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CLINICAL STUDY
Abstract
Objective: To study the prevalence of renal stones and nephrocalcinosis in patients with primary
hyperparathyroidism (PHPT) and to appraise biochemical variables as risk factors for developing renal
calcifications.
Design: Cross-sectional.
Materials and methods: All patients (nZ177) undergoing diagnostic evaluation and surgery for PHPT at
Aarhus University Hospital between 2007 and 2009. All patients underwent routine spiral CT scans of
the abdomen to determine the presence or absence of renal calcifications.
Results: A total of 45 patients (25.4%, 95% confidence intervals: 19.031.4%) had renal stones
(15.3%) and/or renal calcifications (10.2%) on the CT scans. Compared with those without
calcification (nZ132), the group with calcification had a significantly lower plasma creatinine level
(67.0G25.1 vs 74.6G17.5 mmol/l, 2PZ0.03). Moreover, CaE was higher in PHPT patients with
renal calcification than in PHPT patients without (0.91G0.28 vs 0.74G0.40 mmol/mmol,
2PZ0.02). The other measured or derived biochemical variables were similar in the two groups.
No biochemical variable was predictive for renal calcifications in a multiple regression analysis.
Conclusion: We found a high prevalence of renal calcifications among PHPT patients but no
deterioration of renal function. The occurrence of calcifications was related to low plasma creatinine
and a high urine calcium/creatinine ratio. However, biochemical markers in general were poor
predictors for the risk of renal stones or nephrocalcinosis indicating that routine image diagnostics
may be needed for the identification of these complications in order to establish indication for surgery
and ensure proper treatment.
The aetiology of renal stones is multifactorial; consent for the examinations. Owing to lack of consent,
however, hypercalciuria is considered to be one of the some patients do not undergo CT scans. As the study
primary risk factors (16). In accordance, PHPT is a was a retrospective study, no approval from the Ethical
known risk factor for renal stone formation, which Committee was needed under Danish law. The total
is observed with an estimated prevalence of 740% cohort included originally 311 PHPT patients who
(17, 18). Furthermore, among patients presenting with had undergone parathyroid surgery (code KBBA 00-
renal stones, the prevalence of concurrent PHPT is 99). All patients were included in this cohort irrespec-
around 2% (19). However, the precise relationship tive of symptoms or severity of disease. However, from
between the clinical presentation of PHPT and the this cohort, we excluded 43 patients with wrong
increased formation of renal stones is not completely operation codes and parathyroid implantations
understood as only some (20), but not all (19, 21) (KBBA70), 68 because of lack of spiral CT scans due
studies have shown an increased renal calcium to various reasons (previous ultrasound investigation or
excretion in PHPT patients with renal stones. Young CT scan at referring hospital, refusal, no appearance or
age at the time of diagnosis (17, 20, 21, 22, 23, 24) and administrative errors) and 23 for other reasons:
male gender (17, 20, 23, 25) have often been associated hypercalcaemia caused by chronic renal disease
with renal stones, whereas divergent results have been (tertiary hyperparathyroidism) (29), biochemical vari-
reported for other variables including parathyroid ables could not be retrieved (29), and errors in entry of
pathology (17, 21, 22, 23, 26, 27), plasma calcium central personal registration number (13)). Patients
(17, 20, 21, 22, 23, 27), plasma PTH (17, 20, 22, 27), with familial hypocalciuric hypercalcaemia (FHH) were
plasma calcitriol (13, 17, 27), diuresis (17, 26) eliminated based on a low calcium/creatinine clearance
and other biochemical variables such as urinary citrate ratio and evidence of inactivating mutations of the
(17, 26). To prevent stone formation in the urinary CASR gene (30). After exclusion (Fig. 1), the study
tract, there are inhibitors and among these citrate is consisted of 177 hypercalcaemic patients with a mean
the most important. In PHPT, calcium binds to citrate of two to four calcium measurements and plasma intact
and lowers the urinary tracts defence against stone PTH in the upper one-third of the normal range or
formation (28). elevated (P-PTH O5 pmol/l) (31). The patients were
then divided into two groups, with or without renal
calcification on spiral CT scan, and the blood and urine
Aim of the study samples were compared. No patients had both renal
stones and nephrocalcinosis.
We aimed at investigating the present prevalence of
renal calcification among patients operated for PHPT
who had a routine spiral CT investigation performed Methods
and to explore the possible differences in demographic As a part of routine diagnostic work-up, almost all our
and biochemical variables between patients with renal patients had a spiral CT scan (Philips Mx8000) of the
calcification and patients without. In this study, renal abdomen, performed to confirm or disprove the presence
calcification is defined as both renal stones (stones in the of renal calcification. CT findings were subdivided into
urinary tract) and nephrocalcinosis (presence of frank renal stones located in calyces, pelvis and ureters
calcification in the renal tissue).
Original cohort: 311
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 PHPT and renal calcifications 1095
and nephrocalcinosis with calcifications of the renal laboratory (Department of Clinical Biochemistry,
tissue but no calcifications in the urinary tract system. Aarhus University Hospital) with daily quality control
As a routine, we measured plasma and 24-h urine procedures. From plasma and urine variables, we
calcium and creatinine, and plasma Ca2C, albumin, calculated the renal creatinine clearance (ml/min),
creatinine, phosphate and alkaline phosphatase by the renal calcium/creatinine excretion ratio (CaE
standard laboratory methods. We determined plasma mmol/mmol) and the renal TRCa%.
intact PTH using the second-generation Elecsys 2010 For each variable mean value, S.D. and 95% confidence
immunoassay (Roche Diagnostics). The interassay intervals (CIs) were calculated, and they were compared
coefficients of variation (CV) were !6%. We measured by t-tests or F-test as appropriate. A mutually adjusted
plasma 25OHD levels by isotope dilution liquid multivariate logistic regression analysis was performed
chromatographytandem mass spectrometry using to identify potential predictors of presence of renal
calibrators traceable to NIST OSRM 972. The calcifications. Significance level was P%0.05. All
interassay precision was 9.4 and 8.8% at 32.0 and calculations were performed using Microsoft Excel and
59.7 nmol/l respectively, for 25OHD3 and 8.6 and IBM SPSS 19.0 (SPSS Inc., Chicago, IL, USA).
8.0% at 23.4 and 64.4 nmol/l respectively, for
25OHD2. The detection limit was 10 nmol/l for both
metabolites (32). We measured plasma 1,25(OH)2D
by RIA (IDS) with interassay CV from 11 to 18%
Results
at plasma levels from 18 to 111 pmol/l. The renal Among the 177 patients, postoperative pathological
excretion of cross-linked N terminal telopeptide of examinations revealed parathyroid adenomas in 91%
type 1 collagen (NTx/creatinine ratio) was quantified of the patients and hyperplasia in 9% of the patients.
by ELISA on the second void morning urine using In total, 45 had spiral CT-confirmed renal stones
an automated instrument (Vitros ECI; Ortho (nZ27) or nephrocalcinosis (nZ18) while 132 did
Clinical Diagnostics, Amersham, UK). The NTx not, yielding a total prevalence of renal calcifications of
CV was between 4.7 and 8.5% at urine levels at 25.4%, 95% CIs 19.031.9% (Table 1).
73541 nmol BCE/mmol creatinine. All biochemical The average p-creatinine values were within the
analyses were performed in an ISO standardised normal range in both the groups, but patients
Table 1 Demographic and biochemical characteristics of 177 patients referred for primary hyperparathyroidism during the period 2007
2009 who had a routine spiral CT investigation performed to diagnose renal calcification including renal stones and nephrocalcinosis.
Demography
Gender (males/females) 26/106 8/37 0.97
Age (years) 177 62.0 12.3 132 62.1 12.5 45 59.9 11.1 0.31
Height (cm) 119 166.2 8.9 84 165.9 8.8 35 167.1 9.2 0.50
Body weight (kg) 119 78.3 16.2 84 75.9 16.3 35 73.7 16.2 0.49
BMI (kg/m2) 119 27.2 5.2 84 27.5 5.1 35 26.4 5.2 0.28
Plasma
P-ionised calcium (mmol/l) 1.151.30 177 1.47 0.13 132 1.46 0.12 45 1.49 0.17 0.27
P-phosphate (mmol/l) 0.801.50 160 0.84 0.19 118 0.86 0.19 42 0.80 0.19 0.08
P-creatinine (mmol/l) 50100 177 73.2 23.1 132 74.6 25.1 45 67.0 17.5 0.03
P-PTH (pmol/l) 1.66.9 177 14.2 8.73 132 13.6 6.99 45 16.2 12.4 0.19
P-calcitriol (pmol/l) 60180 163 177 71.5 124 171.6 69.3 39 195.4 76.3 0.07
P-25OHD (nmol/l) 50160 174 69.5 30.7 130 70.2 32.0 44 67.6 26.8 0.63
P-alkaline phosphatase (U/l) 35105 112 88.0 28.8 79 86.1 27.1 33 89.9 28.2 0.50
Urine
U-NTx/creatinine 19 66.8 42.3 13 65.5 38.1 6 47.5 36.4 0.35
((nmol/l)/(mmol/l))
24-h urine calcium (mmol) 2.09.0 136 7.7 3.58 103 7.44 3.7 33 8.49 3.1 0.14
24-h urine creatinine (mmol) 6.022.0 111 9.9 3.81 82 9.83 3.33 29 10.3 4.99 0.60
Derived variables
Creatinine clearance (ml/min) 70150 111 101 41.0 82 96.7 33.6 29 113.0 56.1 0.07
Ratio CaE (mmol/mmol) 0.050.80 109 0.78 0.38 82 0.74 0.40 27 0.91 0.28 0.02
TRCa% 97.598.7 108 95.3 13.2 82 94.8 15.1 26 97.0 1.02 0.19
25OHD, all year 25-hydroxyvitamin D; 1,25(OH)2D, 1,25dihydroxyvitamin D; PTH, parathyroid hormone; AP, total alkaline phosphatase; NTx/creatinine, urine
amino-terminal telopeptide of collagen cross link to creatinine ratio; Cr clearance, creatinine clearance, CaE, 24-h urine calcium to creatinine ratio; TRCa%,
rental tubular reabsorption of calcium in percentage of filtered calcium.
a
Comparing patients with and without calcification.
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1096 J Starup-Linde, E Waldhauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166
with renal calcification had lower p-creatinine adjusted model, none of the variables were predictive
(67.0G17.5 mmol/l) than patients without renal calci- of renal calcifications.
fications (74.6G25.1 mmol/l, P!0.03). They also A direct comparison of patients with renal stones and
tended to have a borderline better renal function as patients with nephrocalcinosis without renal stones
measured by creatinine clearance, although the disclosed no significant differences between the two
difference was not significant (96.7G33.6 vs 113.0 groups concerning gender, height, body mass index
G56.1 ml/min, P!0.07). The two groups had the (BMI) or biochemical variables (Table 3). However, the
same degree of elevated plasma PTH, hypercalcaemia mean age was lower in patients with renal stones than
and hypercalciuria expressed as excreted calcium/24 h. in patients with nephrocalcinosis (57.7G12.2 vs
In total, 24% of those with plasma Ca2C %1.45 mmol/l 64.8G7.4 years, PZ0.03). Furthermore, in a mutually
had either renal stones or nephrocalcinosis compared adjusted logistic regression analysis, none of the
with 26% of those with plasma Ca2C O1.45 mmol/l included biochemical variables could predict the nature
(PZ0.70). of the observed calcifications (Table 4). Inclusion of age,
The renal calcium/creatinine excretion ratio gender and BMI did not change these results.
(CaE mmol/mmol) was higher in PHPT patients with
renal calcifications than in PHPT patients without
(0.91G0.28 vs 0.74G0.40 mmol/mmol, PZ0.02). Discussion
However, the power to predict calcifications was low
with a partial squared correlation coefficient of only We found the prevalence of renal calcification among
0.08. In an overlap performance analysis, it did not operated PHPT patients on CT imaging to be 25.4%
seem that a cut-off level for CaE existed below which (95% CI 19.031.9%). This is in contrast to the findings
renal stones did not form. of Odvina et al. (17) who reported a frequency of 60%
The renal TRCa% did not differ between groups, found by a history of passing stone, removal of stone or
neither did plasma phosphate (0.86G0.19 vs 0.80 roentgenogram. They retrieved data from 131 patients
G0.19 mmol/l, P!0.08). aged R18 years and diagnosed with PHPT by
The two groups had equal plasma 25OHD levels with hypercalcaemia, high PTH levels and no secondary
mean values and CIs within the normal range. In cause of hyperparathyroidism. They excluded patients
with moderatesevere diarrhoea syndrome and
contrast, plasma 1,25(OH)2D levels were increased
impaired renal function. Our findings are also in
compared with the reference range in 41.1%, 95% CI
contrast to the prevalence of 7% found by routine
33.549.1%, of the patients. Stone formers had
renal sonography by Suh et al. (18). They retro-
insignificantly (P!0.07) higher plasma 1,25(OH)2D spectively investigated 271 with surgically proven
levels, 195 (95% CI 171219) pmol/l, than non-stone parathyroid adenomas. Berger et al. (26) found a
formers, 172 (159184) pmol/l, but the difference was prevalence of 20% based on the history of patient
not significant (P!0.07). reporting of stone passage and previous stone-related
Table 2 shows a mutually adjusted multivariate procedures. They examined 54 symptomatic patients
logistic regression analysis of biochemical variables vs with PHPT at a referral centre for parathyroid surgery
presence or absence of renal calcifications. In the who completed 24-h preoperative urine collection. In
addition, Bandeira et al. (29) found a prevalence of renal
stones among PHPT-diagnosed patients to be 45%
based on 22 patients and giving no information on how
Table 2 Mutually adjusted logistic regression analysis of bio- they diagnosed renal stone. We would have expected a
chemical variables vs presence or absence of renal calcifications in
177 patients with primary hyperparathyroidism. lower prevalence than that in previous studies because
of the earlier diagnosis and treatment of PHPT in recent
Partial regression times. Taking into account that the study of Odvina et al.
coefficient (17) also includes the history of previous stones, our
Variable (meanGS.E.M.) P study suggests that the prevalence of stones has not
Gender K0.14G0.93 0.88 decreased. It also points to the importance of including
Age K0.01G0.02 0.93 previous stones in the evaluation of risk of stones in
Plasma Ca2C K2.63G3.38 0.44 PHPT. Our prevalence of renal calcification was higher
Plasma phosphate K0.13G1.78 0.94 than the prevalence reported based on sonography (18).
Plasma creatinine 0.02G0.02 0.31
Plasma PTH K0.03G0.05 0.56 This may suggest that a CT scan in a cross-sectional
Plasma calcitriol K0.004G0.005 0.35 setting is more sensitive than sonography in the
Plasma 25OHD K0.01G0.01 0.27 diagnosis of nephrocalcinosis and should be used for
Plasma alkaline phosphatase K0.01G0.01 0.85 the routine examination of the patients. It is difficult to
Urine calcium K0.2G0.1 0.17
Urine creatinine 0.02G0.01 0.22
conclude on the prevalence of renal stones in PHPT as
the reports vary from 7% (18) to 60% (17). The wide
25OHD, 25-hydroxyvitamin D; PTH, parathyroid hormone. range in reported prevalence of stones is difficult to
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 PHPT and renal calcifications 1097
Table 3 Demographic and biochemical characteristics of 45 patients referred for primary hyperparathyroidism during the period 2007
2009 who either had positive renal stones or nephrocalcinosis documented by a routine spiral CT investigation.
Demography
Gender (males/females) 26/106 6/21 2/16 0.53
Age (years) 132 62.1 12.5 27 57.7 12.2 18 64.8 7.4 0.28
Height (cm) 84 165.9 8.8 22 167.4 7.8 14 167.0 11.2 0.66
Body weight (kg) 84 75.9 16.3 22 71.2 14.3 14 77.1 18.2 0.82
BMI (kg/m2) 84 27.5 5.1 22 25.5 4.8 14 27.6 5.7 0.99
Plasma
P-ionised calcium (mmol/l) 1.151.30 132 1.46 0.12 27 1.48 0.16 18 1.51 0.18 0.28
P-phosphate (mmol/l) 0.801.50 118 0.86 0.19 26 0.81 0.18 16 0.78 0.21 0.12
P-creatinine (mmol/l) 50100 132 74.6 25.1 27 64.8 16.5 18 70.3 18.9 0.40
P-PTH (pmol/l) 1.66.9 132 13.6 6.99 27 16.5 13.1 18 15.7 11.7 0.47
P-calcitriol (pmol/l) 60180 124 171.6 69.3 23 193.4 86.0 16 198.2 62.5 0.15
P-25OHD (nmol/l) 50160 130 70.2 32.0 26 71.5 26.7 18 61.9 26.8 0.30
P-alkaline phosphatase (U/l) 35105 79 86.1 27.1 23 95.0 27.9 14 83.4 25.1 0.67
Urine
U-NTx/creatinine 13 65.5 38.1 2 67.0 62.2 5 55.6 44.7 0.52
(nMemolBCE/mmol)
24-h urine calcium (mmol) 2.09.0 103 7.44 3.7 20 8.38 2.55 13 8.67 3.91 0.27
24-h urine creatinine (mmol) 6.022.0 82 9.83 3.33 18 10.8 6.02 11 9.36 2.57 0.66
Derived variables
Creatinine clearance (ml/min) 70150 82 96.7 33.6 18 116.9 60.9 11 106.6 49.5 0.54
Ratio CaE (mmol/mmol) 0.050.80 82 0.74 0.40 18 0.85 0.27 9 1.01 0.27 0.052
TRCa% 97.598.7 82 94.8 15.1 17 97.1 1.00 9 96.8 1.07 0.25
*Significantly different from patients without calcification, 2P!0.01. 25OHD, all year 25-hydroxyvitamin D; 1,25(OH)2D, 1,25dihydroxyvitamin D; PTH,
parathyroid hormone; AP, total alkaline phosphatase; NTx/creatinine, urine amino-terminal telopeptide of collagen cross link to creatinine ratio; Cr clearance,
creatinine clearance; CaE, 24-h urine calcium to creatinine ratio; TRCa%, rental tubular reabsorption of calcium in percentage of filtered calcium.
a
Comparing patients with renal stones and patients with nephrocalcinosis.
explain but may be based on the differences between independent of plasma calcium and thereby increase
studies in study populations, assessment of previous the tendency towards hypercalciuria. The renal TRCa%
clinical stones and methodology used to identify could theoretically influence this tendency, but we
calcifications and persistent stones. It is noteworthy found no difference between the groups in TRCa.
that in our study, none of the biochemical parameters However, the lack of significant differences in these
were predictive of presence of renal calcifications in variables between the two groups preclude any final
an unadjusted model except for plasma creatinine and conclusion regarding the relationship between low
the renal calcium/creatinine clearance rate (CaE). plasma creatinine and renal calcifications. This may
No association between serum calcium levels and
prevalence of renal stones or nephrocalcinosis was
present. It thus did not change the estimates to present
Table 4 Biochemical parameters of significance to presence of
the data separately according to the severity of the renal stones vs nephrocalcinosis. Mutually adjusted in a logistic
disease. This is a key finding, as it shows that even regression analysis.
among patients with seemingly mild disease, the
prevalence of renal calcifications may be high. Regression coefficient
Variable (meanGS.E.M.) P
We found a significantly lower p-creatinine among
PHPT patients with renal calcifications, especially in Alkaline phosphatase 0.01G0.03 0.64
those with renal stones compared with non-stone Creatinine K0.01G0.06 1.00
formers. This finding suggests that the renal stones Urine calcium 0.85G0.53 0.11
Urine creatinine 0.05G0.04 0.22
have not damaged the renal function. The lower plasma Ionised calcium 1.11G9.37 0.91
creatinine levels among patients with renal calcifica- 25OHD K0.01G0.02 0.88
tions could be explained by a better renal function or a Calcitriol 0.02G0.02 0.31
Phosphate 3.26G6.06 0.59
reduced muscle mass. From a physiological point of PTH K0.26G0.35 0.45
view, a higher creatinine clearance in stone formers
would increase the renal filtered calcium load 25OHD, plasma 25-hydroxyvitamin D; PTH, plasma parathyroid hormone.
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1098 J Starup-Linde, E Waldhauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166 PHPT and renal calcifications 1099
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1100 J Starup-Linde, E Waldhauer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 166
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35 Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen PM, 38 Christensen SE, Nissen PH & Schwarz P. Investigation and
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36 Moosgaard B, Vestergaard P, Heickendorff L & Mosekilde L. Plasma
1,25-dihydroxyvitamin D levels in primary hyperparathyroidism Received 13 January 2012
depend on sex, body mass index, plasma phosphate and renal Revised version received 22 March 2012
function. Clinical Endocrinology 2007 66 3542.
Accepted 3 April 2012
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