The Formation, Appearance, and Composition of Casts

Casts, uniquely found in the urine, were initially discovered in the mid-19th century and were at first thought to be associated with renal abnormalities. Time has proven this to be a false assumption, however, since a few casts are also found in the urine of normal individuals. Their presence in disease states is, however, vitally important in the diagnosis of the specific etiology of renal diseases and the physiological conditions in the kidney that prompted their formation. All urinary casts are composed of a proteinaceous matrix. The proteins forming the cast are secreted by the lining cells of the tubules lining the distal nephronspecifically, the distal tubule and collecting duct lining cells. These cells are nonciliated columnar epithelial cells with basally placed nuclei. They, in contrast to the lining cells of the proximal tubule and loop of Henle, have the propensity to excrete a particular type of immunoprotein known as Tamm-Horsfall (TH) mucoprotein. Once excreted into the urinary flow, this protein, along with other proteins secreted by these lining cells, agglutinates and is then molded into a semisolid, fibrillar, cylindrical, amorphous shape, which is the prototypical hyaline cast. The hyaline cast serves as the basic building block for all cast types. In its most elementary form, it is homogeneous, translucent, has a low refractive index, and does not contain any particulate material or cells. In the normal state, cells lining the nephron are continually dying and regenerating. In many diseases, these same lining cells may be affected by chemical toxins, such as lead or mercury, or inflammatory agents, such as bacteria, and die prematurely. In either instance, cell death results. Intrinsic cellular lysosomes, which contain enzymes necessary for cellular degradation, serve as garbage disposals for the cells component parts, especially mitochondria, and convert these organelles into minute, fine, granular particles. The granular products of cell death enter the urinary flow and may become incorporated into the matrix of a forming hyaline cast. When the amount and number of these granules occupies the majority of the casts surface, the cast is called a granular cast. Four cell types may, in a wide variety of diseases, adhere to the surface of or become incorporated into the matrix of a hyaline cast: these are RBCs, WBCs, epithelial cells, and bacteria/fungi. Ultrastructural studies have shown that some of these cells are bound to the casts surface by means of bands of thin proteinaceous material, most likely TH protein. These cellular casts are named according to the type of cell so bound, i.e., RBC cast, WBC cast, epithelial cast, and bacterial cast. Cellular casts are not found in normal patients. Pigment casts are somewhat complex in that the usual hyaline proteinaceous matrix amalgamates with a component in the glomerular filtrate, most often hemoglobin. Other chemical substances that circulate in the serum and remain in high concentration in the urinary flow after being filtered by the glomerulus may 165

Casts

Cast Formation: Tamm-Horsfall Protein

distal tubule

Tamm-Horsfall protein renal tubular epithelial cells The Tamm-Horsfall protein, also known as uromodulin, is a very large glycoprotein that is the most abundant protein in normal urine. Hyaline casts, cylindroids, and mucous strands are all made, at least in part, of Tamm-Horsfall protein fibrils.

hyaline cast

Tamm-Horsfall protein is excreted by epithelial cells in the thick ascending branch of the loop of Henle and the first part of the distal tubules. The molecule polymerizes and forms a gel-like meshwork. Over time, the meshwork becomes more dense as fibrils are added to the initial structure, which begins to take on the shape of the tubule. The cylindrical structure matures into a hyaline cast as other proteins are added to the gel. The cast initially blocks urine flow but hydrostatic pressure eventually dislodges the cast from its attachment to the epithelial cells.

also be incorporated into the cast as it forms within the lumen of the nephron: these include melanin in patients with melanoma, and myeloma protein in patients with multiple myeloma. These so-called pigment casts are infrequently seen, however, with the exceptions of the hemoglobin cast (see Muddy Casts, page 196), which may be prominent in patients with acute renal failure, and bile-stained casts in patients with severe jaundice such as is found in acute cases of viral hepatitis and chronic liver failure. The exact origin of waxy casts is not clear, however. Although they have a proteinaceous matrix, which includes TH immunoprotein, their surface characteristics differ significantly from the usual translucent hyaline appearance. These casts have a high refractive index and appear dense, often with blunted ends and notched margins. It is theorized that waxy casts may be the evolutionary product of preexisting cellular casts in which the cells have completely disrupted and

their cytoplasmic and nuclear components have lost their definition and merged with TH protein already in the cast, increasing their refractive indexhence, the waxy appearance. In summary, there is one prototypical type of cast found in the urinary sediment: the hyaline cast. Other casts may be considered variations, except perhaps the waxy cast. Casts are named according to their microscopic appearance, i.e., hyaline (clear), cellular, pigmented, granular, etc. As the cast forms, products of cell degeneration (granules), crystals, or intact cells may become applied to the casts surface or incorporated within its matrix. Additionally, abnormal products of metabolism in disease states, such as hemoglobin, bilirubin, and melanin, that circulate in the blood and appear in high concentration in the glomerular filtrate may become admixed with TH protein elaborated by the renal tubular epithelium and form what have been called pigmented casts.

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Casts

renal tubular epithelial cell RBC

Cast Formation: Composition

neutrophil eosinophil

crystals Intratubular matter and cells may become attached to the surface or incorporated into the Tamm-Horsfall protein matrix as the cast forms. The type of material may be a clue to renal pathology, such as infection (bacteria and WBCs), glomerular disease (fat and RBCs), and acute tubular necrosis (renal tubular epithelial cells).

bacteria Circulating pigments, such as hemoglobin, melanin, and bilirubin, may add color to the cast.

lipid

Size Comparison of Cast Constituents

RBC bacteria degenerating cell WBC crystals lipid RTE

1 m

7 m

8-15 m

(may swell to 20-30 m)

10-15 m

4-20 m

2-20 m

15-35 m

Casts

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Cast Formation: Evolution and Cellular Degeneration

collecting duct glomerulus Casts form in distal convoluted tubule and the first segments of the collecting ducts (shown in blue) waxy cast Cells and granules tend to break down and lose their definition. Their proteins ultimately fuse with other proteins in the cast. The result is a more highly refractile matrix: a waxy cast.

proximal convoluted tubule

cut-away view of distal convoluted tubule

loop of Henle finely granular cast mixed granular and WBC cast Cellular breakdown products produce a mixed cast and eventually a granular cast. WBC cast If epithelial cells or WBCs are present as the cast forms, they may adhere to the fibrillary protein mesh and be incorporated into the cast. coarsely granular cast

hyaline cast loop of Henle

Cellular, granular, and waxy casts probably represent different stages of cellular degeneration in a cast.

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Casts

Cast Formation: Summary of Types and Appearance

Matrix
The matrix is either hyaline or waxy. Casts in the nephron for extended periods produce a waxy appearance.

hyaline

waxy

Contents

Cellular casts contain red blood cells, white blood cells, renal tubular epithelial cells, and bacteria. Noncellular casts contain granules, lipid, crystals, and hemoglobin. Mixed casts contain several of the components.

RBCs

WBCs RTEs bacteria cellular casts

granules

lipid crystals noncellular casts

Hgb

Size and Shape

Casts can be long or short and take on a variety of cylindrical shapes; size and shape have no clinical significance except for broad casts. These can be of any type but are typically waxy. They are at least 1.5 times the width of a normal cast.

broad casts

hyaline casts of different shapes

Color

Waxy casts may have a faint yellow color. Hemoglobin stains casts reddish, myoglobin brown, and billirubin (which typically stains any cellular contents) greenish-yellow. Muddy casts are brick-red or brown, Drug pigments may also produce colored casts.

waxy

RBC

Hgb

myoglobin

muddy

bilirubin

drug pigment (e.g., phenazopyridine)

Casts

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