Kidney International, Vol. 39 (1991), pp.

370—381

Anatomy of the renal interstitium

Department of Pediatrics, University of Southern California School of Medicine, and Division of Nephrology, Childrens Hospital of Los
Angeles, Los Angeles, California, USA; and Institute of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany

The interstitium of the kidney comprises the extravascular tubule. This has been estimated to apply to 54% (in another
intertubular spaces of the renal parenchyma, with their atten- study 67%; [2]) of the total cortical peritubular capillary sur-
dant cellular elements and extracellular substances. As we face, whereas 26% of the tubular surface is directly juxtaposed
define it here, the interstitium is bounded on all sides by tubular by peritubular capillaries [3]. The capillary endothelium shows
and vascular basement membranes. This suggests including the evidence of a complementary structural polarity: fenestrated
lymphatics within the interstitium. That the vascular compart- areas are asymmetrically distributed, with twice as great an
ment on the other hand should be distinguished from the area of fenestrated capillary surface facing neighboring tubules
interstitium—in contrast to what is often assumed—is sug- across a "narrow" as across a "wide" interstitium [2]. Subdi-
gested by evidence of significant solute polarization between vision of the cortical peritubular interstitium into those parts
capillary plasma and the interstitium [I]. found in the labyrinth and in the medullary rays of the cortex
The interstitium of the kidney is not a simple passive space in may be important with respect to adenosine production by
which the "true" functional units—nephrons and vessels—are cortical interstitial cells [41 (vide infra).
embedded. Rather, it mediates and in fact modulates almost all
exchange among the tubular and vascular elements of the renal Periarterial connective tissue
parenchyma; along with segmental specialization of the neph-
ron, it underlies the functional zonation of the kidney; it The periarterial connective tissue forms a fluid-rich loose
probably influences glomerular filtration through its effects on connective tissue sheath which surrounds the intrarenal arteries
tubuloglomerular feedback; it decisively affects growth and and contains the lymphatic vessels of the kidney (Fig. 2) [5—71.
differentiation of parenchymal cells; it determines the compli- The periarterial sheath extends distally along the intrarenal
ance of the peritubular microvasculature; the cells of the arteries as far as the afferent arteriole, where it becomes quite
interstitium produce a variety of local (autocoid) and systemic attenuated. It is particularly abundant around the arcuate and
hormones; and alterations in the interstitium contribute to the cortical radial arteries. The periarterial connective tissue
clinical manifestations of renal disease. sheathes communicate freely with the peritubular interstitium.
This review will deal with the various cellular and extracel- The lymphatic capillaries begin within these sheaths about at
lular elements of the renal interstitium under normal conditions. the level of the cortical radial arteries in smaller species, more
The studies on which our conclusions are based were con- distally in larger ones; lymphatics do not in general penetrate
ducted principally in experimental animals, in particular the rat. the renal parenchyma proper [6—8]. The lymphatic vessels
possess an open endothelium and lack a complete basement
Subdivisions of the renal interstitium membrane. The lymphatic vessels converge along with the
As shown in Table 1 the renal interstitium may be divided intrarenal arteries to emerge at the renal hilus. Substances in
into cortical and medullary compartments with several subdi- the interstitium may enter the sheath and flow with the lymph
visions each. toward the renal hilus. Toward the hilus, the renal veins begin
to be incorporated in the sheath.
Peritubular interstitium
In the cortex the peritubular interstitium must be distin- Glomerular and extra glomerular mesangium
guished from the periarterial connective tissue sheaths. The
peritubular interstitium comprises the spaces between tubules, The glomerular and the extraglomerular mesangium may be
glomeruli and capillaries; the subcapsular interstitial spaces are considered to be special interstitia inasmuch as their cells are
part of it. In the peritubular interstitium of the cortex a narrow embedded in abundant extracellular matrices, which communi-
and a wide interstitium have been described (Fig. 1) [2], the cate with each other and (the latter) with the cortical interstitial
former accounting for 0.6% of the cortical volume, the latter for spaces. "Resetting" of the TGF in response to changes in
3.4%. The narrow interstitium is that space in which the outer volume and composition of the interstitial fluid probably occurs
surface of a capillary is "directly related" to a neighboring via this route [9]. Mesangial and extraglomerular mesangial
cells are generally considered as having a common origin with
vascular smooth muscle cells. They may thus be regarded as a
type of perivascular cell. Because of the special character of
© 1991 by the International Society of Nephrology these interstitia they will not be considered further here.

370
 Lemley and Kriz: Anatomy of the interstitium 371

Table 1. Renal interstitium studied by several authors [17—201; however, it is still not clear
Cortical how many and which types of interstitial cells are present in the
Pentubular (wide/narrow) kidney [21—231.
labyrinth
medullary rays Fibroblast-like cells
Periarterial
The fibroblast-like cells of the cortical interstitium are exten-
(mci. lymphatics)
Special interstitia sively branched, with long, often sheet-like processes (Figs. 2
Extra- and intraglomerular and 5). Their cytoplasm generally contains an abundant rough
mesangium endoplasmic reticulum. Mitochondria, Golgi complexes and
Meduliary lysosomes are regularly encountered; microfilament bundles
Outer stripe may be prominent in the peripheral cytoplasm and in the
Inner stripe processes. Lipid droplets are occasionally found. These fibro-
Vascular bundle
Interbundle region blast-like cells clearly also represent the predominant cell type
Inner medulla in the outer medullary interstitium. Together with the lipid-
laden cells of the inner medulla, the fibroblast-like cells of the
cortex and outer medulla have been classified as type I inter-
Medullary interstitium stitial cells of the kidney [19].
In the medulla, three types of interstitial space can be
distinguished [10], corresponding roughly to that of the outer Lipid-laden interstitial cells
stripe/vascular bundle, that of the interbundle region of the In the inner medulla, the predominant intrinsic interstitial
inner stripe, and that of the inner medulla. The first is a narrow, cells, lipid-laden interstitial cells, have several unique charac-
sparse interstitium occupying 3 to 5% of outer stripe volume teristics (Figs. 4, 6 and 7) [17, 19, 24, 25]. They contact and/or
(Fig. 3) [11]. The somewhat greater interstitial volume of the connect loops of Henle and \'asa recta, characteristically span-
interbundle region of the inner stripe (10% in the rat) is about ning these axial structures like the rungs of a ladder. In cross
equal to that of the cortical interstitium. The most distinctive sections through the medulla they appear star-shaped, and may
type of regional interstitium is that found in the inner medulla. have close structural relations to several thin limbs and capil-
Here the interstitium comprises a much larger part of the total laries [25]. They increase in number toward the tip of the
tissue volume and in addition unique interstitial cells character- papilla. They have specialized composite junctional connec-
ize this region (Fig. 4). Lymphatic vessels are absent from the tions to each other [26], but not to the thin limbs or capillaries
entire medulla [6, 8]. from which they are separated by a basement membrane. They
As suggested above, the relative interstitial volume is quite contain numerous homogeneous osmiophilic lipid droplets;
differently developed in different parts of the kidney with a hence they are called lipid-laden interstitial cells. They have an
pronounced axial gradient from cortex to medulla. Stereologic abundant RER with cisternae which are often dilated and filled
estimates of the peritubular interstitial volume in experimental with flocculent material (Fig. 7a). Special tubular cytoplasmic
animals range from 7 to 9% of total parenchymal volume in the inclusions (cylindrical bodies) have been described in these
cortex to 30 to 40% in the inner medulla [3, 11—131. Values for cells (Fig. 7c) [17, 24, 27]. The function of these structures is
interstitial volume are quite similar among species as diverse as unclear. A cytoskeleton is especially well developed in their
the Wistar rat, the rabbit and the desert rodent Psammomys most peripheral cell processes (Fig. 7b). In addition to micro-
obesus. Measurement of the functional interstitial volume of the tubules, microfilament bundles often fill the traversely running
rat kidney [14], on the other hand, has revealed a volume cell processes. Mediated by the plasma membrane these micro-
equivalent to 13.1% of the total kidney volume under control filament bundles appear to anchor in the basement membranes
(antidiuretic) conditions. That this value significantly exceeds of loops of Henle and vasa recta (but not collecting ducts). As
the stereologically derived values for accessible interstitial can be deduced from cell culture experiments, these cells
volumes (3 to 5% of the cell-free interstitial space of the cortex possess receptors for angiotensin II and bradykinin [28, 29]. In
and outer medulla) [12] makes clear that the functional intersti- the outer medulla transitional forms between the fibroblast-like
tium includes more than just the peritubular spaces [15, 16]. The cells of the cortex and the lipid-laden cells of the inner medulla
periarterial connective tissue sheaths in fact may account for may be found [19].
half of the entire interstitial volume [51.
Macrophages
Elements of the renal interstitium Macrophages (histiocytes) are found in all renal zones (Fig. 8)
The renal interstitium is composed of cells and extracellular [25, 30]. They appear to be the major fraction of type II
fibrillar structures, proteoglycans, glycoproteins and interstitial interstitial cells described by Bohman [19] and of the "mono-
fluid (Table 2). nuclear" cells described by Bulger and Nagle [18]. These cells
In the peritubular interstitium of the cortex, interstitial cells generally have a rounded shape. They demonstrate primary and
often fill the irregular spaces between tubules and vessels. The secondary lysosomes and characteristic surface folds, which
density of interstitial cells increases with increasing total inter- are especially prominent if they are encountered in the acti-
stitial volume. Compared to the cortex, interstitial cells are vated state. Their phagocytic capacity is well demonstrated by
quite rare in the outer stripe and the vascular bundles, while the uptake of iron dextran when given in low doses [30]. They
they are relatively abundant in the inner medulla. At the have been found to be abundant in the inner stripe and the outer
ultrastructural level the interstitial cells of the kidney have been parts of the inner medulla, and less frequent in the outer stripe
372 Lemley and Kriz: Anatomy of the interstitium

F,-
_4b'—-<'a.--'--
.r ;,.

't-[-
..L. tt..-- -.--

-
1 .'1 d'•
'-If
.sJiI -,
.1

' j2
Fig. 1. Peritubular interstitium of the cortex with narrow (arrows) and wide (stars) portions. Around the efferent arteriole (EA) the interstitium
is somewhat more extensively developed. Interstitial cells are of two types: fibroblast-like cells (1; type I interstitial cells) and rounded cells (2;
type II interstitial cells) are seen. Rat kidney; TEM; x 1,000
Fig. 2. Periarterial interstitium of the cortex. (a) Cross section through a cortical radial artery (CRA); the vessel is surrounded by wide interstitial
spaces which also contain lymphatic capillaries (L). V, vein. (b) Periarterial connective tissue sheath around a cortical radial artery (CRA). Wide
interstitial spaces subdivided by processes (arrows) of fibroblast-like cells (I). The round interstitial cell (2) appears to be a macrophage. N, nerve;
C, collagen. Rat kidney; TEM; (a) x—980; (b) —2,720

and the cortex [30]. Cells of this type are often found in close been clearly distinguished from the fusiform fibroblast-like cells
structural association to a fibroblast-like cell (Fig. 8) [19]. in cortex and outer medulla. Differentiation between these cell
types is difficult, since quite different methods have generally
Interstitial dendritic cells been used to characterize these cells. By immunocytochemis-
Interstitial dendritic cells are apparently also present in large try, it has been demonstrated that the dendritic cells are
numbers in the rat [23, 31, 32]. These stellate cells have not constitutively Ia (that is, they express MHC class II antigen),
 Lemley and Kriz: Anatomy of the interstitium 373

a.els 41— 1

;'iH

I 4;

Fig. 3. Peritubular interstitium of the outer stripe. Note the sparse interstitial spaces between tubules and capillaries, and between descending
(DVR) and ascending vasa recta (AVR) of a vascular bundle. P, proximal tubule; D, distal tubule; CD, collecting duct. Rat kidney; TEM; X - 1,000

Fig. 4. Inner medulla; longitudinal section. Wide interstitial spaces are separated by lipid-laden interstitial cells which are arranged like the rungs
of a ladder between vasa recta (V) and loops of Henle (in this case: between two ascending vasa recta). Note the lipid droplets (arrows) of these
cells. Rat; TEM; x—1,175

but lack classical macrophage/monocyte surface markers such ation or cyclophosphamide treatment [23, 311, presumably due
F- or C3-receptors [231. They appear, rather, to be the same to failure of radiosensitive bone marrow precursors to replenish
type of poorly phagocytic Ia antigen-presenting dendritic cells dendritic cells which have migrated from the cortical intersti-
found throughout the interstitial connective tissues of the rat. tium. On the other hand, Bohman and colleagues [211 have
The similarity in shape and location between type I interstitial shown that despite the dramatic loss of Ia cells from the renal
cells and MHC IT-expressing cells has been previously noted interstitium after irradiation, the overall volume density of
[21]. The dendritic cells have been suggested to be resident in interstitial cells in the cortex and outer medulla remains virtu-
the interstitium for only a few days, since significant tissue ally unchanged, suggesting that the apparent cell loss may
depletion occurs within five days of 1000 rad total body irradi- actually be loss of cell surface antigen expression. The above-
374 Lemley and Kriz: Anatomy of the interstitium

Table 2. Elements of the interstitium electron-lucent core have been described both isolated and
Cells associated with interstitial cell processes (Fig. 11) [18, 201. In
Fibroblast-like cells the medullary interstitial matrix, Furusato [41] has reported
Lipid-laden interstitial cells even thinner fibrils (3 to 15 nm in diameter) which appear to
Macrophages and other non-resident cells underlie a diffuse reticular structure and disappear after treat-
Perivascular cells
Extracellular components ment with hyaluronidase. In contrast to the subcutaneous
Fibrillar structures interstitium, elastic fibers are not found.
Ground substance The interstitial fluid together with the glycosaminoglycans
Proteoglycans (GAG) are responsible for the gelatinous character of the
Glycoproteins matrix. The content of GAG is high, almost 1% of the dry
Interstitial fluid
weight of the medulla in the dog. If hyaluronic acid GAG is
uniformly distributed within the interstitial space, its concen-
tration in the medullary interstitium, for example, probably
mentioned frequent association of fibroblast-like cells with type exceeds 2 mg/mI [42, 431.
II cells (macrophages) may have functional significance, inas- The several different GAG of the ground substance are
much as although dendritic cells are excellent antigen-present- present in different proportions in the various regions of the
ing cells, they are not capable of processing particulate antigens kidney. Their composition has been investigated in most detail
themselves, and thus may associate with macrophages in the in the renal medulla and papilla. In the papilla of the rat [44] the
immune response [331. Thus much about the origins and nature major types of GAG present are hyaluronic acid (34%), heparin
of Ia cells in the renal interstitium remains to be clarified. In (36%) and dermatan sulfate (26%), with much less chondroitin
humans the homologous parenchymal dendritic cells express sulfate (4%). An earlier study in the rat [451 indicated a greater
the CD45 common leukocyte antigen and are probably also proportion of heparan sulfate GAG (51%) in the medulla. In the
antigen-presenting cells [34, 351. Unlike in the rat, in humans dog hyaluronic acid may account for a considerably greater
most Ia cells of the renal cortex are fixed parenchymal proportion (70%) of total medullary GAG [431. Thus the total
(endothelial) cells. Other leukocytes (such as, plasma cells and renal GAG composition may differ considerably from that
mast cells) are also found in lesser numbers in the interstitium. found in different parts of the peritubular interstitial matrix
itself. "Free matrix granules" [41, 441 seen in the interstitium—
Perivascular cells often in association with reticular structures—may represent
Perivascular cells (pericytes) are found in the transitional condensed hyaluronate-proteoglycan aggregates, collapsed as
portion between the cortical efferent arterioles and the peritu- part of a macromolecular phase transition during routine fixa-
bular capillaries (Fig. 5b). They are especially abundant in the tion. Even the relatively uniform matrix network described by
medulla, where they surround the descending vasa recta [36, Furosato [41] after treatment with the GAG insolubilizing agent
37]. Pericytes are often considered to be a transitional cell type cetyl pyridinium chloride has an appearance which one might
between vascular smooth muscle cells and the fibroblasts of the expect from a partially collapsed network of such extended
interstitium. Like vascular smooth muscle cells they are en- aggregates. The composition of the flocculent, basement mem-
closed by a basement membrane. brane-like material often seen in the interstitium is currently
unknown. It also seems to be contiguous with the microfibrillar
Extracellular components reticulum. The appearance of all elements of the matrix is quite
The extracellular components of the interstitium comprise a dependent on fixation conditions [41]. In well-fixed specimens
matrix, which may be thought of as a hydrated gel of ground the ground substance of the interstitial matrix appears to be
substance within a fibrillar reticulum. The ground substance in quite homogeneous.
turn consists of proteoglycans, glycoproteins, and interstitial Various glycoproteins (fibronectin, laminin, and others) are
fluid. Basement membranes are also considered part of the found associated with tubular basement membranes and at
interstitium. other sites in the interstitium. They serve to connect basement
Several fibers make up the interstitial reticulum. Together membranes to cell membranes as well as to fibrillar structures
with the gelatinous matrix, these provide a very resilient and GAG of the interstitial matrix [461. A detailed discussion of
structure, which can perhaps be seen as analogous to man-made these substances is beyond the scope of this review.
composite materials. Typical 'interstitial" collagenous fibers
(types I, III, and VI) are present in the matrix, both isolated and Functional significance of the renal interstitium
in bundles (Figs. 2 and 9). Type I collagen forms typical In the following we will try to summarize the functional
cross-banded fibers of generally more than 30 nm thickness. relevance of the various interstitial components. Specifically
Type III fibers (10 to 40 nm diameter) and type VI fibers (6 to 10 immunological aspects are beyond the scope of this review.
nm diameter) [38, 391 are both seen often associated with type
I fibers. Type III fibers correspond to the classically-described Production and degradation of fibers and ground substance
"reticular fibers," which form a network enveloping the tubules The fibroblast-like cells in the cortex and outer medulla, and
and are well demonstrated by silver staining (Fig. 10). Collagen the lipid-laden cells in the inner medulla are responsible for the
types IV and V are found in the basement membranes. In the production of the extracellular material, fibers and ground
multilayered basement membrane of Bowman's capsule they substance. The well developed rough endoplasmic reticulum of
obviously form filamentous structures [401. In addition, un- these cells indicates a high rate of protein synthesis, the
banded microfibrils with a diameter of 15 to 30 nm and an production of collagenous and non-collagenous extracellular
 Lemley and Kriz: Anatomy of the interstitium 375

a • 'S. •_•
BS
S.
'I

1%

a9

'S
-I
•1
4

\
r1

•t •-I
',-.'

Ca

Fig. 5. (a). Fibroblast-like cell in the cortical peritubular interstitium. Note the smooth contours of the nucleus, the well-developed rough
endoplasmic reticulum, and microfilament bundles (MF). BS, Bowman's space of a renal corpuscle (glomerulus). Note the multilayered basement
membrane of Bowman's capsule (stars). (b) Part of a fibroblast-like interstitial cell containing a well-developed rough endoplasmic reticulum,
several round profiles of mitochondria, a multivesicular body (MV), and Golgi apparatus. In addition, a perivascular cell (3) is seen which contains
a microfilament bundle (MF) and is surrounded by a basement membrane. C, collagen fibres; Ca, capillary. Rat kidney; TEM; (a) X-—7,900; (b)
x —18,000

Fig. 6. Lipid-laden interstitial cell of the inner medulla. This cell contains a few lipid droplets (LD), and a well-developed, widened rough
endoplasmic reticulum. The perinuclear cisternae are often found to be widened (arrow). G, Golgi apparatus. The cell is partly surrounded by
basement membrane-like material. Note cell detritus in the interstitium (star). Rat; TEM; X —13,500

proteins. Widened cisternae of the ER—often seen in cortical widened cisternae of the ER in the lipid-laden interstitial cells in
fibroblast-like cells—are generally taken as evidence for a very the inner medulla have been interpreted as artifacts [25, 47],
active synthesis. On the other hand, the often extremely since they are frequently found as empty spaces in otherwise
376 Lemley and Kriz: Anatomy of the interstitium

C)
It®'

4.
-dr
'I'
.'k7
II

Fig. 7. Details of lipid-laden interstitial cells. (a) Part of a lipid-laden interstitial cell with conspicuously widened cisternae of the RER;
cytoplasmic processes (stars) project into this widened space (arrows). Close applications of the ER-spaces to the plasma membrane (arrow) are
often seen. LD, lipid droplet; MF, microfilament bundle. (b) Process of a lipid-laden interstitial cell nchoring into the basement membrane (BM)
of a ioop of Henle (L). The cytoskeleton of this process consists of abundant microtubules (MT) and microfilaments (MF). C, collagenous fibres.
(c) "Cylindrical bodies" in cross and longitudinal section (arrows). LD, lipid droplet. Rat kidney; TEM; (a) x—18,000;(b) x—24,500;(c) x—2 1,900
Fig. 8. Macrophages in the cortical interstitium. (a) Round cell (type H interstitial cell) exhibiting surface folds and numerous primary lysosomes
(arrows) typical for macrophages. Adjacent, a fibroblast-like cell (1) is seen. Ca, capillary. (b) A macrophage in the activated state. Rat kidney;
TEM; (a) x—i2,000; (b) x—8,S0O

poorly fixed specimens. However, conspicuously widened cis- The lipid-laden interstitial cells synthesize GAG and probably
ternae may also be filled with fiocculent material and may be are the source of most of the hyaluronic acid in the inner
found in well fixed (Fig. 7a) [171 and in cultured lipid-laden medulla [44]. The GAG of the renal interstitium are quite
interstitial cells [44]. dynamic, with a half-life of just a few days [45]. It is possible
 Lemley and Kriz: Anatomy of the interstitium 377
.rrtLtst-.
ztrr-i;

Fig. 9. Peritubular interstitium of the cortex; tangential section through the inteiface between a tubule (left) and a capillary (right). The inset
shows a comparable situation in cross section. Between the two basement membranes (BM; clearly discernable in the inset) collagenous fibers
(arrows; 30 to 40 nm thick) are seen which probably correspond to the "reticular fibers" shown in Fig. 10. Much thinner fibrils (10 to 15 nm thick;
arrow heads) are also encountered. These do not appear to be typical microfibrils (hollow structure; see Fig. 11) but may represent "reticular
microfibrils." T, tubule; C, capillary. Rat kidney; TEM; x22,800; inset, x—23,650
Fig. 10. Longitudinal section through the outer stripe of the rat kidney. "Reticular fibers" are stained by a silver impregnation technique [781. The
"reticular fibers" surround the tubules predominantly in a circular manner. Photograph provided by Professor T. Ishii, University of Sendai,
Japan. Rat kidney; LM; x-340

that prostaglandins (produced by the lipid-laden cells them- II interstitial cells [19]) and not the lipid-laden interstitial cells
selves) regulate GAG production by these interstitial cells are responsible for lysosomal degradation of sulfated GAG [30].
inasmuch as fibroblasts in culture both synthesize prostaglan-
dins and respond to them by increased sulfated GAG produc- Tissue skeleton/structural support
tion [48]. Inhibitor experiments suggest that whereas the fibro- One of the basic functions of any interstitium is to give
blast-like cortical interstitial cells are involved in degradation of structural support to an organ, to its parenchymal and vascular
sulfated GAG in the cortex and part of the outer stripe of the elements. We have not described the coarse connective tissue
medulla, in the rest of the medulla macrophage-like cells (type elements of the kidney, the collagenous capsule and the collag-
378 Lemley and Kriz: Anatomy of the inlerstitium

[52] and specific binding sites between GAG and collagen have
even been suggested [53].
In the medulla the interstitial cells themselves also connect
the axial tubular and vascular structures to one another. The
transversely running microfilament bundles of these cells all
terminate in the most peripheral cell processes which anchor in
the basement membranes of loops of Henle and vasa recta
(although not of collecting duct [25]).
Matrix support is probably particularly important for the
delicate tubular structures in the inner medulla, of which the
venous blood vessels may be little more structurally than
"tunnels in a gel" [54], their compliance characteristics deriv-
ing entirely from those of the extracellular substance. This may
explain the particular susceptibility of these structures to toxic
reactive substances which affect the matrix [55]. Connections to
the matrix network probably also help to keep these thin walled
structures patent, despite changes in interstitial pressure.
Structural support is also provided by perivascular cells
(pericytes), which encircle the precapillary segments of the
cortical vasculature and the descending vasa recta in the
medulla. These cells are undoubtedly contractile, but—in con-
trast to vascular smooth muscle cells—they lack direct inner-
vation. They support these vessels in the way smooth muscle
cells do in arterioles and arteries [37].
Exchange and insulation
All exchanges among tubules and vessels have to pass
through an interstitial compartment; exchange is considered to
occur mainly by diffusion. There seems to be no compelling
morphologic reason to posit the existence of "free fluid" spaces
within the interstitium. When we refer to the interstitial "fluid"
this is actually to be understood as the aqueous component of a
gel. In addition to the distances between the structures, the
properties of this gel, of the ground substance, will have
significant effects on diffusional exchange [56], especially in the
medulla where it is most highly developed [44].
Fig. 11. Peritubular interstitium of the renal cortex between two cap- As already noted, interstitial spaces are quite differently
illaries. In addition to collagenous fibers (C) abundant microfibrils developed in the kidney with respect to site and composition.
(arrowheads) are frequently seen. These microfibrils can be clearly
recognized by their tubular structure (arrows) together with their Narrow interstitial spaces facilitate local exchanges; wide inter-
typical thickness of about P.nm. Rat kidney; TEM; x—54,000 stitial spaces, on the other hand, allow exchange and equilibra-
tion among more distant structures. In the peritubular intersti-
tium of the cortex the "narrow interstitium" would seem to be
responsible for most direct exchange between tubule and cap-
enous arches which are anchored in the peripelvic connective illary. Differences in oncotic and hydraulic pressure found in
tissue and run along the medullary side of the arcuate veins at the "narrow" and the "wide" peritubular interstitium in the
the cortico-medullary border [49]. cortex may account for some of the discrepancies which have
The mechanical integration of renal tubules and blood vessels arisen in attempts to explain proximal tubular fluid reabsorption
via the interstitium is always mediated through their surround- in terms of peritubular physical forces [15]. The loss of facili-
ing basement membranes, which are attached to both cell and tated exchange across a "narrow" interstitium may be a crucial
matrix via glycoproteins such as laminin and fibronectin, and factor in explaining functional derangements when the intersti-
heparan sulfate proteoglycans [46, 50]. The interstitial matrix tium volume increases in some pathological conditions [57].
supports the renal tubules and blood vessels by virtue of its The "wide" parts of the peritubular interstitium of the cortex
resilient network of extracellular fibers and ground substance. may be suggested to establish an interconnected compartment
The finest fibrillar structures (microfibrils, collagen type VI) are which freely and extensively communicates with the periarte-
anchored in the lamina rara interna in the basement membrane rial connective tissue sheathes. Such a communication has been
or, in the case of microfibrils, may sometimes be seen to demonstrated by the distribution of high molecular weight
penetrate into the lamina densa [51]. The fibrillar reticulum is tracers from the subcapsular spaces through the peritubular
connected to the ground substance not simply by steric entan- interstitium into the periarterial sheathes and finally the lym-
glement with its extended proteoglycans: strong electrostatic phatics [2]. The relevance of diffusional equilibration within the
interactions appear to bind collagenous fibers to sulfated GAG cortical peritubular interstitium may be small, however, be-
 Lemley and Kriz: Anatomy of the interstitium 379

cause of the relative sparsity of these spaces and because of the peritubular interstitium outside the sheathes. Along the way to
presence of extensive "mixing" blood flow within the peritu- the hilus, fluid and solutes may gradually enter the lymphatic
bular capillaries. vessels. The periarterial connective tissue is also closely related
The most sparsely developed interstitium is found in the to the intrarenal veins which, given their capillary-like wall
outer stripe and within the vascular bundles in the inner stripe. structure, may be expected to exchange various substances
At these sites countercurrent structures are running side by with the sheath.
side: ascending and descending vasa recta within the vascular In addition to lymphatic drainage, the functions of the pen-
bundles; in the interbundle region of the outer stripe descending arterial connective tissue sheathes probably include intrarenal
tubules (partes rectae of proximal tubules and collecting ducts) distribution of renin and angiotensin [71, and the intrarenal
and ascending vasa recta [10, 58]. The close juxtaposition of movement of lymphocytes, macrophages, etc. In particular,
these structures favors countercurrent trapping of solutes in the renin from the granular cells of the juxtaglomerular apparatus is
medulla. Together with the lack of medullary lymphatics, this released into the periarterial interstitium [63] from which both
arrangement establishes the insulation of the medulla. Cortical the renin and the angiotensin generated by it can gain access to
and medullary interstitia are virtually completely separated. structures at the vascular pole of the glomerulus as well as the
The interstitium in the interbundle region of the inner stripe is renal arteries and veins. Similar considerations may be relevant
similar to the peritubular interstitium in the cortex, albeit with respect to the lymphatic distribution of the adenosine
slightly more abundant. In both cortex and the interbundle formed by fibroblast-like cells within the cortical labyrinth (vide
region the convective element of fluid and solute transport infra).
(represented by blood flow in the peritubular capillary plexus)
overwhelms the effects of local diffusion across the interstitium. Hormonal significance of interstitial cells
A very narrow, insulating interstitium would be inconsistent Interstitial cells of the kidney are involved in the synthesis of
with the random, non-countercurrent arrangement of blood several systemic and autocoid hormones. Erythropoietin (EPO)
flow in this region. has long been known to be synthesized in the kidney. By in situ
In the inner medulla the interstitium must be assumed to hybridization it has recently been shown that the synthesizing
establish rather extensive regions over which tubular and cells are located in the cortical peritubular compartment [64,
vascular structures exchange and equilibrate with each other. 65]. It remains unclear whether the endothelial cells of peritu-
However, the high GAG content of the matrix will limit water bular capillaries or peritubular interstitial cells express the
and probably also solute movement [59, 601. It seems reason- erythropoietin mRNA detected in these studies. Only a very
able to conclude that there is effectively no bulk flow of water small number of peritubular cells express EPO in nonanemic
within the interstitial spaces. Together with a relative paucity of mice; these cells are located in the inner cortex [661. Increasing
laterally running capillary segments there, this means that in the EPO production is a result of increasing cell recruitment, not of
inner medulla most interstitial exchange is mediated by lateral changes in the level of EPO synthesis within individual cells.
diffusion. Based on dye injection studies the existence of Even under conditions of severe anemia, however, it is esti-
longitudinal "channels" in the interstitial matrix along the mated that less than 10% of interstitial cells express EPO
collecting ducts and under the papillary epithelium has been mRNA [661.
proposed [61], but structural studies have so far failed to Recent studies have also shed light on the renal localization
demonstrate such channels. The orientation and density of of adenosine production [4, 67]. The enzyme ecto-S-nucleotid-
lipid-laden inner medullary interstitial cells would also seem to ase catalyses the cleavage of AMP into adenosine and phos-
hinder axial diffusion in this region, helping to create lateral phate. Adenosine from this process is released into the extra-
medullary microcompartrnents in which the histotopography cellular space. The peritubular localization of this enzyme has
establishes specific exchange relations among the tubules and been clearly demonstrated; only the interstitial cells, most
vessels [101. In addition, other characteristics of the ground probably fibroblast-like cells (termed fibroblasts by the authors)
substance (such as high negative charge density) may decrease of the cortical labyrinth (and not of the cortical medullary rays
the potential for interstitial stone nucleation and metastatic or the medulla) contained this enzyme. Endothelial cells were
calcification, despite very high concentrations and long resi- negative.
dence times of the reactant species [62]. In the kidney adenosine represents an autocoid which con-
tracts the afferent arteriole, inhibits renin release and decreases
Lymphatic drainage sodium reabsorption. Since adenosine production increases
The renal cortex has a lymphatic drainage, whereas the during hypoxia [68], adenosine has been interpreted as part of
medulla does not [6, 8, 16]. The drainage of the cortical an intrarenal mechanism protecting the kidney from hypoxic
interstitium is effected by the periarterial connective tissue injury by decreasing the workload of the kidney [69, 70].
sheath [7]. The peritubular interstitium in the cortex freely The synthesis of both erythropoietin and adenosine is stimu-
communicates with these sheathes. Thus, substances from the lated by hypoxia. Moreover, several studies have suggested
cortical interstitium may enter the periarterial connective tissue that adenosine stimulates erythropoietin production [71, 72].
from all sides. Within this tissue, bulk flow outside the lym- Thus, it is possible that adenosine represents a transduction
phatic vessels probably occurs both because there is a hydro- signal between the sensor of decreased 02 availability and the
static pressure gradient from interstitium to hilus (perhaps cells responsible for subsequent erythropoietin production. The
approximately equal to the gradient within the venous system) site of p02 "sensation" and EPO production is perhaps not
and the intrinsic resistance to flow within the loose connective surprising, if the local P°2 of the renal cortex approximates that
tissue of the sheath is considerably less than that of the of arterial blood as is commonly believed. Given that the
380 Lemley and Kriz: Anatomy of the interstitium

"sensing" system for arterial p02 must lie in cells resident in 12. PFALLER W, RITTINGER M: Quantitative Morphologie der Niere.
some organ, the best site would seem to be an organ so highly Mikroskopie 33:74—79, 1977
perfused that oxygen tension there reflects arterial P°2 and not 13. GABEL A: Die quantitative Zusammensetzung der inneren Mark-
zone der Niere bei Psammomys obesus. Heidelberg, University of
the effects of local metabolism. Heidelberg, 1980
In the medulla, the lipid-laden interstitial cells have long been 14. LARSON M, SJONQUIST M, WOLGAST M: Renal interstitial volume
considered to be important for renal medullary prostaglandin of the rat kidney. Acta Physiol Scand 120:297—304, 1984
production. The lipid droplets of these cells contain polyunsat- 15. WOLGAST M, LARSON M, NYGREN K: Functional characteristics of
urated fatty acids which appear to be precursors for prostaglan- the renal interstitium. Am J Physiol 241 :F105—Fl 11, 1981
16. PINTER GG, GARTNER K: Peritubular capillary, interstitium, and
dins and other lipid-derived hormones [73]. In tissue culture lymph of the renal cortex. Rev Physiol Biochem Pharmacol 99:184—
these cells have been found to synthesize prostaglandins in 202, 1984
increased amounts when exposed to angiotensin II or bradyki- 17. OSVALDO L, LATTA H: Interstitial cells of the renal medulla.
Ultrastruct Res 15:589—613, 1966
nm [28, 29]. They produce, as well, an antihypertensive effect 18. BULGER RE, NAGLE RB: Ultrastructure of the interstitium in the
when transplanted subcutaneously into several models of hy- rabbit kidney. Am JAnat 136:183—204, 1973
pertension in the rat, possibly due to production of the lipid 19. BOHMAN S-O: The ultrastructure of the renal interstitium, in
hormones, medullipin I and II [74, 75]. Differences in the size Contemporary issues in nephrology, edited by BM BRENNER, JH
and number of lipid droplets are observed between salt-resis- STEIN, New York, Churchill Livingstone, 1983, pp. 1—34
tant and salt-sensitive Dahi hypertensive rats [761 as well as 20. LANGER KH: Renal interstitium ultrastructure and capillary per-
meability, in Functional Ultrastructure of the Kidney, edited by AB
between Brattleboro and normal Long-Evans rats [77], but MAUNSBACH, TS OLSEN, El CHRISTENSEN, London, Academic
consistent morphologic differences associated with normal Press, 1980, pp. 431—442
physiologic changes in medullary function have not been dem- 21. BOHMAN S-0, SIJNDELIN B, FORSUM U, TRIBUKAIT B: Experi-
onstrated. mental depletion of different renal interstitial cell. Am J Med Sci
295:252—257, 1988
22. STEINIGER B, KLEMPNAUER J, WONIGEIT K: Phenotype and his-
Acknowledgments tological distribution of interstitial dendritic cells in the rat pan-
creas, liver, heart, and kidney. Transplantation 38:169-175, 1984
The authors gratefully acknowledge the technical assistance of Ms. 23. GURNER AC, SMITH J, CATTEL V: The origin of Ia antigen-
Hiltraud Hosser and Ms. Bruni Hähnel; we also thank Ms. Ingrid Ertel expressing cells in the rat kidney. Am J Pathol 127:342—348, 1987
for doing the photographic work and Ms. Helene Dehoust for secre- 24. BULGER RE, GRIFFITH LD, TRUMP BF: Endoplasmic reticulum in
tarial help. This work would not have been possible without the rat renal interstitial cells: Molecular rearrangement after water
generous support of 'Deutsche Forschungsgemeinschaft" (Forscher- deprivation. Science 151:83—86, 1966
gruppe 'Niere", Heidelberg). 25. BOHMAN S-O: The ultraStructure of the rat renal medulla as
observed after improved fixation methods. J Ultrastruct Res 47:
Reprint requests to Kevin V. Lemley, M.D., Ph.D., Division of 329—360, 1974
Nephrology, Box 40, Childrens Hospital of Los Angeles, 4650 Sunset 26. SCHILLERA, TAUGNERR: Junctions between interstitial cells of the
Blvd., Los Angeles, California 90027, USA. renal medulla: A freeze-fracture study. Cell Tissue Res 203:231—
240, 1979
27. LEDINGHAM JM, SIMPsoN FO: Bundles of intracellular tubules in
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