Role of the urinary calcium in the growth of calcium stone.

Abstract

We analyzed the relationship between the rate and clinical factors. The growth rate per year of the stone was measured by Nabeshima's method in 29 male patients with renal calcium stones including 7 pure calcium oxalate (CaOx) stones and 22 mixed calcium oxalate and calcium phosphate (CaOx-CaP) stones. The 24-hour urinary excretion of calcium, phosphate, uric acid and magnesium were assayed under an ambulatory free diet in 5 patients with CaOx stones and 15 with CaOx-CaP stones. The relationship between the growth rate and the urinary excretion of stone-forming parameters was examined. We found a significant positive correlation between the growth rate of calcium stones and the urinary excretion of calcium (p<0.02). In addition, the growth rate of CaOx-CaP stone was significantly higher than that of pure CaOx stone (p<0.05). In conclusion, urinary calcium is important for the growth of renal calcium stones.

Full text

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TitleRole of the urinary calcium in the growth of calcium stone
Author(s)
Murayama, Tetsuo; Sakai, Naoki; Takano, Takano; Yamada,
Tetsuo
Citation泌尿器科紀要 (2004), 50(7): 451-455
Issue Date2004-07
URLhttp://hdl.handle.net/2433/113414
Right
TypeDepartmental Bulletin Paper
Textversionpublisher
KURENAI : Kyoto University Research Information Repository
Kyoto University

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Acta Uro!. Jpn. 50: 451-455, 2004 451
ROLE OF THE URINARY CALCIUM IN
THE GROWTH OF CALCIUM STONE
Tetsuo MURAYAMA, Naoki SAKAI, Tetsuzou TAKANO and Tetsuo YAMADA
From the Department of Urology, Sagamihara National Hospital
We analyzed the relationship between the rate and clinical factors. The growth rate per year of
the stone was measured by Nabeshima's method in 29 male patients with renal calcium stones
including 7 pure calcium oxalate (CaOx) stones and 22 mixed calcium oxalate and calcium phosphate
(CaOx-CaP) stones. The 24-hour urinary excretion of calcium, phosphate, uric acid and magnesium
were assayed under an ambulatory free diet in 5 patients with CaOx stones and 15 with CaOx-CaP
stones. The relationship between the growth rate and the urinary excretion of stone-forming
parameters was examined. We found a significant positive correlation between the growth rate of
calcium stones and the urinary excretion of calcium (p<0.02). In addition, the growth rate ofCaOx-
CaP stone was significantly higher than that of pure CaOx stone (p<0.05). In conclusion, urinary
calcium is important for the growth of renal calcium stones.
(Acta Urol. Jpn. 50: 451-455, 2004)
Key words: Growth of calcium stone, Urinary calcium, Stone composition
INTRODUCTION
The nidus of nephrolith is initially formed in the
renal tubulus. When this nidus is excreted in the
renal pelvis and lodged there for a long time, the
crystal aggregates on the surface of the nidus and the
clinical stone develops. The growth of the renal
calcium stone is closely associated with the crystal
formation, growth and aggregation. The crystal
formation occurs in the supersaturated urine with
respect to calcium oxalate and calcium phosphate,
the components of the calcium stone.
Urinary pH also affects crystal formation. The
calcium oxalate (CaOx) crystal is formed when the
pH is below 6.2, while that of calcium phosphate
(CaP) is formed at a pH beyond 6.21). Several stone-
growth promoting factors have been proposed, such
as male, renal pelvic stone, high output of urinary
calcium and low value of urinary magnesium/cal-
cium2)
The purpose of this study is to determine
how stone-forming parameters especially urinary
excretion of calcium influence stone growth.
METHODS
We investigated the relationship between the
composition and the size of renal and ureteric calcium
stones in 376 male patients treated at Sagamihara
National Hospital from 1980 to 2001. The analysis
of the composition of stones obtained by spontaneous
passage, surgery and extracorporeal shockwave
lithotripsy (ESWL) by means of infrared spectros-
copy revealed 175 calcium oxalate (CaOx) stones and
201 mixed calcium oxalate and calcium phosphate
(CaOx-CaP) stones, which included 158 CaOx-CaP
stones predominantly calcium oxalate(CaOx>CaP)
and 43 CaOx-CaP stones predominantly calcium
phosphate (CaOx<CaP). We considered the stone
to be CaOx stone if the rate of phosphate in it was less
than 2%. Among these patients, we could examine
the growth rate of renal calcium stones per year by
means of the method described by Nabeshima et a1.2)
only in 29 patients including 7 with a CaOx stone and
22 with a CaOx-CaP stone including 18 CaOx>CaP
stones and 4 CaOx<CaP stones. The stone growth
was observed for 6 to 123 months, with a mean
observation period of 40 months. The growth rate
per year was defined as follows; (the stone volume at
the end of the observation -the volume at the start) X
l/the volume at the start Xl/year of the observation X
100%. The 24-hour urinary excretion of calcium,
phosphate, uric acid and magnesium was measured
in 20 of these 29 patients under an ambulatory free
diet. Collected urine during 24 hours at room
temperature without adding any antibacterial agent
was measured immediately after collection was com-
pleted by the following method: calcium; methyl-
xylenol method, phosphate; enzyme colorimetric
method, uric acid; uricase peroxidase method and
magnesium; xylidyl blue method. Dietary manage-
ment to prevent stone recurrence was not done except
for recommendation of water intake. Patients with
primary hyperparathyroidism and treated with
allopurinol, uricosuric agents, diuretics and steroid
hormones were excluded from the present study.
The relationship between the composition and the
size of calcium stones was statistically analyzed by the
chi squared test. The correlation between the
growth rate of the stone and 24-hour urinary excretion
of each stone-forming parameter was analyzed by
Fisher's z-test. The growth rate was compared
between CaOx stones and CaOx-CaP stones by
Student's t test. The data were considered statis-

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452
Acta Urol. Jpn. Vol. 50, No.7, 2004
tically significant at p< 0.05.
RESULTS
Patients with CaOx stones had a significantly
higher rate of stones less than 10 mm compared to
those with CaOx>CaP stones and CaOx<CaP
stones, respectively. However, no significant differ-
Table I. Relationship between composItion
and SIze of stone (male patient)
Size of stone
Composition
CaOx
CaOx>CaP
CaOx<CaP
Total
<lOmm
163*#
108
29
300
IOmm<
12
50
14
76
Total
175
158
43
376
•. p<O.OI compared with CaOx>CaP, #. p<O.OI
compared with CaOx<CaP, CaOx: calcium oxalate
stone, CaOx>Cap: mixed calcium oxalate and calcium
phosphate stone prerdominantly calcium oxalate,
CaOx<CaP: mixed calcium oxalate and calcium
phosphate stone predominantly calcium phosphate.
Case Age Composition
I
2
3
4
5
6
7
8
9
10
II
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
54
44
35
18
55
36
44
35
21
63
52
48
57
47
49
65
50
37
43
55
24
36
56
81
30
46
48
34
66
CaOx
CaOx
CaOx
CaOx
CaOx
CaOx
CaOx
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx>CaP
CaOx<CaP
CaOx<CaP
CaOx<CaP
CaOx<CaP
Table 2.
Observed
months
Growth rate
(%/year)
54
36
33
123
26
II
28
42
10
13
16
48
43
28
62
46
84
II
37
17
6
20
54
59
38
31
110
6
54
73.1
9.3
20.4
26.2
4.2
11.7
2.3
4.9
175
167
38.6
8.9
124
73.3
2
247
4.8
60.4
14.5
2.4
366
85.2
8.3
62.1
87.8
389
3.4
441
II.!
ence was found between the size of CaOx>CaP
stones and CaOx<CaP stones (Table 1). The pa-
tient's age, composition of stone, observation period,
growth rate, 24-hour urinary excretion of stone-
forming parameters and urine volume per day are
summarized in Table 2. The excretion of calcium
alone showed a significant positive correlation be-
tween the growth rate and 24-hour urinary excretion
of stone forming parameters (Fig. I). Six of eight
calculi with a 24-hour calcium excretion of more than
300 mg per day showed an extremely high growth
rate. No significant correlation was found between
the growth rate and 24-hour urinary excretion of
phosphate, uric acid and magnesium. With regard
to the relationship between 24-hour urinary excretion
of calcium and other stone-forming parameters, sig-
nificant positive correlations were found between cal-
cium and phosphate (Fig. 2), and uric acid. The
mean growth rate per year ofCaOx stones was 21.0±
24.5% (n=7), while those of CaOx>CaP, CaOx<
CaP and CaOx-CaP were 92A± 98.8% (n = 18),
210.9±236.7% (n=4) and 108.0±135.9% (n=22),
Patient data
24 hour urinary excretion (mg/day)
Calcium Phosphate Uric acid Magnesium
247
249
262
114
231
444
528
349
273
336
384
154
215
307
244
285
92
370
287
448
701
734
752
630
1,191
810
1,135
749
893
897
1,550
616
426
889
505
1,041
357
7ll
904
929
591
504
621
407
855
624
714
599
447
1,047
986
429
521
702
583
912
616
682
578
885
99
135
67
84
149
66
108
78
130
50
100
129
130
104
102
140
139
Urine
(ml/day)
2,750
2,770
3,740
670
3,000
3,000
1,860
3,120
4,700
2,300
3,100
1,600
1,760
1,940
2,350
2,160
2,880
3,630
2,470
2,950
CaOx: calcium oxalate s ~ o n e , CaO.x>Cap: mixed calcium oxalate and calcium phosphate stone predominantly calcium
oxalate, CaOx<CaP: mixed calcIUm oxalate and calcium phosphate stone predominantly calcium phosphate.

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MURAYAMA, et al.: Growth of renal calcium stone
453
450
400
~
<!)
<' 350
~
'-" 300
<!)
f=l .s
'"
4-<
0
~
0
5h
250
200
150
100
50
•
•
•
•
•
•
;;:.
«I
"t)
bD
,§
~
0
.0
o·
-50
50
100 150 200 250 300 350 400 450 500 550
urinary excretion of calcium (mg/day)
Relationship between the growth rate of
stone per year and 24-hour urinary
excretion of calcium under ambulatory
free diet in patients with renal calcium
stone. There was a positive correlation
between the growth rate of stone and the
urinary excretion of calcium (y=0.513 ;
p=0.0147, y=0.625x-87.546). Cal-
cium oxalate stone (0), mixed calcium
oxalate and calcium phosphate stone
predominantly calcium oxalate (e),
mixed calcium oxalate and calcium
phosphate stone predominantly calcium
phosphate (©).
Fig. 1.
2000,---------------------------,
1500
0

«I
..:
c..
<II
0
..:
c.. ...
0
c
~ ... ...
u ,-.
...
t'
«I
C ·c =
1000
500
0
0
0
100 200
300 400
500
600
uri.nary excretion of calcium (mg/day)
Fig. 2. Relationship between 24-hour urinary
excretion of calcium and that of phos-
phate under ambulatory free diet in pa-
tients with renal calcium stone. There
was a positive correlation between the
urinary excretion of calcium and that of
phosphate (y=0.579; p=0.0065, y=
1.446x +400.230).
respectively. A statistically significant difference
was noted between the growth rate of CaOx stones
and those of CaOx> CaP and CaOx-CaP stones,
respectively (p<0.05). The 24-hour urinary excre-
tion of calcium was higher in patients with CaOx-
CaP stone (314± 114 mg/day) than those with CaOx
stones (221 ±61 mg/day), but not significantly.
DISCUSSION
It has been generally accepted that urinary calcium
and oxalate play an important role in stone
formation. In the present study, we showed that
urinary calcium excretion is an important factor for
the growth of calcium stones. In addition, we have
also demonstrated a characteristic stone growth
pattern dependent on stone composition.
Sutor et al. reported that CaOx stones were more
likely to be expelled than CaOx-CaP stones and that
CaOx stones were lighter than CaOx-CaP stones in
weight3). Table I also shows the similar results.
From this, we can safely say that CaOx stones are
smaller than CaOx-CaP stones. The fact that CaOx
stones are small and CaOx-CaP stones large suggests
that CaOx stones grow slowly while CaOx-CaP
stones grow rapidly.
I t has been reported that patients with CaOx stones
excrete significantly more acidic urine with a lower
calcium4) and higher oxalate5) content than those
with CaOx-CaP stones. In this study, we found that
the 24-hour urinary excretion of calcium was higher in
patients with CaOx-CaP than in those with CaOx,
although the difference between them was not
statistically significant, probably due to the small
number. The slow growth of CaOx stones in the
high-oxalate and low-calcium urine and rapid growth
of CaOx-CaP stones in the normal oxalate and high-
calcium urine lead us to consider that urinary calcium
plays a more important role in the growth of calcium
stone than urinary oxalate does. In addition, we
found a positive correlation between urinary calcium
and phosphate excretion probably due to recent
trends in dietary habit such as excess intake of animal
protein and alcohol ingestion which result in
increased excretion of urinary calcium as well as
phosphate6)
We consider that increased urinary
calcium excretion and phosphate excretion are
responsible for the fast growth of CaOx-CaP stones.
We analyzed the stone structure of the calcium
stones. CaOx stones are classified into 3 groups
according to their components, CaOx-monohydrate
(COM), CaOx-dihydrate (COD), and CaOx-mono
and dihydrate. COM stones are smoothly surfaced,
and hard stones composed of COM crystals arrangied
orderly and tightly. COD stones are irregularly
surfaced and brittle stones consisting of COD crystals
arranged at random7). COD stones are more
common than COM stones among patients with
higher urinary calcium excretion levels and with a
higher urinary pH and significant differences have
not been found between the urinary excretion of
oxalate in patients with COM stones and those with
COD stones8)
In addition, the CaOx component in
the majority of CaOx-CaP stones has been shown to

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454
Acta Urol. Jpn. Vol. SO, No.7, 2004
be COD rather than COM and the interspace of
COD to be occupied by CaP components9)
From these findings we speculate that the low
growth rate of the COM-type CaOx stone is due to
the lower urinary calcium excretion as well as small
interspaces between COM crystals, and the higher
growth rate of the CaOx-CaP stones is due not only to
higher calcium and phosphate excretion but also to
the large inters paces between COD crystals.
From a therapeutic standpoint, we consider that
diet therapy such as recommendation of water intake
and restriction of excess intake of animal protein,
alcohol and salt may help to prevent the increase of
calcium stones by lowering urinary calcium 10)
Thiazide therapy may be needed especially in
patients with a 24-hour urinary calcium excretion of
more than 300 mg.
In this study, we could not measure the urinary
oxalate and citric acid concentrations. In addition,
it is not known how high molecular weight inhibitors
or promoters affect the growth of calcium stones.
The full understanding of the growth of calcium
stones awaits future studies.
In conclusion, the urinary calcium excretion is an
important factor for the growth of calcium containing
stones. The growth rate of CaOx-CaP stones is
higher than that of CaOx stones.
REFERENCES
I) Robertson WG, Peacock M and Nordin BEC:
Calcium crystalluria in recurrent renal stone former.
Lancet 2: 21-24, 1969
2) Nabeshima S, Masai M, Shimazaki T, et al.:
Prognostic factors influencing the growth of renal
calculi. Jpn J Urol 85: 1593-1600, 1994
3) Sutor DJ and Wooley SE: Some data on urinary
stones which were passed. Br J Uro147: 131-135,
1975
4) Murayama T, Sakai N, Yamada T, et al. : Role of
the diurnal variation of urinary pH and urinary
calcium in urolithiasis: a study in outpatients. Int
J Urol: 8: 525-532, 2001
5) Ueda H: Urinary oxalate excretion in the patients
with upper urinary tract calculi. lpn J Urol 76:
338-347, 1985
6) Zechner 0, Latal D, Pfluger H, et al. : Nutritional
risk factors in urinary stone disease. J Urol 125:
51-54,1981
7) Koide T, Itatani H, Yoshioka T, et al.: Clinical
manifestations of calcium oxalate monohydrate and
dihydrate urolithiasis. .J Urol 127: 1067-1069,
1982
8) Pierratos AE, KhalaffH, Cheng PT, et al.: Clinical
and biochemical differences in patients with pure
calcium oxalate monohydrate and calcium oxalate
dihydrate kidney stones. J Urol 151: 571-574,
1994
9) Tanikawa K, Matsushita K and Matsuzaki S: The
Japanese Symposium For Urolithiasis Research
3: 29-34, 1993
10) Lifshitz DA, Shalhav AL and Lingeman JE:
Urolithiasis-Patient evaluation and medical treat-
ment. In: Treatment of Urolithiasis. Edited by
Akimoto M, Higashihara E, Kumon H, et al. ed., pp
37-59, Springer-Verlag, Tokyo, 2001
Received on October 1, 2003)
Accepted on March 20, 2004
(