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Urolithiasis
DOI 10.1007/s00240-014-0703-y
INVITED REVIEW
Randall’s plaque as the origin of calcium oxalate kidney stones
Michel Daudon · Dominique Bazin ·
Emmanuel Letavernier
Received: 16 June 2014 / Accepted: 23 July 2014
© Springer-Verlag Berlin Heidelberg 2014
Keywords Randall’s plaque · Kidney stones · Calcium ·
Oxalate · Apatite
Introduction
Calcium oxalate (CaOx) stones are now identified as the
main type of urinary calculi in most countries through-
out the world. They account for at least 70 % of all stones
developed in the upper urinary tract and even more in male
patients [1]. In some parts of the world, CaOx was found as
the main component of about 90 % of all kidney stones [2].
Such a progression in CaOx stones accounts for the increase
in the prevalence of kidney stone disease frequently reported
during the past decades from countries where longitudinal
epidemiological surveys are available as in the United States
[3], in Europe [4, 5] or in Japan [6]. Among the risk factors
involved in stone formation, low diuresis and imbalance in
diet are well documented [7–9]. Although a lot of inherited
or acquired diseases may induce kidney stone formation, all
together account for less than 10–15 % of calcium stones in
the general population. Thus, most of calcium stones result
from biological disorders in urine such as hypercalciuria,
hyperoxaluria and/or hypocitraturia without any “identified”
pathology. Moreover, these disorders are inconstantly found
when urine biochemistry is performed, suggesting the anom-
alies are intermittent or transient, or simply related to low
diuresis, which results in an increased concentration of poorly
soluble salts in urine. Thus, the so-called idiopathic nephro-
lithiasis is the bulk of calcium stones. However, during the
last decade, a series of investigations by the group of Evan,
Lingeman and Coe, highlighted the role of calcium phosphate
deposits in the papilla tip as a starting point of CaOx stone
formation [10–12]. Such deposits, termed Randall’s plaque
because they were first described by Alexander Randall in
Abstract Eight decades ago, Alexander Randall identi-
fied calcium phosphate deposits at the tip of renal papil-
lae as the origin of renal calculi. The awareness that these
“Randall’s plaque” promote renal stone formation has
been amplified during the past years by the development
of endoscopic procedures allowing the in situ visualization
of these plaques. Recent studies based upon kidney biop-
sies evidenced that apatite deposits at the origin of these
plaque originate from the basement membranes of thin
loops of Henle and then spread in the surrounding inter-
stitium. In addition, scanning electron microscopy exami-
nation of calcium oxalate stones developed on Randall’s
plaque evidenced that plaque may also be made of tubules
obstructed by calcium phosphate plugs. Hypercalciuria has
been associated to Randall’s plaque formation. However,
several additional mechanisms may be involved resulting
in increased tissular calcium phosphate supersaturation and
the role of macromolecules in plaque formation remains
elusive. At last, apatite crystals are the main mineral phase
identified in plaques, but other calcium phosphates and var-
ious chemical species such as purines have been evidenced,
revealing thereby that several mechanisms may be respon-
sible for plaque formation.
M. Daudon (*) · E. Letavernier
Laboratoire des Lithiases, Service des Explorations
Fonctionnelles, Hôpital Tenon, APHP, 4, rue de la Chine,
75970 Paris Cedex 20, France
e-mail: michel.daudon@tnn.aphp.fr
M. Daudon · E. Letavernier
Unité INSERM UMRS 1155, UPMC, Paris, France
D. Bazin
CNRS, Laboratoire de Chimie de la Matière Condensée de Paris,
UPMC, Collège de France, Paris, France
Urolithiasis
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the 1930s, initiate in the basement membrane of the long
Henle’s loops and spread out in the interstitium around the
Bellini’s ducts close to the papillary epithelium. When the
epithelium is disrupted, the calcium phosphate deposits are in
contact with the supersaturated urine issued from the vicinal
nephrons, thus favouring CaOx crystallization and trapping of
the crystals at the surface of the plaque. Thereafter, the stone
growth is driven by urine supersaturation.
Original description of papillary calcified plaques
by Randall
More than 75 years ago, Alexander Randall reported a study
on “The origin and growth of renal calculi”, which appeared
first in the New England Journal of Medicine [13] and the
following year in the Annals of Surgery [14]. In this seminal
paper, he described a hitherto unrecognized papillary lesion
consisting in calcium phosphate deposits in the intertubular
spaces of the renal papilla, observed in 19.6 % of 1,154 pairs
of kidneys examined at autopsy. He made three observations:
–– first, this papillary lesion which appeared as a cream-
coloured area near the tip of the papilla was not on its
surface, but was subepithelial in location;
–– second, the chemical composition of papillary plaques
was shown to be made of calcium phosphate and car-
bonate;
–– third, small calculi were found to be attached to plaque
at the tip of papillae in 65 kidneys (2.8 %), their compo-
sition differing from that of the plaque. The stones were
made of calcium oxalate;
–– fourth, CaOx stones collected in routine practice often
exhibited a portion which was smooth and somewhat
depressed, resembling a facet corresponding with the
morphology of the papilla.
Examining by light microscopy some calculi actually
attached on a papillary plaque, Randall found that the stone
was continuous with the interstitial plaque and that the epi-
thelial covering of papilla was lost. Such aspect of calcium
phosphate deposits in the interstitium was termed papillary
lesion type 1 by Randall who proposed that papillary calcium
deposits could act as a nidus for urinary salt accretion if epi-
thelial covering of the papilla is lost. Randall also found in
some cases Bellini’s ducts filled by calcium phosphate plugs
(termed papillary lesion type 2). He suggested the phosphate
plugs may be another way for CaOx stone formation.
Scanning electron microscopy examination of CaOx stones
developed from a Randall’s plaque provides evidence that
plaque is made of a mixing of tubules with calcified walls
(white arrow, Fig. 1a) and of tubules obstructed by calcium
phosphate plugs (black arrow, Fig. 1a or white arrow, Fig. 1b).
Please note in Fig. 1b, the calcium phosphate cluster
within the tubular lumen (white arrow), while other tubules
are empty with calcified walls.
In other cases, much less frequent, the nidus of the stone
appears only as a tubular plug (Fig. 2, black arrow).
At the time Randall performed his studies, he could not
identify the exact location and nature of calcium depos-
its within the papillary structure. Nor, due to the forensic
nature of his study material, could he evaluate urinary sol-
ute excretion in the affected individuals.
Epidemiological considerations
Other authors confirmed the findings of Randall in autopsy
studies during the same period: for example, Rosenow
Fig. 1 Scanning electron microscopy photographs of calcium oxalate
calculi initiated from a Randall’s plaque. a The plaque is made of a
mixing of tubules with calcified walls (white arrow) and of tubules
obstructed by calcium phosphate plugs (black arrow). b Randall’s
plaque at the surface of another calcium oxalate stone with calcified
tubules and a calcium phosphate plug partly obstructing the lumen of
a collecting duct
Urolithiasis
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found plaques in 22.2 % of 239 kidneys, whereas Anderson
observed plaques in 12 % of kidneys in a series of 1,500
necropsies [15, 16]. In South Africa, Vermooten [17] exam-
ined 1,060 pairs of kidneys. He found Randall’s plaques in
17.2 % of Caucasians and only 4.3 % of Bantus, a finding
in keeping with his observation of the lower incidence of
calcium nephrolithiasis in the local population of African
descent than Caucasian descent. Papillary calcifications
were seen in the subepithelial interstitial tissue together
with collagen fibres, and were not found in the lumen of
collecting ducts [18]. Forty years after the first description
of papillary calcified deposits acting as a nidus for calcium
stone formation, Luis Cifuentes-Delatte, a Spanish urolo-
gist enthusiastic for research on stone formation observed
with his colleagues that 142 out of 500 consecutive calculi
exhibited a concavity characteristic of a papillary origin
[19]. In 61 (43 %) of these umbilicated calculi, plaques
were typically made of apatite, some of them showing cal-
cified collecting ducts [20].
In our experience, based upon 45,774 calculi referred
to the Necker hospital stone laboratory over the past three
decades, we found by morphologic examination coupled
with FTIR analysis that 8,916 (19.5 %) calculi exhibited a
depressed surface (umbilication) suggestive of a papillary
attachment [21]. Most of these stones (92.5 %) were made
of CaOx monohydrate (whewellite) either pure (Fig. 3) or
admixed with CaOx dihydrate (weddellite) as observed in
Fig. 4. As previously reported, the composition of Randall’s
plaque is carbapatite in 90 % of cases, but other crystal-
line phases may be found as main component of Randall’s
plaque such as amorphous calcium phosphate, brushite or
whitlockite, or trioxypurines like sodium urate [19, 21].
However, detailed endoscopic examination of renal
cavities during percutaneous nephrolithotomy (PNL) or
ureteroscopic procedures suggests a much higher preva-
lence of Randall’s plaques than that deduced from stone
examination. An explanation could be that modern uro-
logical treatment to remove stones often use fragmenta-
tion techniques such as shockwaves, ultrasounds or laser.
As a consequence, stone fragments collected for analysis
may have lost both the part of Randall’s plaque fixed to the
stone and the typical depressed face. In 1997, using endo-
scopic procedures, Low and Stoller reported the presence
of Randall’s plaques on one or more papillae in 74 % of
57 stone formers, the prevalence being 88 % for CaOx
stones [22]. In 2006, Matlaga et al. [23] found that 91 %
of papillae in 23 patients with idiopathic CaOx nephrolithi-
asis harboured plaques and half of papillae had attached
calculi. Digital imaging provided undisputable evidence
of stone attachment to plaque. Indeed, epidemiological
differences in the occurrence of Randall’s plaques may be
Fig. 2 Scanning electron microscopy photograph of a tubular plug
(black arrow) at the origin of a calcium oxalate monohydrate stone
Fig. 3 Whewellite stone initiated from a carbapatite Randall’s plaque
(white arrow)
Fig. 4 Mixed stone made of whewellite and weddellite nucleated
from a Randall’s plaque (white arrow)
Urolithiasis
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observed according to the investigated population. Recent
reports from European countries suggest that Randall’s
plaque could be less frequent in Europe than in the United
States. In Italy, Ruggera et al. reported the occurrence of
Randall’s plaque in 44.4 % of 27 stone formers who under-
went ureterorenoscopy or PNL and renal papillae biopsy
[24]. In France, Olivier Traxer found Randall’s plaques in
57 % of 287 stone formers who underwent flexible ureter-
orenoscopy. They were observed on all papillae in 54 % of
these patients. Such plaques were visible in only 27 % of
173 non-stone forming patients [25, 26].
Of note, in France, stones harbouring an umbilication
were found to be three times more frequent in the recent
years than at the beginning of the 1980s and patients were
younger and younger [27]. Children may form CaOx stones
from Randall’s plaque. As shown in Fig. 5, when consid-
ering only unfragmented stones spontaneously passed or
removed by urological procedures without fragmentation,
the part of stones developed from a Randall’s plaque is
very high and dramatically increasing with age from child-
hood up to the age class 20–30 years, then slowly decreas-
ing thereafter. In our experience, 39 % of all spontaneously
passed stones had a typical umbilication on their surface
and 5,728 among 8,662 (66.1 %) of spontaneously passed
CaOx monohydrate calculi were umbilicated and were
developed from a Randall’s plaque.
Randall’s plaques begin in basement membranes
of thin Henle’s loops
In an elegant study, Evan and co-workers recently pro-
vided substantial advances in the pathogenesis and struc-
ture of Randall’s plaques in patients with CaOx stones [10].
They took superficial biopsy specimens from papillae in
the upper, middle and lower poles of a kidney during PNL
performed for stone removal in 15 patients with recurrent,
idiopathic CaOx nephrolithiasis, all of whom were hyper-
calciuric, and in 4 patients with CaOx stones and hyperox-
aluria due to jejuno-ileal bypass for obesity.
By light microscopy, they confirmed Randall’s plaques
to be in subepithelial position at the papillary tip, surround-
ing the openings of the ducts of Bellini. Calcium-containing
deposits were found surrounding primarily the thin loops of
Henle. Electron microscopy revealed these deposits to be
located within the basement membrane of Henle’s loops
and around adjacent vasa recta, but not within the cyto-
plasm of the cells. Infrared microspectroscopy of deposits
identified spectral bands characteristics of hydroxyapatite,
associated with calcium carbonate in about 20 % of cases.
In summary, papillary plaques are interstitial and composed
of apatite, originate in the basement membrane of the thin
loops of Henle and subsequently spread into the surround-
ing interstitium, in the vasa recta and in the basement mem-
branes of collecting ducts, without affecting collecting
duct cells themselves. As said by the authors, “the overall
impression is that the basement membrane of thin limbs is
indeed the origin of plaque”.
In contrast, none of the four patients with enteric hyper-
oxaluria due to jejuno-ileal bypass exhibited such papillary
plaques. Instead, they exhibited intratubular hydroxyapatite
crystals in the lumen of some collecting ducts, attached to
their apical surface. Thus, the site of initial crystallization
differed according to the underlying metabolic abnormal-
ity. Of note, four non-stone-formers subjected to nephrec-
tomy, taken as controls, had neither papillary plaques nor
tubular crystals [10]. Looking for risk factors associated
with Randall’s plaque formation, Kuo et al. found that low
urine output, high calcium content and low urine pH were
significantly more frequent in calcium stone formers with
than without Randall’s plaque [28]. Moreover, Kim and co-
workers reported that stone episodes were proportional to
the coverage of papilla by Randall’s plaques [29].
Role of hypercalciuria in the pathogenesis of Randall’s
plaques
Evan and co-workers speculate that hypercalciuria should
be the main explanation at the origin of Randall’s plaques
[10]. Before examining their arguments, one may remem-
ber that an epidemiologic case/control study identified
high urinary calcium concentration to be the major risk
factor for idiopathic calcium nephrolithiasis [30], whereas
oxalate, uric acid and citrate concentrations did not differ
between incident stone formers and contemporary controls.
In the study of Evan et al. [10], the mean calcium excre-
tion was 312 mg/day (7.8 mmol/day) in the 15 CaOx stone
Fig. 5 Occurrence (%) of Randall’s plaque at the origin of spontane-
ously passed calcium oxalate stones according to the patient’s age
Urolithiasis
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formers, compared to 113 mg/day (2.8 mmol/day, p < 0.01)
in the 4 non-lithiasic controls.
According to the authors and to the editorial comments of
their work by Bushinsky [31], the sequence of events could
be as follows. Hypercalciuria is associated with intestinal cal-
cium absorption, which results in postprandial peaks in serum
calcium, reflected in increased calcium concentration in glo-
merular filtrate and in the fluid presented to the thin limbs,
then to the thick ascending limb. High calcium reabsorption
at this site enriches the outer medulla with calcium, which is
washed into the deep medulla by the descending vasa recta.
The origin of calcium phosphate deposits in the inter-
stitium may be the consequence of several mechanisms. As
reported by Asplin and co-workers [32], the narrow part of
the long loops of Henle is often supersaturated for calcium
phosphate, which may precipitate. Despite the short tran-
sit time in that part of the nephron (20–30 s), where most
particles remain free in the tubular lumen, some of them
may be attached to the apical cell membrane, especially if
urinary macromolecules and other inhibitors such as citrate
are in low concentration or if an oxidative stress was able
to damage the cell surface. Then, an endocytosis process
may be initiated to eliminate them by intracellular dissolu-
tion [33]. Calcium and phosphate ions resulting from the
apatite dissolution are transferred in the interstitium and
may locally induce high CaP supersaturation favouring
new crystallization of apatite in the basement membrane
of thin limbs, which is unusually thick and is composed of
collagen with abundant mucopolysaccharides. Apatite crys-
tals, once initiated, are able to accumulate and extend in
the interstitium. At the microscopic scale, Evan et al. have
shown that apatite crystals are composed of successive lay-
ers of mineral and macromolecules such as osteopontin
[11]. Extensive accumulation of interstitial calcium depos-
its up to the papillary epithelium may result in a disruption
of the epithelium by a yet poorly understood mechanism,
thus making the apatite crystals exposed to the supersatu-
rated urine. In the first following steps, new layers of cal-
cium phosphate and macromolecules may cover the plaque,
after what CaOx crystals formed in the surrounding super-
saturated urine may be attached on the plaque, thus initiat-
ing stone formation [11, 26].
As underlined by Tiselius [34], calcium phosphate pre-
cipitation requires high CaP supersaturation, which is
favoured by high pH value, high concentration of calcium
and/or phosphate ions. Indeed, the physicochemical envi-
ronment in the interstitium of the inner medulla favours cal-
cium phosphate supersaturation around the tip of Henle’s
loops, especially in the presence of hypercalciuria and low
urine output. In case of an excessive acid load, as observed
in patients who eat large amounts of animal proteins, an
increased excretion of H
+
ions by the collecting duct cells
results in a low urine pH and an increased production of
bicarbonate ions transferred to the interstitium. High pro-
tein intake is also responsible for a high excretion of phos-
phate ions, which could be another favouring factor for
explaining calcium phosphate supersaturation in tubular
lumen and the papillary interstitium.
As a result of the high acid load (the same is observed
in the case of antidiuresis), the pH increases in the inner
medulla, inducing supersaturation of calcium phosphate
that may precipitate. Moreover, in hypercalciuric states,
which appear to be more frequent in patients with Randall’s
plaques, a default of calcium reabsorption in the proximal
part of the tubule results in an increased delivery of calcium
in the distal part of the nephron, which may contribute to
the supersaturation of calcium phosphate and/or CaOx
[35]. In the case of low diuresis, the hyaluronic acid content
in the inner medulla decreases [36] thus reducing its avail-
ability to act as an inhibitor of crystallization and results in
increased concentration of solutes in the interstitium.
While endocytosis of CaP particles or secondary precip-
itation of CaP in the basement membrane of the cells may
result from local high supersaturation, another phenom-
enon could explain why CaOx crystals may be secondary
deposited on the CaP Randall’s plaque after the papillary
epithelium has been lost by a yet unexplained mechanism.
Indeed, it is well known that CaP particles are the most fre-
quent mineral phases found in urine [37]. In the case of low
diuresis or high acid load, the secretion of H
+
in the distal
part of the nephron results in a rapid decrease of the pH
inducing dissolution of CaP particles. As a consequence,
an increased calcium concentration may increase enough
the CaOx supersaturation to induce nucleation of CaOx
crystals that are excreted in the caliceal cavities [3, 38] and
then may be fixed on the CaP particles at the surface of the
papilla [26]. Then, the stone growth depends on the level
of CaOx supersaturation, which is linked to the diuresis,
and the concentration of both calcium and oxalate, and also
of inhibitors such as citrate. When the stone is too large or
too heavy for the mechanical resistance of the Randall’s
plaque that plaque may be disrupted and the stone free in
the caliceal space. Thereafter, it may be rapidly spontane-
ously passed (the most frequent situation) or retained in the
calyx. In such case, new CaOx crystals may progressively
cover the umbilication and the calcium phosphate plaque,
which disappears at the surface of the stone. When removed
or spontaneously expelled, the stone does not exhibit any
Randall’s plaque which is found in the core of the stone as
suggested by Miller et al. [39] and illustrated in Fig. 6.
Randall’s plaque and stone composition
First studies by Evan and co-workers suggest that apatite
crystals are the mineral phase for interstitial plaque and
Urolithiasis
1 3
that amorphous calcium phosphate (ACP) deposits may
cover the plaque secondly after it outcrops at the surface
of the epithelium [11]. However, as suggested by Tiselius
[34] ACP formation is favoured by high CaP supersatura-
tion, which may occur not only in the urine, but also in
the interstitium. In fact, other works suggest that ACP may
be more abundant in the interstitial part of the Randall’s
plaque than at its surface [40]. As previously reported,
Randall’s plaque is made of carbapatite in most cases, but
other calcium phosphates and other chemical species, such
as sodium urate may be identified within Randall’s plaque
[21]. As shown in Table 1, about 15 different crystalline
species were found among 11,016 calculi exhibiting a pap-
illary umbilication. Carbapatite was identified in 97.6 %
of cases, either pure or mixed with other calcium phos-
phates or other compounds such as purines. However, in
some cases, carbapatite was not detected and then, another
mechanism than Randall’s plaque may be involved in
stone formation. We cannot exclude that some of these
compounds such as uric acid were only deposited at the
surface of the papilla because of a local tissue lesion and
then acted as a factor for heterogeneous nucleation of cal-
cium oxalate. Of note, around the Randall’s plaque the first
layers of the stone are made in most cases by CaOx mono-
hydrate [21, 38].
Conclusion
Idiopathic CaOx stones, the occurrence of which has
been frequently reported as increasing during the past
half century, mainly from a Randall’s plaque made of
carbapatite. In parallel, the progress in endoscopic mate-
rial and optics, making easy the visual inspection of kid-
ney papillae provides evidence that Randall’s plaques
are become very common in stone formers as in the gen-
eral population. Such changes are in line with in-depth
modifications in dietary habits in industrialized coun-
tries over the past decades. A better knowledge regard-
ing the mechanisms involved in the formation of calci-
fied deposits within the inner medulla of the kidney is
required in order to provide efficient advices able to
reduce the occurrence of Randall’s plaque and stone
formation.
Fig. 6 Section of a whewellite stone exhibiting a whitish core made
of carbapatite containing holes highly suggestive of Randall’s plaque
with calcified tubules
Table 1 Occurrence of
crystalline species found as
Randall’s plaque at the stone
surface
Components of papillary deposits Main Minor Total occurrence
Calcium phosphates 10716 (97.3) – 10894 (98.9)
Carbapatite 10404 (94.4) 351 (3.2) 10755 (97.6)
Amorphous carbonated calcium phosphate 264 (2.4) 629 (5.7) 893 (8.1)
Whitlockite 30 (0.3) 87 (0.8) 117 (1.0)
Octacalcium phosphate 3 (0.03) 13 (0.12) 16 (0.15)
Brushite 15 (0.14) 23 (0.2) 38 (0.34)
Other species 300 (2.7) – 503 (4.6)
Struvite 3 (0.03) 9 (0.08) 12 (0.1)
Bobierrite 2 (0.02) 0 2 (0.02)
Calcite 9 (0.08) 12 (0.1) 21 (0.2)
Sodium hydrogen urate 232 (2.1) 138 (1.25) 370 (3.4)
Uric acid 43 (0.4) 24 (0.2) 67 (0.6)
Ammonium urate 4 (0.04) 3 (0.03) 7 (0.06)
Potassium urate 4 (0.04) 0 4 (0.04)
Opaline silica 2 (0.02) 1 (0.01) 3 (0.03)
Porphyrines 1 (0.01 16 (0.15) 17 (0.15)
Total number of samples 11016 (100) 1291 (11.7) –
Urolithiasis
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Conflict of interest The authors declare no conflict of interest.
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