephrol. 2013;9:266–277. 33. Kriz W, Hähnel B, Hosser H, et al. Structural analysis of how podocytes detach from the glomerular basement membrane under hypertrophic stress. Front Endocrinol (Lausanne). 2014;5:Article 207. 34. Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: Alpern RJ, Caplan MJ, Moe OW, eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. New York: Academic Press; 2013:595–691. 35. Maunsbach AB. Functional ultrastructure of the proximal tubule. In: Windhager EE, ed. Handbook of Physiology: Section on Renal Physiology. 2nd ed. New York: Oxford University Press; 1992:41–108. 36. Sabolic I, Brown D. Water channels in renal and nonrenal tissues. News Physiol Sci. 1995;10:12–17. 37. Bankir L, Trinh-Trang-Tan MM. Urea and the kidney. In: Brenner BM, ed. The Kidney. 6th ed. Philadelphia: Saunders; 2000:637–679.
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38. Madsen KM, Verlander JW, Kim J, Tisher CC. Morphological adaptation of the collecting duct to acid-base disturbances. Kidney Int. 1991;40:S57–S63. 39. Mundel P, Bachmann S, Bader M, et al. Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int. 1992;42:1017–1019. 40. Harris RC, McKanna JA, Akai Y, et al. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;94:2504–2510. 41. Kaissling B, Hegyi I, Loffing J, Le Hir M. Morphology of interstitial cells in the healthy kidney. Anat Embryol. 1996;193:303–318. 42. Krüger T, Benke D, Eitner F, et al. Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J Am Soc Nephrol. 2004;15:613–621. 43. Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem. 1993;41:335–341. 44. Kaissling B, Spiess S, Rinne B, Le Hir M. Effects of anemia on the morphology of the renal cortex of rats. Am J Physiol. 1993;264:F608–F617. 45. Ichimura K, Kakuta S, Kawasaki Y, et al. Morphological process of podocyte development revealed by block-face scanning electron microscopy. J Cell Sci. 2016;130:132–142.
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CHAPTER 1 Renal Anatomy
SELF-ASSESSMENT QUESTIONS 1. Podocytes: A. Are unable to replicate B. Are connected by gap junctions C. Have a positively charged glycocalyx D. Are connected to the GBM by hemidesmosomes E. Are in direct contact with mesangial cells 2. The glomerular basement membrane: A. Consists of α1 and α2 chains of type IV collagen B. Is produced mainly by the endothelium of glomerular capillaries C. Transforms at the urinary pole of a glomerulus into the basement membrane of the parietal epithelium D. Has a thickness of roughly 300 µm in humans E. Serves as the effector structure of mesangial cell contraction 3. The slit membrane has a width of roughly: A. 30 nm B. 100 nm C. 300 nm D. 1 µm E. 3 µm 4. Macula densa cells: A. Are a cell plaque within the distal convoluted tubule B. Are connected to the extraglomerular mesangial cells by gap junctions C. Are densely innervated by sympathetic nerve terminals D. Contain nitric oxide synthase E. Produce renin
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13.e1
