Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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60 Chung et al.

is favored from a thermodynamic perspective (23). According to Randolph and Drach,

aggregation is different from agglomeration (3). Aggregation, by their definition, is the

grouping of two or more particles held together by strong intermolecular forces, which

cannot be dispersed by shear forces. The definition of agglomeration, on the other hand,

is the grouping of two or more particles held together by weak cohesive forces, which

can be broken up by dispersion with shear forces or water solvents. Most authors use the

term aggregation, when referring to the binding of urinary crystals.

Despite the fact that aggregation is thermodynamically favored in nature, it does not

always occur. Aggregation or disaggregation depends on the final combined effect of

opposing forces. Van der Waals forces, viscous binding, and solid bridges help to hold

particles together, whereas electrostatic repulsion (zeta potential) tends to disaggre-

gate crystal particles. Van der Waals forces are attractive forces between molecules

(2). There are three principal types of intermolecular (van der Waals) forces: dipole–

dipole attractions; hydrogen bond forces; and London forces (2). The van der Waals

force is inversely proportional to the distance between two particles to the sixth power

when they are at a short distance from each other, or inversely proportional to the

squared distance between them at a further distance (39). The viscous binding is

derived from the “sticky” properties imparted by hydrophilic molecules on the particle

surface. This occurs when adsorbed substances on the particles adhere to each other.

The zeta potential reflects the repulsive force between two particles; it is the electric

potential at the interface between a colloid particle and its surrounding solution (39).

Human urine is a colloid system consisting of urinary stone components and macromo-

lecular organic particles. The macromolecular organic particles are responsible for

stabilizing this colloid system (39). For example, COM in water has a zeta potential of

approx +20 mV (40). In urine, however, the zeta potential of COM shifts to approx -5

mV. It is believed that the adsorption of negatively charged urinary components such

as citrate, pyrophosphate, and acidic polymers results in the reduction of the zeta poten-

tial of COM. Further reduction in COM zeta potential (approx -20 mV) can be induced

by the adsorption of Tamm-Horsfall protein derived from normal subjects (39). Reduc-

tions of the zeta potential lead to energy barriers that minimize COM crystal aggrega-

tion. Shear forces can either enhance or inhibit aggregation. For example, shear forces

increase the probability of particle collision, which favors aggregation but also at the

same time disrupts aggregated particles (41). Aggregation is influenced by the satura-

tion of the solution, although it can occur in supersaturated as well as undersaturated

solutions (24,42).

Crystal aggregation likely plays an important role in urinary stone formation. Several

pieces of evidence support this theory. Crystalline clumps are frequently seen in the

center of calculi, particularly in whewellite/weddellite, uric acid, and brushite stones

(25).

Highly aggregated structures are noted in microscopic examinations and ultrastruc-

tural analyses of renal stones. Iwata et al. developed a partial dissolution method and

used a scanning electron microscope to examine the internal architecture of COM uri-

nary calculi (43). They found all calculi have three distinct zones. A core zone is com-

posed of randomly aggregated platelike crystals with frequent rosette formations. An

intermediate area is composed of radially arranged piles of sheetlike crystals. The periph-

eral layer shows concentric laminations and each layer of lamination is composed of

minute crystals. Khan and Hackett also studied architectural details and intercrystalline

associations of urinary calculi and demonstrated that all stones have a central nucleus

region and a peripheral zone (44). The former contains an aggregate of discernible

Chapter 4 / Theories of Stone Formation 61

individual crystals. The peripheral region, on the other hand, consists of concentric

layers of either discrete crystals or solid striated material.

Robertson et al. found that recurrent calcium stone formers tend to excrete larger

calcium oxalate crystals (10–20 µm in diameter) than those (3–4 µm in diameter) in

nonstone formers (12). Moreover, the crystals of stone formers often fused into poly-

crystalline aggregates 20–300 µm in diameter. In a study, measuring the effects of urines

from healthy subjects and from calcium oxalate stone formers, Kok et al. demonstrated

that the urines from stone formers had a similar effect on the solubility, but a significantly

lower ability to inhibit the crystal growth and the crystal aggregation (45). They con-

cluded that defective inhibition of the kinetic process of crystal aggregation constitutes

a major physiochemical mechanism of calcium oxalate renal stone formation, which

appears to be modulated by urinary citrate concentrations. Subsequent studies have

suggested that Tamm-Horsfall protein from stone formers bear functional abnormalities

resulting in decreased ability to inhibit calcium oxalate crystal aggregation (39,46,47).

Furthermore, a single crystal can never reach a size large enough to be retained within

the kidney by crystal growth alone (48) but the speed of aggregation is rapid enough to

allow development of significantly sized particles within seconds (42). These observa-

tions reveal the potential role of crystal aggregation in urinary stone formation.

EPITAXY

Multicomponent urinary stones are frequently observed. These stones, when sec-

tioned, have distinct concentric rings. Different layers contain different components but

each layer has a homogeneous crystalline composition (25). Although the mechanism of

growth in these multicomponent stones is not fully understood, epitaxy has been sug-

gested to play a significant role.

During the process of multicomponent stone formation, the molecules on the surface

of one layer must bind to the molecules of a different component in a specific order such

that the growth of the new component can be incorporated and promoted. For this to

happen, the regular and predictable crystal lattices of the two different components must

be chemically compatible and supportive of each other at the contact zone. Epitaxy

describes the process of oriented growth of one crystalline lattice over another crystal-

line lattice whose dimensions are similar (49). In general, epitaxy can be considered a

special type of heterogeneous nucleation. The major forces holding these structures

together can be explained by analyzing the crystal structures of the common components

of renal calculi. In cation-containing structures, such as whewellite, weddellite, brushite,

apatite, and monosodium urate monohydrate, the major force is cation–anion attraction.

In the noncation-containing structures, such as uric acid, uric acid dihydrate, and

L-

cystine, the major force is a hydrogen bonding network (49).

A clinical example to support the theory of epitaxy is the association of hyperurico-

suria with calcium oxalate stone formation. It has been well documented that patients

with hyperuricosuria may form calcium-salt stones even if they are normocalciuric and

otherwise have no other risk factors for stone formation (50,51). It is postulated that

monosodium urate or uric acid first crystallizes because of hyperuricosuric supersatu-

ration. These crystals either act as seed crystals for inducing epitaxy of calcium oxalate

or adsorb normally occurring macromolecular inhibitors of calcium oxalate crystalliza-

tion in urine that may not have been sufficiently supersaturated for the spontaneous

nucleation of calcium oxalate crystals (52,53). Based on a crystallographic dimensional

62 Chung et al.

comparison for a substrate crystal of uric acid and an epitaxial layer of calcium

oxalate monohydrate, the crystalline lattice of both components match (49). This

theoretical comparison of the dimensions of the prominent crystal growth faces was

first published by Lonsdale in 1968 (54). Mandel et al. extended the calculation of

the percentage misfit. The criteria used by them included the lengths of the two

lattice vectors in the selected two-dimensional slice through the three-dimensional

structure, the angles between these two lattice vectors defining the possible contact

face, and a parameter indicating the general complexity of the associated atomic

pattern on the potential contact plane (49). In addition, they analyzed the atomic

structures of the two contacting crystal lattices. The atomic overlay at the interface

is excellent in the calcium oxalate monohydrate–uric acid system. The two-dimen-

sional misfit in this system is predicted to be less than 5% (49). Clinically, treatment

of hyperuricosuria with allopurinol or purine restriction has been found to reduce the

recurrence rate of hyperuricosuric calcium-based stones (50,51,55,56).

MATRIX

Analysis of urinary stones reveals that they are not simply composed of crystals but

rather contain a noncrystalline protein-like component, termed matrix. The percentage

of matrix, by weight, in urinary stones varies. In general, most solid urinary stones have

a matrix content of about 3% by weight (57). Matrix stones, however, may contain up

to 65% of matrix (58,59). Although the matrix can be found throughout a urinary stone,

it is not evenly distributed. Warpehoski and colleagues reported that matrix from the core

of calcium oxalate stones weighed an average of 2.7% but total matrix weight was 5.7%

when the outer zone of the stones was analyzed (60).

Chemical analysis of stone matrix reveals approx 65% is hexosamine and 10% is

bound water (61). Many other compounds have been isolated from matrix, such as matrix

substance A (62), a protein containing large amounts of γ-carboxyglutamic acid (63),

nephrocalcin (64), Tamm-Horsfall glycoprotein (65), renal lithostatine (66), albumin

(61), glycosaminoglycans (67–69), and free carbohydrates (70).

Nephrolithiasis is one of the manifestations of pathological calcification, which by

definition includes all calcium salt deposits in soft tissues as well as concretions of

calcium salts in the secretory and excretory passages of the body. In humans, calcium

salts are deposited normally in the formation of bone. In the process of bone formation,

osteoblasts produce the extracellular organic matrix, which initially lacks mineral

deposits (71). Deposits of inorganic mineral salts then begin to appear throughout the

matrix. These deposits increase in size and number and begin to coalesce, thereby

progressively displacing water until the matrix becomes completely mineralized.

Whether the stone matrix has a role in the promotion of urinary stone formation, like the

bone matrix described previously, or whether it is incorporated by nonspecific adsorp-

tion is unknown (72). Many studies have been conducted to identify the role of matrix

in urinary stone formation (67,68,73–75). Although several encouraging findings have

been reported, there is still no satisfactory theory to explain the importance of urinary

stone matrix in the development of urinary stones.

INHIBITORS AND PROMOTERS

This review of the pathogenesis of urinary stone formation would be incomplete

without mentioning inhibitors and promoters. Urine contains substances that influence

Chapter 4 / Theories of Stone Formation 63

crystallization processes, and therefore regulate stone formation. Substances that reduce

the crystallization are called inhibitors whereas those that increase crystallization are

termed promoters. Inhibitors and promoters of urinary stones will be discussed in sub-

sequent chapters.

CRYSTAL RETENTION

Previous sections in this chapter have explained theories about crystal precipitation,

growth, and aggregation. None of these elements would result in urinary stone forma-

tion if the nucleated crystals were flushed out by urinary flow. Crystal retention is

therefore a key factor. Crystal retention will result if the crystals grow large enough to

be trapped in renal tubules or if they adhere to urothelium before excretion. The earliest

evidence of crystal retention was the finding of macroscopic plaques of subepithelial

deposits of calcium crystals in renal papillae by Randall in 1940 (76). He proposed that

these calcific deposits originate in damaged renal tubule epithelial basement mem-

branes and later erode into the urinary collecting system. These plaques, now known as

Randall’s plaques, are thought to serve as a nidus for urinary stone formation (77,78).

The incidence of calcified papillary plaques was 19.6% of cadaveric renal units (76).

Stoller et al., by using high resolution radiography, demonstrated papillary calcifica-

tions in 57% of radiographically imaged cadaveric kidneys (77). They also showed a

correlation between a history of hypertension and papillary calcifications. To further

investigate the association between papillary calcifications and urinary stone forma-

tion, the presence, pattern, and distribution of Randall’s plaques were mapped endo-

scopically in patients (78). This study revealed the incidence of plaques varied with the

primary composition of extracted stones. In addition, the incidence of papillary plaques

was significantly more common in patients with calcium oxalate (88%) and calcium

phosphate stones (100%) than in patients without a history of urinary stone disease

(43%) (78). These findings suggest that the presence of papillary plaques is associated

with calcium nephrolithiasis and may contribute to the pathogenesis of calcium urinary

stones.

Many groups have investigated the concept of crystal retention leading to our current

understanding. Normal urothelium has been shown to bear a protective mechanism

against nucleation and adhesion of calcium oxalate crystals (79). Chemically injured

urothelium will lose this property resulting in the adherence of calcium oxalate crystals

(79–81). Gill and associates have demonstrated that heparin, a sulfated heteropolysac-

charide of glucuronic acid and glucosamine, could restore the anticrystal adherence

property of injured urothelium (81). Other sulfated polysaccharides, sulfated glycosami-

noglycans, and monosaccharides were, however, not effective in the restoration of pro-

tection against calcium oxalate crystal adhesion. The glycosaminoglycan layer of normal

urothelium plays an important role against bacterial adherence and is also responsible

for preventing crystal adherence (82,83). The exact mechanism of action is unknown but

it has been postulated that the sulfur groups on glycosaminoglycan molecules will bind

large quantities of water molecules forming a “water barrier” on the cell surface thereby

inhibiting calcium oxalate crystal and bacterial adherence (84). Pantazopoulos et al.

have demonstrated that treating chemically injured urothelium with sodium

pentosanpolysulfate, a semisynthetic glycosaminoglycan with an electric charge similar

to that of natural glycosaminoglycan, and carbenoxolone sodium, an ester of β-glycyrren-

tinic acid and succinic acid having the ability of increasing production of glycosami-

64 Chung et al.

noglycan, could restore the protective property of urothelium to prevent crystal adhesion

(85). It has been postulated that the crystal adherence reaction is mediated through cell

surface substances, termed crystal-binding molecules (86). Several compounds, includ-

ing phosphatidylserine (87,88), sialic acid (89), collagen type IV (90), osteopontin (91),

and hyaluronan (86), have been shown to be candidates of crystal-binding molecules.

Despite decades of research focusing on crystal–cell interaction, the definite crystal-

binding molecules and the mechanisms of urothelial injury in recurrent stone formers are

awaiting to be elucidated.

The crystal–renal cell interaction is supported by clinical observations and laboratory

studies (92). For example, endocytosis of calcium oxalate crystals was observed in a

patient with type 1 primary hyperoxaluria (93). In studies using monkey renal epithelial

cells as a model of the distal tubular epithelium, COM crystals were endocytosed by the

cells and cellular proliferation was induced (94,95). The interaction is influenced by the

type of crystal (22), the presence of a crystal coat (96), the type of cell surface (97), and

the surface electric charge (89,98). Once adhered, the particles are subsequently inter-

nalized into the epithelial cells through endocytosis; altered gene expression, cytoskeletal

alterations, and cellular proliferation can then occur (92).

CONCLUSIONS

Urinary stone formation likely starts after crystallization, which is induced by urinary

supersaturation. Supersaturation alone cannot explain the process of stone formation.

Urine is a complex solution with frequent changes in pH. The presence of multiple inor-

ganic and organic constituents and interactions between promoters and inhibitors, all

modulate the already complicated pathogenesis of stone formation. Crystalline material

is nucleated somewhere inside the nephron. Crystals of calcium phosphate are predomi-

nantly formed in the proximal and distal renal tubules, whereas, calcium oxalate is the

primary crystallization product in the collecting ducts (38,99). The formed calcium

phosphate crystals flow toward collecting ducts and likely serve as nidi and induce

heterogeneous nucleation of calcium oxalate. These particles grow via crystal aggrega-

tion into the size range of, or even greater than, the inner diameter of the collecting ducts

and thus might be retained (100). The aggregated particles may also adhere to the renal

epithelium through the mechanism of crystal–renal cell interaction or may be retained

by anatomic abnormalities, such as ectatic tubules or ureteropelvic junction obstruction.

Either way, these particles will have chance to grow into clinically significant stones,

which may be unable to pass through the urinary tract in a spontaneous fashion. There

is insufficient evidence to understand the entire process of urinary stone formation,

however, the processes described above help explain how a crystal will form, grow,

aggregate with other crystals, and ultimately be retained in the kidney.

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From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Structure and Compositional

Analysis of Kidney Stones

Ian Mandel and Neil Mandel, PhD

CONTENTS

INTRODUCTION

CHEMISTRY AND STRUCTURES FOUND IN STONES

CRYSTALLURIA AND STONE MORPHOLOGY

STONE ANALYSIS

CONCLUSIONS AND RECOMMENDATIONS

ACKNOWLEDGMENTS

REFERENCES

Key Words: Nephrolithiasis; crystal; stone composition.

INTRODUCTION

It is well established that human urine is supersaturated with respect to ions and

molecules, which can crystallize as clinical crystalluria with a potential for stone devel-

opment. Regardless of the specific site of crystallization within the nephron, crystals can

either pass from the kidney into the bladder and be excreted or attach to cells in the late

collecting duct and grow into mature kidney stones. The crystalline composition of a

stone reflects the urine chemistry and abnormalities in tubular physiology during the

process of stone development. Accurate knowledge of the composition of the stone is

critical to elucidating the underlying etiology of the patient’s clinical disorder(s) that

precipitated the stone disease.

Crystalline material is the primary constituent of most human urinary tract stones. All

stones contain macromolecules and other cellular components from the urine, termed

matrix, and the amount of matrix normally approaches 2–5%, although some stones can

be composed entirely of matrix. Most human stones contain more than one crystalline

component and are termed multicomponent stones. The presence of multicomponent