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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

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