Stesura Seveso


101Archivio Italiano di Urologia e Andrologia 2016; 88, 2

ORIGINAL PAPER

Metabolic assessment of recurrent 
and first renal calcium oxalate stone formers

Basri Çakıroğlu 1, Erkan Eyyupoğlu 2, Aydin Ismet Hazar 3, Bekir Sami Uyanik 4, Barış Nuhoğlu 3

1 Department of Urology, Hisar Intercontinental Hospital, Umraniye, Istanbul, Turkey;
2 Department of Urology, Amasya Sabuncuoğlu Serefeddin Training and Research Hospital, Amasya, Turkey;
3 Department of Urology, Taksim Training and Research Hospital, Gaziosmanpasa, Turkey;
4 Department of Clinical Biochemistry, Hisar Intercontinental Hospital, Umraniye, Istanbul, Turkey.

Objectives: This study aimed to demon-
strate the dominant role of metabolic dis-

orders in the formation of calcium oxalate stones in patients
with recurrent urolithiasis, as well as in patients experiencing
their first episode of urolithiasis.
Patients and Methods: The records of the patients who
attended our kidney stone outpatient clinics between 2008
and 2012 were reviewed, and the data of 318 calcium oxalate
stone patients who had undergone a metabolic assessment
were retrospectively analysed. The patients were divided in
two groups. The first group included the patients who pre-
sented with their first episode of urolithiasis (Group 1,
n = 170), and the second group included patients with recur-
rent urolithiasis (Group 2, n = 148); intergroup comparisons
of metabolic disorders were performed. 
Results: A significant difference was found between the two
groups in mean urine calcium levels (Group 1, 0.25; Group 2,
0.31; p = 0.001); the mean serum calcium level was found to
be significantly  higher although at less extent in Group 2
(Group 1, 9.4; Group 2, 9.6); p = 0.04). Significant differ-
ences were also found in mean urine citrate (Group 1, 481.9;
Group 2, 397.2, p < 0.0001) and oxalate levels (Group 1,
22.1; Group 2, 28.5; p < 0.0001) . 
Conclusions: This study revealed a metabolic tendency to
hypercalciuria in calcium oxalate stone patients, predomi-
nantly in those with recurrent calcium oxalate urolithiasis.
Urinary oxalate excretion was found to be higher in recur-
rent urolithiasis in comparison to the first episode of calcium
oxalate urolithiasis and urinary citrate excretion lower in
recurrent urolithiasis. 

KEY WORDS: Kidney stone; Calcium oxalate; First episode;
Recurrent.

Submitted 18 June 2015; Accepted 4 December 2015

Summary

No conflict of interest declared.

occur within the first five years after the first episode of
urolithiasis (1). Calcium oxalate stones (CaOx) are the
most common type of urinary stones (60% pure calcium
oxalate stones and 20% mixed stones) (2, 3). We decid-
ed to analyse the metabolic states of our patients with
CaOx urolithiasis since our sample size was adequate to
have a significant evaluation. Urine volumes and urine
components both give an indication about the health of
the kidneys and constitute a collective indicator of com-
plex body functions, all interacting with each other.
Therefore, we tried to achieve an understanding about
the metabolism of the patients who presented with a first
episode of urolithiasis and with recurrent CaOx urolithi-
asis by interpreting their 24-hour urine analyses (2, 3-5).

MATERIALS AND METHODS

Study population
The admissions/follow-up records of 3,500 patients who
attended two different kidney stone outpatient clinics of
two different Departments of Urology between 2008 and
2012 were reviewed in order to achieve an adequate
sample size to investigate any differences between the
patients who presented with the first episode of urolithi-
asis and patients with recurrent urolithiasis, regarding
metabolic abnormalities underlying idiopathic CaOx
stones. A total of 2,653 cases at the first episode and 847
cases of recurrent urolithiasis were identified. Stone
analyses were performed using a Fourier Transform
Computed Infrared (FT-IR) Spectrometer. CaOx stones
(including monohydrate and dehydrate calcium oxalate,
pure or mixed wirh apatite) were detected in 176
patients who experienced their first episode of urolithia-
sis and in 210 patients with recurrent urolithiasis.
Anamnesis, past medical history, previous surgery, and
medication use that had been recorded in the patient
files were reviewed in terms of exclusion criteria.
Exclusion criteria included age younger than 18 years;
missing height and weight data; use of thiazide, tri-
amterene, or loop diuretics; use of potassium or potassi-
um citrate; use of other antihypertensive agents; dia-
betes, hyperlipidemia, coronary heart disease, stroke, or

DOI: 10.4081/aiua.2016.2.101

INTRODUCTION
Today, about 10% of the male population and 5% of the
female population suffer from kidney stone disease,
which is more prevalent between 30 to 40 years of age.
The recurrence rate in patients who recover from a firs
kidney stone episode, either spontaneously or through
intervention, was found to be about 4% to 5% per year;
based on this percentage, the cumulative rate of recur-
rence will be 75% within 20 years. Most recurrences



Archivio Italiano di Urologia e Andrologia 2016; 88, 2

B. Çakıroğlu, E. Eyyupoğlu, A. Ismet Hazar, B. Sami Uyanik, B. Nuhoğlu

102

the use of chronic disease medications such as anticoag-
ulants and vasodilators; having a solitary kidney; corti-
costeroid use; being on treatment for osteoporosis;
known parathyroid disease or known disorders of
aminoacid or carbonhydrate metabolism; use of gout
medications; a history of gastrointestinal surgery; thyroid
disorders and oncologic diseases; being on dialysis; uri-
nary tract obstructions and abnormalities (ureteropelvic
stenosis, horseshoe kidney, etc.). Finally, the data for a
total of 318 patients who met the inclusion criteria were
analysed: 170 first-episode patients were included in
Group 1 and 148 patients with recurrent disease were
included in Group 2.
For metabolic assessment blood and urine samples were
randomly collected during asymptomatic periods, in order
to obtain results that might reflect the common dietary
habits of the patients; the samples of the patients who
underwent surgery or Shock Wave Lithotripsy (SWL)
were obtained one and a half month after the procedure.
Standard methods were used to collect 24-h urine samples
in plastic containers that did not react with urine, and the
samples were stored at 2-8° C. Volume, pH, and density
of the urine, as well as the creatinine, uric acid, calcium,
sodium, potassium, phosphate, oxalate, citrate and mag-
nesium concentrations were determined. In addition,
these two groups were compared to each other in terms of
the blood urea, creatinine, uric acid, calcium, sodium,
potassium, phosphate, magnesium, parathormone, and
vitamin D3 levels, if available. Furthermore, the urine cit-
rate/creatinine (Cit/Crea), calcium/citrate (Ca/Cit), phos-
phorus/creatinine (P/Crea), calcium/creatinine, and
oxalate/creatinine ratios were assessed and the two groups
were compared to each other regarding these ratios.

Statistical analysis
Not every parameter could be studied for each individual
patient, due to the retrospective design of the study.
However, the data that reflected the mean value for each
group were compared to each other. Descriptive data were
tabulated and box plot graphs and bivariate linear regres-
sion models were used. SPSS 12.0 (SPSS Inc. Chicago, IL,

USA) statistical software package was used to analyse the
data, which were tested by an independent t-test to deter-
mine the significance of the differences between the mean
values of the groups; the Levene test was used to assess the
equality of the variances. A p < 0.05 value was considered
statistically significant. In addition, the data were pooled
and Pearson’s correlation test was used to test whether
there was a correlation between the urinary metabolites of
the patients with idiopathic CaOx urolithiasis and the
ratios of these metabolites to each other.

RESULTS
A significant difference was found between the two groups
in age (Group 1, 32.5 years; Group 2, 36.8 years;
p = 0.004).However, the female/male ratios were similar
in the two groups (Group 1, 1.92; Group 2, 2.16; p >
0.05). Mean body mass index was found to be higher in
Group 2 (24.2 years/26.1 years; p > 0.05). Urine volumes
were similar (Group 1, 1795; Group 2, 1777; p > 0.05). A
significant difference was found between the two groups
in urine calcium levels (Group 1, 0.26; Group 2 2, 0.32;
p = 0.001), while the serum calcium level was found to be
significantly higher in Group 2 (Group 2, 9.4; Group 2,
9.6; p = 0.04), although this difference was less significant
than the difference in the urine. Significant differences
were also found in urine citrate (Group 1, 481.8; Group 2,
397.1; p < 0.0001) and oxalate (Group 1, 22.1; Group 2,
28.5; p < 0.0001) levels. No statistically significant differ-
ences were found between the two groups in serum
parathormone (Group 1, 43.3; Group 2, 48.2; p > 0.5)
and vitamin D3 (Group 1, 23.5; Group 2, 23.9; p > 0.5)
levels. No significant difference was found between the
two groups in the urine pH (Group 1, 6.9; Group 2, 5.7;
p > 0.5), urine sodium (Group 1, 165.7; Group 2, 166.1;
p > 0.5), and urine magnesium (Group 1, 0.8; Group 2,
0.4; p > 0.5) levels. However, there was a significant dif-
ference between the two groups in urine potassium levels
(Group 1, 41.5; Group 2, 46.9; p < 0.05). The 24-hour
urinary excretion of calcium was higher than normal in
patients with recurrent urolithiasis (310 mg), and 24-hour

Figure 1. 
Box plots of 24 hr
urinary oxalate
excretion in first-
time and recurrent
urolithiasis. 



urine volume was lower than 2 litres in both groups. No
cases of hyperoxaluria and hypocitraturia were detected.
In addition, a statistically significant difference was found
between the two groups in the urinary Cit/Crea ratio
(p < 0.05), and the difference between the two groups in
Ca/Cit ratio was strongly significant (p < 0.001). 
The differences between the two groups in urinary
P/Crea (p < 0.05), Ca/Crea (p < 0.05), and Ox/Crea
ratios (p < 0.05) were also statistically significant
(Table 1) (Figures 1-4).

103Archivio Italiano di Urologia e Andrologia 2016; 88, 2

Metabolic assessment of recurrent and first renal calcium oxalate stone formers

Figure 2. 
Box plots of 24 hr
urinary calcium 
excretion and
calcium/citrate
ratio in first-time
and recurrent
urolithiasis.

Figure 3. 
Box plots of 24 hr
urinary potassium
and creatinine
excretion in 
first-time and
recurrent
urolithiasis.

Figure 4. 
Correlations between 24 hr urinary
oxalate and calcium excretion in the
cases with urolithiasis.



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104

DISCUSSION
We could not find a comprehensive review on the meta-
bolic assessment of the patients presenting with the first
episode of idiopathic CaCOx urolithiasis in spite of the
presence of a number of studies of 24-hour urine and
spot urine regarding nephrolithiasis (6-13). Therefore,
our study probably address a relevant question.
Although the retrospective design of the study may be
considered a limitation, meticulous attention given to the
inclusion-exclusion processes and lack of interventions
that may occur in an ongoing study prove the reliability
of this study. 
Demographics data of our patients show an age differ-
ence between the recurrent group and first-episode
group that may be considered as related to the charac-
teristics of the groups; sex distribution was comparable
between the groups although BMI was higher in group 2.
In relation to metabolic assessment, we focused on mean
24 hour urine volumes that were less than 2 litters in
both groups and mean urinary calcium of recurrent
stone formers that was higher than 300 mg (hypercalci-
uria).
Fluid intake is closely related to supersaturation and
acidic pH (14) and the importance of fluid intake in the
prevention of recurrences has been demonstrated in ran-
domized prospective studies (15).
In a previous comprehensive study of patients with
recurrent urolithiasis, the metabolic abnormalities asso-

ciated with recurrent urolithiasis were found
to be (listed in a decreasing order) hypercalci-
uria, low urinary volume, hypocitraturia,
hyperoxaluria, and hyperuricosuria, and their
incidences were found to be 65%, 62%, 41%,
38%, and 24%, respectively (15). Urine vol-
ume was not mentioned in another study of
the metabolic abnormalities in patients experi-
encing their first episode of urolithiasis and in
patients with recurrent urolithiasis. In this
study the observed metabolic abnormalities
were hypocitraturia, hypercalciuria, hyperox-
aluria, and hyperuricosuria (listed in a
decreasing order) with reported incidences of
45%, 39%-43%, 32%-33%, and 29%-23%,
respectively (16). 
In the first-episode group and in the recurrent
group, the mean daily amounts of citrate and
oxalate excreted in urine were found to be 481
± 188 mg versus 397 ± 146 mg and 22 ± 9 mg
versus 28 ± 12 mg. The mean values of these
parameters did not suggest the presence of
hyperoxaluria and hypocitraturia since the
mean daily amount of oxalate excreted in the
urine was less than 40 mg and the mean daily
amount of citrate excreted in the urine was
more than 300 mg. 
Hyperoxaluria may occur via three ways:
increased oxalate production (primary hyper-
oxaluria), increased hepatic turnover and
increased oxalate absorption. A mild metabol-
ic hyperoxaluria may be observed in 37% of
the patients with idiopathic CaOx urolithiasis.
Hyperoxaluria has been explained by pyridox-

ine deficiency. When dietary oxalate restriction failed to
treat hyperoxaluria, oral supplementary calcium may be
given to reduce intestinal oxalate absorption and pyri-
doxine may also be used empirically for this purpose.
Mean serum calcium level was found as 9.44 ± 0.89
mg/dl in group 1 (n = 167) and 9.63 ± 0.71 mg/dl (ref-
erence range: 8.5-10.5 mg/dl) in group 2. These values
were within normal limits and the p value of the differ-
ence between two groups was found to be less than 0.05. 
Changes in urine acidity are as important as urine vol-
ume in the formation and recurrence of urinary stones
(17, 18) but no statistically significant difference was
found between the two groups in urine pH (urine pH 6.9
and 5.7, respectively) (p > 0.05).
The levels of urinary magnesium, which lower the uri-
nary free oxalate amount by forming complexes with
oxalate, were found to be 165 ± 52 mEq/day in group 1
(42) and 166 ± 46mEq/day in group 2 (30) and no sig-
nificant difference was found between the mean values
detected in the first-episode and in the recurrent group
(p > 0.05). Daily urinary magnesium reference range was
50-150 mg/day in our study. However, the difference in
magnesium variances indicated that low magnesium was
more important in the recurrent group. 
Hyperuricosuria is another important issue. Urinary lev-
els of uric acid higher than 750 mg in non-acid-pre-
served 24-hour urine are considered as a risk factor. In
our study hyperuricosuria was found in 7% of the sam-

First-time Recurrent P
Mean ± SD Mean ± SD Value

Age (years) 32,5 ± 12,9 36,8 ± 13.6 **0.004

Volume, urine (mL/d) 1795 ± 567 1777 ± 570 0.802

pH, urine 6.0 ± 0.7 5.8 ± 0.8 0.359

Calcium, serum (mg/dL) 9.4 ± 0.9 9.6 ± 0.7 *0.040

Uric acide, serum(mg/dL) 5.5 ± 1.3 5.8 ± 1.4 0.143

Creatinine, serum (mg/dL) 0.75 ± 0.21 0.78 ± 0.23 0.228

Parathormone, serum(pg/mL) 43.3 ± 18.5 48.2 ± 33.6 0.135

Vitamin D3(25-OH), serum(ng/mL) 23.5 ± 10.9 23.9 ± 14.0 0.780

Creatinine, urine (g/d) 0.75 ± 0.21 0.78 ± 0.23 0.720

Calcium, urine (g/d) 0.26 ± 0.13 0.32 ± 0.15 **0.001

Phosphorus, urine (g/dL) 1.05 ± 0.57 0.89 ± 0.40 *0.012

Potassium, urine (mEq/d) 41.5 ± 8.9 46.9 ± 10.9 *0.037

Sodium, urine (mEq/d) 165.7 ± 52.6 166.2 ± 46.2 0.973

Magnesium, urine(g/d) 0.70 ± 0.46 0.51 ± 0.37 0.204

Cystin, urine (mg/d) 481.8 ± 188.7 397.1 ± 146.3 0.807

Citrate, urine (mg/d) 481.8 ± 188.7 397.1 ± 146.3 ***0.000

Oxalate, urine (mg/d) 22.1 ± 9.9 28.5 ± 12.4 ***0.000

Calcium/Creatinine(g/g Crea) 0.16 ± 0.9 0.28 ± 0.23 *0.049

Calcium/Citrate (g/g Citrate) 0.65 ± 0.46 1.02 ± 0.74 ***0.000

Phosphorus /Creatinine (g/g Crea) 0.82 ± 0.31 0.64 ± 0.19 *0.010

Citrate/Creatinine (mg/g Crea) 501.6 ± 181.4 337.7 ± 191.4 **0.006

Oxalate/Creatinine (mg/g Crea) 19.7 ± 5.8 23.8 ± 5.9 *0.023

Table 1. 
Laboratory data in first-time and recurrent urolithiasis.

Student’s T Test: Significance (p): * < 0.05,  ** < 0.01, ***< 0.001  Ns: Not significant



ples that we tested for uric acid, and this result was not
consistent with the data in the medical literature.
Therefore, the mean urinary uric acid levels, which were
found as 480 mg mg in Group 1 and 550 in Group 2,
were not included in the discussion. Mean levels of
uricemia in our patients were also in the normal range
(group 1, 5.51 ± 1.37, n = 122 and group 2, 5.78 ± 1.43,
n = 114), and similar (p = 0.14) in the two groups.
However, we still want to put emphasis on the studies
suggesting that hyperuricosuria might be a major risk
factor for recurrent stone formation when associated
with a low urinary pH (9, 18). Recent studies have also
demonstrated that the metabolic syndrome characterized
by obesity, hyperlipidemia, hypertension and diabetes
might be associated with a higher incidence and
increased severity of kidney stone disease (19).

CONCLUSION
Mean values, standard deviations, and variances were
used to compare the metabolic values of the patients
experiencing their first episode of calcium oxalate
urolithiasis and patients with recurrent urolithiasis, and
to analyse these data on the basis of the reference ranges
accepted in the literature. From this perspective, while
the serum values were quite similar, the major difference
in the urinary metabolites was in calciuria that was high-
er in patients with recurrent urolithiasis. Although there
was a difference between the groups in the amount of
oxalate excreted in urine, the mean values in both
groups were found to be lower than 40 mg per day.
These data are relevant for preventive treatment and
indicate that pharmacotherapy is not required in patients
who present with the first episode of urolithiasis. In con-
sideration of the increasing incidence of stone disease
and the importance of prophylactic treatment, we
believe that the reference values and the values that indi-
cate a metabolic risk should be partially revaluated.

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This article of ethical approval Istanbul Gaziosmanpaşa Taksim
Training and Research Hospital local ethical committe no;
30.03.2015.E.P.K.K No.18

105Archivio Italiano di Urologia e Andrologia 2016; 88, 2

Metabolic assessment of recurrent and first renal calcium oxalate stone formers

Correspondence
Basri Çakıroğlu, MD (Corresponding Author)
drbasri@gmail.com
Department of Urology, Hisar Intercontinental Hospital
Saray Mah.Siteyolu Cad. No.7 34768 Umraniye, Istanbul, Turkey

Erkan Eyyupoğlu, MD 
Department of Urology, AmasyaSabuncuoğluSerefeddin Training 
and Research Hospital, Amasya, Turkey

Aydin Ismet Hazar, MD

Barış Nuhoğlu, MD  
Department of Urology, Taksim Training and Research Hospital,
Gaziosmanpasa, Turkey

Bekir Sami Uyanik, MD 
Department of Clinical Biochemistry, Hisar Intercontinental Hospital
Umraniye, Istanbul, Turkey