The Formation, Appearance, and Composition of Casts
The Formation, Appearance, and Composition of Casts
The Formation, Appearance, and Composition of Casts
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<strong>The</strong> <strong>Formation</strong>, <strong>Appearance</strong>,<br />
<strong>and</strong> <strong>Composition</strong> <strong>of</strong> <strong>Casts</strong><br />
<strong>Casts</strong>, uniquely found in the urine, were initially discovered<br />
in the mid-19th century <strong>and</strong> were at first thought<br />
to be associated with renal abnormalities. Time has<br />
proven this to be a false assumption, however, since a<br />
few casts are also found in the urine <strong>of</strong> normal individuals.<br />
<strong>The</strong>ir presence in disease states is, however, vitally<br />
important in the diagnosis <strong>of</strong> the specific etiology <strong>of</strong><br />
renal diseases <strong>and</strong> the physiological conditions in the<br />
kidney that prompted their formation.<br />
All urinary casts are composed <strong>of</strong> a proteinaceous<br />
matrix. <strong>The</strong> proteins forming the cast are secreted by<br />
the lining cells <strong>of</strong> the tubules lining the distal nephron—specifically,<br />
the distal tubule <strong>and</strong> collecting duct<br />
lining cells. <strong>The</strong>se cells are nonciliated columnar epithelial<br />
cells with basally placed nuclei. <strong>The</strong>y, in contrast<br />
to the lining cells <strong>of</strong> the proximal tubule <strong>and</strong> loop<br />
<strong>of</strong> Henle, have the propensity to excrete a particular<br />
type <strong>of</strong> immunoprotein known as Tamm-Horsfall (TH)<br />
mucoprotein. Once excreted into the urinary flow, this<br />
protein, along with other proteins secreted by these lining<br />
cells, agglutinates <strong>and</strong> is then molded into a semisolid,<br />
fibrillar, cylindrical, amorphous shape, which is<br />
the prototypical hyaline cast. <strong>The</strong> hyaline cast serves<br />
as the basic building block for all cast types. In its most<br />
elementary form, it is homogeneous, translucent, has a<br />
low refractive index, <strong>and</strong> does not contain any particulate<br />
material or cells.<br />
In the normal state, cells lining the nephron are<br />
continually dying <strong>and</strong> regenerating. In many diseases,<br />
these same lining cells may be affected by chemical<br />
toxins, such as lead or mercury, or inflammatory<br />
agents, such as bacteria, <strong>and</strong> die prematurely. In either<br />
instance, cell death results. Intrinsic cellular lysosomes,<br />
which contain enzymes necessary for cellular degradation,<br />
serve as “garbage disposals” for the cell’s component<br />
parts, especially mitochondria, <strong>and</strong> convert<br />
these organelles into minute, fine, granular particles.<br />
<strong>The</strong> granular products <strong>of</strong> cell death enter the urinary<br />
flow <strong>and</strong> may become incorporated into the matrix <strong>of</strong><br />
a forming hyaline cast. When the amount <strong>and</strong> number<br />
<strong>of</strong> these granules occupies the majority <strong>of</strong> the cast’s<br />
surface, the cast is called a granular cast.<br />
Four cell types may, in a wide variety <strong>of</strong> diseases,<br />
adhere to the surface <strong>of</strong> or become incorporated into<br />
the matrix <strong>of</strong> a hyaline cast: these are RBCs, WBCs, epithelial<br />
cells, <strong>and</strong> bacteria/fungi. Ultrastructural studies<br />
have shown that some <strong>of</strong> these cells are bound to the<br />
cast’s surface by means <strong>of</strong> b<strong>and</strong>s <strong>of</strong> thin proteinaceous<br />
material, most likely TH protein. <strong>The</strong>se cellular casts are<br />
named according to the type <strong>of</strong> cell so bound, i.e., RBC<br />
cast, WBC cast, epithelial cast, <strong>and</strong> bacterial cast. Cellular<br />
casts are not found in normal patients.<br />
Pigment casts are somewhat complex in that the<br />
usual hyaline proteinaceous matrix amalgamates with<br />
a component in the glomerular filtrate, most <strong>of</strong>ten hemoglobin.<br />
Other chemical substances that circulate in<br />
the serum <strong>and</strong> remain in high concentration in the urinary<br />
flow after being filtered by the glomerulus may<br />
<strong>Casts</strong> 165
Tamm-Horsfall<br />
protein<br />
<strong>The</strong> Tamm-Horsfall protein,<br />
also known as uromodulin, is<br />
a very large glycoprotein that<br />
is the most abundant protein<br />
in normal urine. Hyaline<br />
casts, cylindroids, <strong>and</strong> mucous<br />
str<strong>and</strong>s are all made, at least<br />
in part, <strong>of</strong> Tamm-Horsfall protein<br />
fibrils.<br />
Cast <strong>Formation</strong>:<br />
Tamm-Horsfall Protein<br />
also be incorporated into the cast as it forms within<br />
the lumen <strong>of</strong> the nephron: these include melanin in<br />
patients with melanoma, <strong>and</strong> myeloma protein in patients<br />
with multiple myeloma. <strong>The</strong>se so-called pigment<br />
casts are infrequently seen, however, with the exceptions<br />
<strong>of</strong> the hemoglobin cast (see “Muddy <strong>Casts</strong>,” page<br />
196), which may be prominent in patients with acute<br />
renal failure, <strong>and</strong> bile-stained casts in patients with severe<br />
jaundice such as is found in acute cases <strong>of</strong> viral<br />
hepatitis <strong>and</strong> chronic liver failure.<br />
<strong>The</strong> exact origin <strong>of</strong> waxy casts is not clear, however.<br />
Although they have a proteinaceous matrix, which includes<br />
TH immunoprotein, their surface characteristics<br />
differ significantly from the usual translucent hyaline<br />
appearance. <strong>The</strong>se casts have a high refractive index<br />
<strong>and</strong> appear dense, <strong>of</strong>ten with blunted ends <strong>and</strong><br />
notched margins. It is theorized that waxy casts may<br />
be the evolutionary product <strong>of</strong> preexisting cellular<br />
casts in which the cells have completely disrupted <strong>and</strong><br />
166 <strong>Casts</strong><br />
renal tubular epithelial cells<br />
distal tubule<br />
hyaline cast<br />
Tamm-Horsfall protein is excreted by epithelial cells in the thick<br />
ascending branch <strong>of</strong> the loop <strong>of</strong> Henle <strong>and</strong> the first part <strong>of</strong> the<br />
distal tubules. <strong>The</strong> molecule polymerizes <strong>and</strong> forms a gel-like<br />
meshwork. Over time, the meshwork becomes more dense as<br />
fibrils are added to the initial structure, which begins to take on<br />
the shape <strong>of</strong> the tubule. <strong>The</strong> cylindrical structure matures into<br />
a hyaline cast as other proteins are added to the gel. <strong>The</strong> cast<br />
initially blocks urine flow but hydrostatic pressure eventually<br />
dislodges the cast from its attachment to the epithelial cells.<br />
their cytoplasmic <strong>and</strong> nuclear components have lost<br />
their definition <strong>and</strong> merged with TH protein already in<br />
the cast, increasing their refractive index—hence, the<br />
waxy appearance.<br />
In summary, there is one prototypical type <strong>of</strong> cast<br />
found in the urinary sediment: the hyaline cast. Other<br />
casts may be considered variations, except perhaps<br />
the waxy cast. <strong>Casts</strong> are named according to their<br />
microscopic appearance, i.e., hyaline (clear), cellular,<br />
pigmented, granular, etc. As the cast forms, products<br />
<strong>of</strong> cell degeneration (granules), crystals, or intact cells<br />
may become applied to the cast’s surface or incorporated<br />
within its matrix. Additionally, abnormal products<br />
<strong>of</strong> metabolism in disease states, such as hemoglobin,<br />
bilirubin, <strong>and</strong> melanin, that circulate in the blood <strong>and</strong><br />
appear in high concentration in the glomerular filtrate<br />
may become admixed with TH protein elaborated by<br />
the renal tubular epithelium <strong>and</strong> form what have been<br />
called pigmented casts.
RBC<br />
renal tubular<br />
epithelial cell<br />
crystals<br />
Intratubular matter <strong>and</strong> cells may<br />
become attached to the surface<br />
or incorporated into the Tamm-Horsfall<br />
protein matrix as the cast forms. <strong>The</strong> type <strong>of</strong><br />
material may be a clue to renal pathology, such<br />
as infection (bacteria <strong>and</strong> WBCs), glomerular disease<br />
(fat <strong>and</strong> RBCs), <strong>and</strong> acute tubular necrosis<br />
(renal tubular epithelial cells).<br />
RBC<br />
bacteria<br />
Cast <strong>Formation</strong>:<br />
<strong>Composition</strong><br />
Size Comparison <strong>of</strong> Cast Constituents<br />
degenerating<br />
cell<br />
WBC<br />
crystals<br />
bacteria<br />
Circulating pigments, such as<br />
hemoglobin, melanin, <strong>and</strong> bilirubin,<br />
may add color to the cast.<br />
neutrophil<br />
1 µm 7 µm 8-15 µm 10-15 µm<br />
(may swell to 20-30 µm)<br />
4-20 µm 2-20 µm<br />
15-35 µm<br />
lipid<br />
RTE<br />
eosinophil<br />
lipid<br />
<strong>Casts</strong> 167
glomerulus<br />
proximal<br />
convoluted<br />
tubule<br />
loop <strong>of</strong> Henle<br />
Cast <strong>Formation</strong>:<br />
Evolution <strong>and</strong> Cellular Degeneration<br />
Cellular breakdown<br />
products produce a<br />
mixed cast <strong>and</strong> eventually<br />
a granular cast.<br />
mixed granular<br />
<strong>and</strong> WBC cast<br />
WBC cast<br />
If epithelial cells or WBCs<br />
are present as the cast<br />
forms, they may adhere<br />
to the fibrillary protein<br />
mesh <strong>and</strong> be incorporated<br />
into the cast.<br />
collecting duct<br />
cut-away view <strong>of</strong> distal<br />
convoluted tubule<br />
hyaline cast<br />
loop <strong>of</strong> Henle<br />
168 <strong>Casts</strong><br />
<strong>Casts</strong> form in distal convoluted<br />
tubule <strong>and</strong> the first<br />
segments <strong>of</strong> the collecting<br />
ducts (shown in blue)<br />
waxy cast<br />
Cells <strong>and</strong> granules<br />
tend to break down<br />
<strong>and</strong> lose their definition.<br />
<strong>The</strong>ir proteins<br />
ultimately fuse with<br />
other proteins in the<br />
cast. <strong>The</strong> result is a<br />
more highly refractile<br />
matrix: a waxy cast.<br />
finely granular cast<br />
coarsely granular cast<br />
Cellular, granular, <strong>and</strong><br />
waxy casts probably<br />
represent different<br />
stages <strong>of</strong> cellular<br />
degeneration in a cast.
Matrix<br />
Contents<br />
Size <strong>and</strong> Shape<br />
Color<br />
Cast <strong>Formation</strong>:<br />
Summary <strong>of</strong> Types <strong>and</strong> <strong>Appearance</strong><br />
<strong>The</strong> matrix is either hyaline or<br />
waxy. <strong>Casts</strong> in the nephron for<br />
extended periods produce a<br />
waxy appearance.<br />
Cellular casts contain<br />
red blood cells,<br />
white blood cells, renal<br />
tubular epithelial<br />
cells, <strong>and</strong> bacteria.<br />
Noncellular casts<br />
contain granules,<br />
lipid, crystals, <strong>and</strong><br />
hemoglobin.<br />
Mixed casts contain<br />
several <strong>of</strong> the components.<br />
<strong>Casts</strong> can be long or<br />
short <strong>and</strong> take on a<br />
variety <strong>of</strong> cylindrical<br />
shapes; size <strong>and</strong><br />
shape have no clinical<br />
significance except for<br />
broad casts. <strong>The</strong>se can<br />
be <strong>of</strong> any type but are<br />
typically waxy. <strong>The</strong>y are<br />
at least 1.5 times the<br />
width <strong>of</strong> a normal cast.<br />
Waxy casts may<br />
have a faint yellow<br />
color. Hemoglobin<br />
stains casts reddish,<br />
myoglobin brown,<br />
<strong>and</strong> billirubin (which<br />
typically stains any<br />
cellular contents)<br />
greenish-yellow.<br />
“Muddy casts” are<br />
brick-red or brown,<br />
Drug pigments may<br />
also produce colored<br />
casts.<br />
hyaline<br />
waxy<br />
RBCs WBCs RTEs bacteria granules lipid crystals Hgb<br />
cellular casts<br />
broad casts<br />
noncellular casts<br />
hyaline casts <strong>of</strong> different shapes<br />
waxy RBC Hgb myoglobin muddy bilirubin drug pigment<br />
(e.g., phenazopyridine)<br />
<strong>Casts</strong> 169