Clinica Chimica Acta 302 (2000) 89–104
www.elsevier.com / locate / clinchim
Uric acid calculi: types, etiology and mechanisms of
formation
´ Grases a , *, Ana I. Villacampa a , Antonia Costa-Bauza´ a ,
Felix
b
¨
Otakar Sohnel
a
Laboratory of Renal Lithiasis Research, Faculty of Sciences, University of Illes Balears,
Ctra. Valldemossa Km 7.5, 07071 Palma de Mallorca, Spain
b
´ ´ n.L., Czech Republic
Spolchemie, Revolucni 86, 400 32 Ustı
Received 9 May 2000; received in revised form 17 July 2000; accepted 25 July 2000
Abstract
The study of the composition and structure of 41 stones composed of uric acid was
complemented by in vitro investigation of the crystallization of uric acid. Uric acid dihydrate
(UAD) precipitates from synthetic urine under physiological conditions when the medium is
supersaturated with respect to this compound, though uric acid anhydrous (UAA) represents the
thermodynamically stable form. Solid UAD in contact with liquid transforms into UAA within 2
days. This transition is accompanied by development of hexagonal bulky crystals of UAA and
appearance of cracks in the UAD crystals. Uric acid calculi can be classified into two groups,
differing in outer appearance and inner structure. Type I includes stones with a little central core
and a compact columnar UAA shell and stones with interior structured in alternating densely
non-columnar layers developed around a central core; both of them are formed mainly by
crystalline growth at low uric acid supersaturation. Type II includes porous stones without inner
structure and stones formed by a well developed outermost layer with an inner central cavity; this
type of stones is formed mainly by sedimentation of uric acid crystals generated at higher uric acid
supersaturation.  2000 Elsevier Science B.V. All rights reserved.
Keywords: Uric acid; Renal calculi; Structure; Classification; Crystallization
*Corresponding author. Tel.: 134-971-17-3257; fax: 134-971-17-3426.
E-mail address: [email protected] (F. Grases).
0009-8981 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0009-8981( 00 )00359-4
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F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
1. Introduction
Calculi predominantly composed of uric acid represent a sizeable proportion
of human kidney stones, around 13% [1]. However, considerably less attention
has been devoted to their investigation compared to other kinds of concretions,
such as calcium oxalate or phosphatic uroliths. A relatively simple and
frequently effective medical treatment of uric acid calculi based on systematic
alkalization of urine, increased fluid intake and a low purine diet [2,3] probably
partially accounts for such remarkable lack of interest. Furthermore, uric acid
crystallizes from an aqueous solution according to the prevailing reaction
conditions as an anhydrous compound (hereafter UAA), a dihydrate (hereafter
UAD) or a mixture of both modifications [4], and UAD readily transforms into
the anhydrous salt [5,6]. These properties of uric acid substantially complicate
analysis of processes taking place at calculogenesis and this may represent an
additional reason for absence of in-depth studies of uric acid calculi. As a result,
information available on morphology, structure and formation mechanism of
uric acid calculi is considerably limited [7,8].
Contemporary knowledge concerning uric acid calculi can be summarized as
follows: uric acid occurs most often in calculi in a pure state rarely accompanied
by urates, phosphates or calcium oxalate. Uric acid calculi largely form pebblelike objects with a smooth, but not polished surface, though uneven and globular
surface is also occasionally encountered. A cross-section of uric acid stone
usually shows concentric layers of microcrystalline material forming typical
laminations with radial striation converging to the core area. Less frequently
some calculi exhibit a course granular interior without a sign of lamination,
texture or preferred orientation of constituting crystals. The calculus core is
commonly composed of randomly oriented plate-like crystals of uric acid.
Calculi of uric acid contain also around 2 wt.% of filamentous organic matrix
forming a fine meshwork uninterrupted by the crystal border. It is believed that
organic matrix is incorporated in uric acid crystals and does not exist between
columnar crystals constituting radial striation [1,9–12].
Different conditions of crystallization are held responsible for generation of
diverse groups of uric acid stones. These calculi largely consist of UAA, but
around 20% contain significant amount of UAD and 3% comprise over 95% of
UAD [5]. In the case of stones constituted by UAA it is not known whether
UAD precipitated first and later underwent transformation into anhydrous
substance or UAA was formed directly, or if both processes participated in uric
acid stone formation. Formation mechanism of these calculi is suspected to be
similar to that which gives rise to calcium oxalate monohydrate concretions [10].
It should be emphasized, however, that quoted conclusions are based on
observing a limited number of specimens and therefore must be regarded as
tentative.
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
91
In vitro studies of the crystallization behaviour of uric acid demonstrated that
UAA is the stable phase from the thermodynamic viewpoint. Temperature, pH,
present admixtures and concentration of a liquid medium determine the nature of
solid phase actually precipitating under given conditions. As a rule, UAD
sometimes accompanied by the anhydrous form precipitates readily under
physiological conditions [4,13]. However, UAD in contact with a liquid phase
undergoes a gradual transition into UAA. The transition rate, depending on both
reaction conditions and the size of transforming crystals, is reported for
physiological conditions to be relatively slow [4,14] and rather fast [5]. Both
conclusions, though contradictory, were called upon to substantiate and explain
observation that uric acid in calculi occurs mostly as UAA, occasionally in a
mixture with UAD [5,15].
As is evident, insufficient information is available on structure, formation
mechanism and composition of uric acid calculi. Moreover, uric acid crystallizing behaviour under physiological conditions is far from clear and even
hitherto performed in vitro studies did not shed much light on existing serious
discrepancies and uncertainties. In order to contribute to the better understanding
of uric acid calculogenesis, a thorough investigation of composition, morphology and inner structure of 41 uric acid calculi was carried out and a first in vitro
attempt at a crystallization study of uric acid under physiological conditions was
carried out.
2. Materials and methods
2.1. Uric acid crystallization
Precipitation of uric acid from the synthetic urine [16] at pH 5.5 and 4 was
studied at 378C. The precipitation was carried out in a beaker equipped with four
baffles and mixed throughout each experiment with a double-bladed stirrer.
Three solutions, A (62.5 ml), B (375 ml) and C (62.5 ml), preheated to 378C
were in the succession introduced into the beaker situated in a constant
temperature water bath. Solution A contained 44.08 g / l Na 2 SO 4 ? 10H 2 O, 5.84
g / l MgSO 4 ? 7H 2 O, 18.56 g / l NH 4 Cl, 48.62 g / l KCl and 4.16 g / l CaCl 2 ?
3.5H 2 O, solution C 10.6 g / l NaH 2 PO 4 ? 2H 2 O, 75.28 g / l Na 2 HPO 4 ? 12H 2 O,
52.2 g / l NaCl, 4.0 g / l trisodium citrate dihydrate and 0.30 g / l C 2 O 4 Na 2 and
solution B contained uric acid in an appropriate amount to achieve a predetermined uric acid concentration in a resulting mixture and a quantity of
NaOH ensuring complete dissolution of the substance. The final concentrations
of key ions in the synthetic urine are summarized in Table 1. All solutions were
prepared by dissolving pure (analytical grade) chemicals in distilled water.
Immediately after introducing the solution C, the reaction mixture pH was
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
92
Table 1
Final composition of the media used as synthetic urine
Species
Concentration (mol / l)
1
0.2125
0.0815
0.0434
3.0310 23
3.0310 23
0.2425
0.0200
0.0348
2.8310 24
1.7310 23
1.0310 23 –8.9310 23
Na
K1
NH 1
4
Mg 21
Ca 21
Cl 2
SO 22
4
PO 32
4
C 2 O 22
4
C 6 H 5 O 32
(citrate)
7
C 5 H 4 N 4 O 3 (uric acid)
adjusted to 4 or 5.5 by addition of concentrated HCl. Then, the induction time,
i.e., time elapsed between the instant of establishing supersaturation through pH
adjustment and appearance of crystals, was determined. Crystal appearance was
detected by naked eye observing the beaker content against black background
perpendicularly to the coherent light beam illuminating the reaction mixture.
Detection of bright sparkles in the liquid signifying presence of crystals was
regarded as a termination of induction period. Each experiment was repeated
three times and the observations performed by two different people to ensure the
reproducibility of the presented results.
The transformation of UAD to UAA was studied in contact with both air and
mother liquor. UAD crystals were precipitated from the synthetic urine, isolated
by filtration and subjected to thermogravimetry (hereafter TG) and X-ray
diffraction analysis (hereafter XRD). Thereafter crystals were put in a desiccator
filled with either silica gel or water when transformation in a dry or 100% humid
air, respectively, was studied. The desiccator was placed in a constant temperature box kept at 4, 20 or 408C. The solid was regularly sampled and analyzed by
TG and XRD. When studying the transformation taking place in contact with a
mother liquor, UAD crystals were precipitated from synthetic urine containing
500 and 1500 mg / l of uric acid at pH 5.5. A part of suspension was filtered and
the solid phase thus obtained was analyzed. The remaining volume of suspension was kept at 378C, agitated for 12 h and then left still. In selected time
intervals the suspension was sampled, a drop of suspension was placed on a
microscopic cover glass and left still for a while to allow present crystals to
deposit on the glass. Then liquid was removed by filtration paper, sediment
sputtered with gold and observed by a Hitachi scanning electron microscope
(hereafter SEM). At the experiment end the solid phase was isolated from
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
93
suspension on a Millipore filter, carefully dried in a desiccator over silica gel
and without delay subjected to TG and XRD.
2.2. Uric acid calculi
Forty-one spontaneously passed or surgically removed calculi from 34
patients (from several patients more than one stone was investigated) composed
of uric acid as major component (‘pure’ uric acid calculi) were studied. If other
minor components were present they were not detected in the first classification
performed by stereoscopic microscopy plus infrared spectroscopy (hereafter IR).
No calculi with ammonium or sodium urate or calcium oxalate, as major
components were included.
The stone external morphology was first observed using an optical stereomicroscope and photographically documented. Then every stone was cut by a razor
into approximately two halves, usually lengthways first. One half was retained
for further inspection and the other was cut again perpendicularly to the longer
axis. Thus the inner stone structure could be observed in two, mutually
perpendicular, planes and this permitted its reconstruction with a high degree of
fidelity. The over-all texture of the cut planes was observed under a low
magnifying stereomicroscope, macroscopic structure of stone interior reconstructed, recorded and photographically documented. Thereafter these fragments
were metallized, their macroscopic structure observed and the fine structure of
selected areas studied by SEM equipped with an energy dispersive X-ray
analyzer (EDS).
A foreign solid phase, when present in a studied calculus, was identified by
the EDS through a semi-quantitative analysis on Ca, Mg and P. The solid
substance containing only Ca was regarded as calcium oxalate. Magnesium and
phosphorus were in no case detected. When neither of these elements was
present, the analyzed solid was regarded as of organic nature.
Calculi composition was determined by IR and XRD. Fragments of calculi not
used for the structure observation were powdered and immediately subjected to
XRD.
2.3. Physicochemical calculations of uric acid solubility
Uric acid (H 2 U) in aqueous solution dissociates according to
1
H 2 U↔H 1 HU
2
22
Further dissociation and hence a concentration of U ion is negligible in our
experimental pH range [17]. The first dissociation constant, Kd1 , and the
solubility product, Ksp , of uric acid are defined as
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
94
Kd1 5 a(H 1 )a(HU 2) /a(H 2 U)
1
2
Ksp 5 a(H )a(HU )
(1)
(2)
where a(X) represents the activity of a component X. Solubility, S, is defined as
the total (analytical) concentration of uric acid, i.e.,
S 5 [H 2 U] 1 [HU 2 ]
(3)
where square brackets denote molar concentration. Combining expressions
(1)–(3) and realizing that pH5 2log a(H 1 ) yields
S 5 Ksp [1 1 (Kd1 /f 10 2pH )] /Kd1
(4)
where f is the activity coefficient of HU 2 ions. Expression (4) also applies in
the case of UAD since the water activity, rigorously appearing in expression for
Ksp can be regarded as equal to 1 because of a low solute content in urine.
The relative supersaturation was calculated as
s 5 [c(H 2 U) /S] 2 1
(5)
where c(H 2 U) represents the initial total molar concentration of uric acid and S
the solubility of UAA or UAD in mol / l pertinent to the actual pH reaction
mixture.
The solubility of both compounds was calculated at 378C as a function of pH
and plotted in Fig. 1 using Ksp values 2.25310 29 and 9.87310 210 mol 2 l 22 for
26
21
UAD and UAA, respectively [4], and Kd1 54.2310 mol l [17].
3. Results
3.1. Uric acid crystallization
Precipitation of uric acid was induced in synthetic urine at 378C by a sudden
decrease of reaction mixture pH to 4 or 5.5, respectively, caused by an addition
of HCl. The total initial concentration of uric acid in a reaction mixture varied
between 170 and 1500 mg / l. The experimentally determined induction time as a
function of initial supersaturation is plotted in Fig. 2. In all cases only UAD
crystals either relatively thin or elongated (Fig. 3a), or agglomerates of thin
plates (Fig. 3b), were detected in the reaction mixture 4 h after the experiment
onset when initial solution contained 170 mg / l (pH 4.0) or 1500 mg / l (pH 5.5)
of uric acid, respectively. However, the solid phase separated from suspension
after 8 h of experiment duration, contained already some thick hexagonal
crystals of UAA (Fig. 4a). UAD crystals were still present in suspension when
36 h elapsed from the experiment onset, but almost disappeared during further
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
95
Fig. 1. A plot of solubility of UAA (a) and UAD (c) in synthetic urine at 378C as a function of pH.
Curve (b) relative supersaturation with respect to UAA equal 1. Curves (c) and (d) relative
supersaturation with respect to UAD equals 1 and 1.5, respectively. Region 1: undersaturated
zone, no crystallization of uric acid can take place. Region 2: only UAA crystal growth is possible.
Region 3: UAA by heterogeneous nucleation can be formed; Region 4: only UAD crystals can be
formed if an adequate template is available; Region 5: UAD crystals can be formed and some of
them can acquire enough size to sediment within time of residence in urinary cavities; Region 6:
acute risk of sedimentary uric acid calculi formation.
12 h, i.e., 48 h after the suspension origin. XRD confirmed that solid phase after
48 h of contact with liquid consisted only of UAA. At low supersaturation (220
mg / l of uric acid and pH 5.5 that corresponds to s 51 for UAA and is
undersaturated for UAD) UAA crystals are directly formed (Fig. 4b). XRD
confirmed that the solid phase formed in such conditions consisted only of UAA.
The conversion of UAD to UAA in contact with dry air was completed within
4 days at 48C and 3 h at 408C. The phase transformation proceeding in contact
with either wet air at 208C or a mother liquor at 378C was finished in 2 days.
Elongated prismatic UAD crystals during transformation on both dry and wet air
partially disintegrated into numerous irregularly bound small crystals of UAA.
However, when the transition took place in contact with a mother liquor, a
quantity of new thick hexagonal crystals of UAA developed, though deep
longitudinal cracks evolved in some prismatic UAD crystals whose original
shape was nevertheless retained (Fig. 3c).
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Fig. 2. Induction time in seconds as a function of initial relative supersaturation (t5300 s, relative
error58%).
3.2. Uric acid calculi
All studied calculi were composed of UAA, sometimes in a mixture with
small amount of UAD as determined by XRD. However, abundant presence of
crystals exhibiting large cracks, a typical sign of UAD crystals transformed into
anhydrous compound, in some calculi points out to preferential formation of
UAD during a certain stage(s) of calculogenesis. Calcium oxalate monohydrate
(hereafter COM) crystals forming the calculus core or disseminated in the stone
mass were sometimes detected. Exceptionally small spiky globules of ammonium urate were also observed by SEM. Calcium and magnesium phosphates
were not detected in the studied stones.
Uric acid stones can be classified into two types:
Type I: stones formed by crystalline growth.
This type of calculus is formed by crystalline growth of uric acid particles
and can comprise little or no large particles deposited from urine. According
to the inner structure of the urolith, this type of calculi can be further divided
into two subgroups.
( Ia) Stones developed by a regular crystalline growth from a core situated
in the calculus center. The central core consisted of several well-developed and only loosely connected UAA crystals (Fig. 5a). Compact
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
97
Fig. 3. (a) Thin elongated and (b) agglomerated plate-like crystals of UAD crystallizing at 378C
from synthetic urine when initial solution contained 170 or 1500 mg / l of uric acid, respectively.
(c) Longitudinal cracks developed in UAD crystals during phase transition to UAA.
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F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
Fig. 4. (a) Hexagonal UAA crystals formed as a consequence of UAD transformation in contact
with a mother liquor. (b) UAA crystal aggregates directly formed at low supersaturation (220
mg / l uric acid and pH 5.5).
stone interior was formed by seemingly columnar crystals radiating
towards the calculus periphery (Fig. 5b). Columnar crystals were flat
plate-like crystals stuck together. Concentric laminations were often
visible. The laminations, in fact boundaries between adjacent columnar
layers, were composed of disoriented small crystals of UAA. UAA,
largely a predominant component of this sort of stones, evidently
crystallized directly from urine and was not formed secondarily as a result
of UAD phase transformation. UAD transformed in various extents to
UAA rarely formed the calculus interior. These calculi, exhibiting an outer
appearance of pebbles were only several millimetres in diameter. The
surface was smooth but not polished and was covered by an organic
matter.
( Ib) Calculi with a centrally situated core, but exhibiting a porous interior.
Relatively large UAA crystals, largely unconnected, assembled without
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
99
Fig. 5. (a) Core of Ia type calculi consisting of few well-developed and loosely connected UAA
crystals; (b) columnar UAA crystals forming the interior of the Ia type stones (confirmed by EDS);
(c) core of Ib type calculi (d) cross-section of calculus of the Ib type.
any apparent order represented the stone core (Fig. 5c). A porous calculus
interior was composed of small crystals of UAA originating on the core.
The interior was apparently structured into alternating densely and
sparsely populated non-columnar layers, creating an impression of concentric laminations (Fig. 5d). Individual crystals of both UAD and UAA
were observed only exceptionally. Organic matter was present in a
substantially increased amount compared to the Ia type.
Approximately 53% of examined stones belonged to the type I.
Type II: stones formed predominantly by sedimentation
Crystalline growth, in addition to sedimentation, plays some and often
significant role in forming this type of calculi.
Stones, with a porous interior, formed by material of an organic origin,
crystals of UAA and COM of shape and size characteristic for particles
appearing in urine during crystalluria, and smaller crystalline objects with a
regular internal structure distributed randomly in a calculus volume (Fig. 6a).
No prevailing inner structure, even over a limited area, could be distinguished. A thin, rather compact, layer of a crystalline material constituted
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F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
Fig. 6. (a) Interior of a sedimentary stone exhibiting a structure without any apparent order. (b)
Large blocks of originally UAD transformed later into UAA, observed in the interior of a
sedimentary stone.
the calculus outer part. This layer mostly formed a smooth lower and side
surface of a calculus. A thicker layer of a crystalline material arranged
without much order usually formed the stone upper irregular surface,
characterized by frequent occurrence of globules. The outer layer enveloping
stone and the calculus interior contained particles of comparatively large size
that could only be formed by a subsequent growth of initially small crystals
deposited from urine. The main constituent of the II type stones, UAA, was
accompanied by typical COM particles disseminated in the calculus mass and
by large blocks of originally UAD that were later transformed into UAA as
signified by an occurrence of the parallel longitudinal cracks (Fig. 6b). A
modification of the II type calculi, typified by an absence of a thin outer layer
and by a substantially increased content of organic matter in comparison to
regular calculi of this type, was also occasionally encountered.
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
101
The II type of calculus represented roughly 39% of the studied uric acid
concretions.
4. Discussion
Calculated solubility of UAD and UAA plotted in Fig. 1 as a function of pH
basically corresponds to a similar plot of uric acid (not further defined) solubility
in the whole urine [18]. All crystallization experiments reported herein were
carried out from solutions supersaturated with respect either to both UAD and
UAA or only to UAA, as transpires from Fig. 1. UAD was the only solid phase
precipitating from the systems supersaturated with respect to both phases,
though supersaturation with respect to UAA was invariably higher than that to
UAD. Therefore, the energy barrier for nucleation of UAD in a urine-like liquor
had to be substantially lower compared to that for UAA. Thus, UAD is the only
solid phase formed from synthetic urine supersaturated with respect to this
compound. However, when synthetic urine is supersaturated just in respect of
UAA (Fig. 1, domains 2, 3), UAD cannot appear and only UAA may be formed.
The transformation of UAD to UAA under physiological conditions is
sufficiently rapid, 2 days for small crystals at the outside, to account for a
conspicuous absence of a larger amount of UAD in the studied calculi. UAD,
that might have been initially formed in abundance, had to transform into UAA
either in vivo during calculus evolution or subsequently in vitro during urolith
storage before analysis.
Based on performed in vitro experiments combined with solubility calculation, a region of pH at which uric acid stones can be formed in the kidney from
urine with varying content of uric acid can be roughly estimated. Normal urinary
pH values oscillate between 5.0 and 6.5, but values can be found in the range
4.5–7.0. Uric acid concentration in urine varies between 170 and 500 mg / l for
the normal population [19], exceeds 550 mg / l for hyperuricosuric patients [20]
and reaches maximally 1200 mg / l [2]. From Fig. 2 it transpires that a minimum
relative supersaturation for nucleating uric acid crystals in the urine-like liquor is
around 1, but these crystals are too small, around 10 mm, to sediment within
given time span into a cavity. Therefore, prevailing urinary supersaturation for
forming sedimentary uroliths (the II type) must be higher than this value. Since
the actual necessary value of supersaturation is not known, let us assume that
s 51.5 would be sufficient for nucleation of uric acid crystals and their
subsequent growth to about 100 mm in size. Conditions for generating the
‘growth type’, i.e., the I type stones are different. Urine has to be just
supersaturated with respect to UAA or UAD according to the component
forming the stone and the minimal required level of supersaturation for their
origin is s 51. A urinary pH at which required supersaturation is achieved for a
certain concentration of uric acid can be calculated from Eq. (4). Thus, the
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values of urinary pH and uric acid concentration at which the relative
supersaturation equals 0, i.e., urine is just saturated with respect to UAA or
UAD (curves a and c, respectively), 1 (curves b and d, respectively) or 1.5 for
UAD (curve e) are represented in Fig. 1. The resulting curves delineate several
domains with different characteristics related to uric acid stone formation. New
crystals of both forms of uric acid cannot be formed in urine, and hence a uric
acid calculus cannot originate under any circumstances, within the region 1. In
the region between the (a) and (d) curves the I type of stones composed of UAA
can develop if a suitable growth center, i.e., some large crystals of uric acid
were already present. New crystals of UAA can generate in the region between
the (b) and (d) curves, but those formed in the region 4 can reach a bigger size
and be retained in a renal cavity. The ‘growth type’ stone consisting of UAD can
be formed in the regions 4 and 5, but only if an adequate template was available.
In the domain 5, new crystals of UAD also originate in the urine, but their size
is insufficient for their being deposited in a cavity and therefore most of them
are voided as crystalluria, since only some of newly formed crystals can reach
size adequate for their retaining in the kidney, and thus the formation of a new
‘growth type’ stone is feasible. Conditions prevailing in the last domain 6 ensure
uric acid stone formation, since new crystals of UAD formed in urine reach
large enough size to be deposited in a cavity forming there a sediment.
Mechanism of formation of uric acid stones can be deduced from their inner
structure and results of in vitro experiments. The stones of the type I, i.e., of the
‘growth type’, originate obviously on a ‘core’ formed by several large crystals of
UAA, a relatively large sedimentary body consisting of numerous crystals. This
core is retained in an open cavity of the kidney which is freely accessible to
urine. On the core, which is in a continuous contact with urine supersaturated
with respect to UAA, but undersaturated with respect to UAD, a compact
crystalline layer, predominantly composed of UAA, starts to develop. Columnar
crystals constituting this layer form the majority of the stone interior. This
signifies a relatively low supersaturation prevailing during stone generation and
consequently a comparatively slow crystal growth. However, a periodic appearance of the concentric laminations composed of small disoriented crystals
implies an occurrence of transitional short episodes of suddenly increased urine
supersaturation. Long periods of high supersaturation would result in a formation of abundant new UAA or UAD crystals and that would cause a complete
breakdown of the columnar structure. The stone interior, in this case consisting
of small, largely disorganized and loosely arranged crystals, was observed in a
few calculi. UAD, if formed, undergoes a phase transition into UAA during later
stages of stone development since UAD was not detected by XRD in the studied
uroliths. This transition cannot proceed by a solution-mediated mechanism
owing to a continuously renewing stone surface by its crystalline growth. The
phase transition occurs later in the bulk of solid calculus causing cracks
development in the stone mass. A developing urolith, which is not attached to
F. Grases et al. / Clinica Chimica Acta 302 (2000) 89 – 104
103
the cavity wall, incessantly ‘rocks’ due to constant body movement. This
ensures an unrestricted access of supersaturated urine, i.e., a uniform supply of
the stone building material, to the whole stone surface and this, in turn, ensues
development of a round shaped stone with a core situated near its center.
The sedimentary stones, i.e., the II type, exhibited a more complex structure
than calculi of the I type. This complexity results from a superposition of three
independent processes — crystalline growth, sedimentation and solution-mediated phase transformation — proceeding successively and / or simultaneously
during a part or the whole period of calculogenesis. The II type calculi started
first by developing crystalline deposits in a cavity in the kidney, consisting of
either UAA formed only on the cavity bottom or UAD covering the whole
cavity. Particles present in urine, i.e., crystals of uric acid, calcium oxalate or
organic debris, deposited under favourable conditions in the cavity. These
particles obviously remained in intimate contact with urine for a considerable
period and therefore could grow further and in the case of UAD could also later
transform by solution-mediated process into bulky hexagonal crystals of UAA.
Thus the cavity interior became filled with a mixture of large and often
intergrown UAA crystals, particles of COM, organic material and UAA crystals
appearing in urine during crystalluria, according to the actual conditions
prevailing in the kidney. The stone interior was porous without any ordered
structure due to this chaotic and random pattern of its formation. When this
cavity was full of material, the compact layer over the top part of the stone
developed and closed thus the calculus interior and practically terminated its
further development. However, individual smaller globules could be subsequently formed on this layer giving rise to a frequently encountered nodular upper
surface of a stone.
The conclusions concerning pH range and uric acid concentrations in which
uric acid stone can be generated represent just the first approximation of the
reality due to uncertainties in the solubility calculation. However, according to
clinical experience, the uric acid uroliths form from urine of pH 5.5 and less [2]
and this roughly corresponds to the calculated boundary of the domain 6 in Fig.
1, where a risk of this calculi formation is acute.
The question why uric acid stones are not formed by all those with low
urinary pH remains to be solved. As probably hyperuricosuria and certainly low
urinary pH are not a prerequisite for uric acid lithiasis [2], absence of inhibitors
of uric acid crystallization in urine of the respective stone-former seems to be a
viable explanation [21].
Acknowledgements
´ General de Investigacion
´ Cientifica y
Financial support from Direccion
´
Tecnica
(Grant No PM97-0040) is gratefully acknowledged.
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