The tubular maximum for calcium ... with chronic active thoracic sarcoidosis

Eur Respir J
1990, 3, 447-449
The tubular maximum for calcium reabsorption in patients
with chronic active thoracic sarcoidosis
P.D. Broulik*, V. Votava**, V. Pacovsky*
The tubular maximum for c.alcium reabsorption in patients with chronic active
thoracic sarcoidosis. P.D. Broulik, V. Votava, V. Pacovsky.
ABSTRACT: The tubular maximum for calcium reabsorption (TmCa) was
evaluated in 52 patients with chronic active thoracic sarcoidosis. Hypercalcaemia was found In five patients (9.6%). The mean serum calcium value
of 2.54±0.18 mmoH"1 in patients with sarcoidosis was significantly higher
than that obtained In the control group (2.42±0.11 mmol·l"1). The mean
TmCa In patients with sarcoidosis (2.11±0.26 mmol·t1 glomerular filtrate
(GF)) was not statistically different from the mean TmCa for the group of
healthy subjects (2.18±0.23 mmoH"1 GF). Urinary sodium corrected TmCa
In both groups or patients was affected In a similar way. Our study
demonstrates for the first time that there Is no Increase In TmCa in
patients with chronic active thoracic sarcoidosis. Hypercalcaemia is not a
result of an Increased TmCa.
Eur Respir J., 1990, 3, 447-449.
Hypercalcaemia, with or without hypercalciuria, is a
well-known complication of sarcoidosis. The reported
incidence of hypercalcaemia associated with sarcoidosis
varies from 2-63% [1]. Hypercalcaemia tends to be transient in subacute sarcoidosis, but in chronic sarcoidosis,
depending on the activity of the disease, the serum level
of calcium may fluctuate [2). Hypercalciuria is considerably more common [3]. Absorptive hypercalciuria is
related to the development of sarcoidosis and can be
explained by high free 1 ,25-dihydroxy vitamin D 3
(1, 25(0H)p3). Resorptive hypercalciuria seems to be
linked with disease extension [4, 5].
The plasma calcium concentration is determined by
the relationship between three factors: 1) the rate of flow
of calcium into the extracellular space from gut or bone;
2) the rate of filtration of calcium through the glomeruli;
and 3) the rate of tubular reabsorption of calcium. In
spite of the growing knowledge about sarcoidosis the
mechanism of hypercalcaemia has rarely been
investigated.
We have used a method which has been developed for
measuring the tubular maximum for calcium in man [6].
The tubular maximum relative to the glomerular filtration rate (GFR) can be calculated in any subject [7] based
on the known relationship between the plasma and urine
calcium before and during calcium infusions in normal
subjects.
The purpose of the present study was to examine the
tubular maximum for calcium in an unselected group of
patients with chronic active thoracic sarcoidosis.
* Third Dept of Internal Medicine and ** First Dept
of Tuberculosis and Respiratocy Diseases, Charles
University, Faculty of Medicine, Prague,
Czechoslovakia.
Correspondence: P.D. Broulik, 3rd Internal Clinic,
Prague 2, Czechoslovakia.
Keywords: Calcium metabolism; sarcoidosis; tubular
maximum for calcium reabsorption.
Received: April 1989; accepted after revision
November 2, 1989.
Patients and methods
The subjects were 52 patients with chronic thoracic
sarcoidosis (25 men and 27 women, aged 20-71 yrs)
who had been followed-up for varying periods (mean 4.2
yrs). The diagnosis of sarcoidosis was based on clinical,
radiographic and laboratory features consistent with the
disease and was supported by a tissue biopsy showing
noncaseating epitheliod-cell granulomas. Diagnosis of
thoracic active sarcoidosis was related to presence of
prolonged respiratory symptoms and to duration of findings on chest X-ray pulmonary examination (more than
two years) with a slow progression. The biological marker
of activity that was considered was the lymphocyte
percentage, i.e. the percentage of lymphocytes in
bronchoalveolar lavage fluid. No subjects in either the
observation or the control group used any medical treatment to affect calcium and phosphorous metabolism. No
patient was taking corticosteroids at the time of the
investigations.
To minimize dietary influences the patients were fasted
overnight and urine samples (collected over 2 h) and
blood samples were obtained. Each sample was analysed
for calcium, phosphate, sodium and creatinine content.
The calcium/creatinine ratio was calculated according to
NoRDIN [8]. Fasting calcium excretion (C~) was calculated from the formula: C~ = Uc. X (Per·Uc,). The tubular
maximum for calcium reabsorption was calculated
according to NEED et al. [6], from the formula: TmCa =
((0.56 P c.)-C~)-(1-0.08 logc(0.56 P c;C~)) mmol·Z· 1
P.D. BROULIK, V. VOTAVA, V. PACOVSKY
448
glomerular filtrate (GF). The term (0.56 Pc.) is an approximation to the plasma ultrafiltrable concentration. The
tubular maximum for calcium reabsorption was also
calculated after correction for urinary sodium [6]. The
renal phosphate threshold concentration (TmPO/GFR)
was calculated using the nomogram of W ALTON and
BINOET [9]. Inorganic phosphate in the serum and urine
was determined photometrically [10]. Serum and urine
creatinine were measured by the method of HARE [11].
Serum and urine calcium were determined by a
complexometric method [12]. A control group matched
for age and sex was selected from the original health
screening register. Group data are expressed as mean±sn
and a comparison made using Students t-test for unpaired
data [13].
Table 1. - Mean values±so of measured variables in
fasting blood and urine collected from 52 patients with
sarcoidosis and 40 healthy subjects
Sarcoidosis
n=52
Age yrs
45.6±13
Serum calcium mmoH 1
2.54±0.18•
Serum creatinine mmoH 1
0.08±0.013
Urine Ca/Cr mmol·mmol· 1
0.31±0.28
0.027±0.019
C~ mmoH 1 GFR
N~ mmoH 1 GFR
1.08±0.84
TmCa mmoH 1 GFR
2.11±0.26
TmCa/Na corr. mmoH 1 GFR 2.40±0.25
TmP04 mmoH 1 GFR
1.16±0.28*
Controls
n=40
44.5±8
2.42±0.11
0.08±0.011
0.28±0.11
0.025±0.011
0.89±0.45
2.18±0.23
2.44±0.20
1.01±0.14
Ca: calcium; Cr: creatinine; C~: calcium excretion; N~: sodium
excretion; GFR: glomerular filtration rate; TmCa: tubular
maximum for calcium reabsorption; TmCa/Na corr.: sodium
corrected TmCa; TmP04 : tubular maximum for phosphate
reabsorption; •: p<O.Ol.
Results
The mean values of the measured variables are shown
in table 1. At the time of investigation all 52 patients
had chronic active thoracic sarcoidosis. The mean serum
calcium value of 2.54±0.18 mmoH 1 in patients with
sarcoidosis was significantly higher than that obtained in
the group of healthy subjects (2.42±0.11 mmoH 1). Five
patients were unmistakably hypercalcaemic.
Hypercalcaemia was diagnosed if serum calcium levels
were equal to or greater than the mean of the control
values plus three standard deviations. The mean tubular
maximum for calcium reabsorption (TmCa) in patients
with sarcoidosis, 2.11±0.26 mmol·l·' GF (range
1.72-2.64), was not statistically different from the mean
TmCa for the group of healthy subjects, 2.18±0.23
mmoH 1 GF (range 1.72-2.64). The range is mean±2sn.
The range of TmCa was reduced by taking urinary sodium
into account. Thus urinary sodium corrected TmCa in
patients with sarcoidosis was affected in a similar way to
TmCa uncorrected. The values were within the normal
range without significant differences between the means
of the groups.
Renal function as measured by the serum creatinine
was normal in all of the patients with sarcoidosis. In
seven patients the fasting urinary calcium/creatinine
ratios were increased above the normal range
0.40. Measurement of this ratio minimizes dietary
influences. Increased values indicate either, increased
bone resorption of calcium or, less commonly, decreased
renal tubular reabsorption of calcium.
The mean TmPO/(JFR in sarcoidosis was significantly
higher than in controls (p<0.01), but still within the
normal range for TmPO/GFR (0.8-1.25 mmoH' GF).
Fourteen patients with sarcoidosis had functional
hypoparathyroidism as measured by the renal phosphate
threshold concentration, the TmPO/GFR was increased
above the normal range 1.25 mmol-1- 1 GF (1.34±0.24
mmoH 1 GF).
Discussion
The present study revealed abnormal calcium metabolism in 12 (23%) patients. Five patients were hypercalcaemic and seven patients showed an abnormal calcium/
creatinine ratio. The present data concerning the frequency
of hypercalcaemia (9.6%) in sarcoidosis are consistent
with those of LEBACQ et al. [14]. However, the whole
group of patients with sarcoidosis had significantly higher
plasma calcium levels than the group of healthy subjects.
The bulk of calcium studies in sarcoidosis was essentially dedicated to the dearrangement of vitamin D
metabolism. In this respect, two major steps were the
demonstration that the serum 1,25(0H)p3 level is elevated in sarcoidosis [15] and the evidence that sarcoid
granulomas are able to elaborate 1,25(0H)p3 or 1 alpha
hydroxylase [16]. In spite of this growing knowledge, no
attempts have been made to examine the tubular
maximum for calcium reabsorption in patients with sarcoidosis.·Increased TmCa is one of three variables which
can contribute to the pathogenesis of hypercalcaemia.
Using a very sensitive method, a range for TmCa in
patients with sarcoidosis has been established for the first
time. Our range of TmCa in the control group is in good
correlation with the work of NEED et al. [6]. Because
urinary sodium excretion has been reported to influence
urinary calcium excretion we determined the effect of
sodium excretion on tubular reabsorption of calcium and
derived a corrected TmCa in patients with sarcoidosis
which takes into account the urinary sodium. Correcting
the TmCa for urinary sodium excretion reduced the range
ofTmCa.
If hypercalcaemia is associated with a normal TmCa it
must be due to increased entry of calcium into the plasma
or a reduced glomerular filtration rate. In all of our patients
with sarcoidosis renal functions were normal. From our
results, it is obvious that there is no increase in TmCa in
patients with chronic active thoracic sarcoidosis. Even
the five patients with elevated serum calcium levels had
normal TmCa. Thus, increased TmCa does not contribute to the pathogenesis of hypercalcaemia in sarcoidosis.
In seven patients the fasting urinary calcium/creatinine
ratios were elevated. Mean TmCa of these seven patients
CALCIUM REABSORPTION IN CHRONIC SARCOIDOSIS
449
(1.95±0.37 mmol-/·1 GF) was statistically different from
mean TmCa for the group of healthy subjects (2.18±0.23
mmol-I-1 GF); but still within the normal range for TmCa.
The mechanism for abnormal calcium metabolism
remains very complex. Among factors which might cause
hypercalcaemia in sarcoidosis, parathyroid hyperplasia
does not play a role [15]. When the data for all of our
patients with sarcoidosis were considered as a whole, the
mean TmPOiGFR was within the normal range. Only
14 of these patients had functional hypoparathyroidism
as measured by the TmP04 ; the TmPOiGFR was
increased to 1.34±0.24 mmol·l-1 GF. However, from
TmPOiGFR it is very difficult to assess whether serum
parathormone (PTH) levels are in the low-normal range
or renal phosphate excretion is augmented in response to
the elevation of the serum calcium concentration. Any
additional influence of PTH on the tubular handling of
calcium in the majority of our patients with sarcoidosis
remained negligible.
At present the factors causing the inappropriate elevation of I ,25(0H)zD3 in serum are sarcoid granulomas
which are able to elaborate 1,25(0H)2 D3 or 1 alpha
hydroxylase [16]. Whereas the effects of 1,25(0H)p3
on the skeleton and intestine have been well documented
(17], the intrinsic effects of vitamin D on the kidney
remain unclear [18].
Ninety nine per cent of the calcium filtered by the
kidney is reabsorbed even in vitamin D deficiency,
rendering any influence of vitamin D on calcium reabsorption of questionable physiological importance [19].
Our data support evidence that circulating active vitamin
D metabolites have 1iule or no influence on the TmCa.
Hypercalcaemia in patients with chronic thoracic
active sarcoidosis is not a result of an increased tubular
reabsorption of calcium.
7. Marshal! DH. - Calcium and phosphate kinetics. In:
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Proc Soc Exper Bioi Med, 1950, 74, 148-150.
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References
Le maximum tubulaire pour la reabsorption calcique chez les
patients aJteints de sarcoidose thoracique chronique active. P.
Broulik, V. Votava, V. Pacovsky.
RESUME: Le maximum tubulaire de reabsorption calcique
(fmCa) a ete evalue chez 52 patients atteints de sarcoi"dose
thoracique chronique active. Unc hypercalcemie a ete trouvee
chez 5 patients (9.6%). La valeur moyenne du calcium serique
de 2.54±0.18 m.mol-11 chez les patients atteints de sarcoldose,
s'avcre significativement plus elevee que celle obtenue dans le
groupe controle (2.42±0.11 m.moH 1). La TmCa moyenne chez
les patients aueints de sarcoi"dose (2.11±0.26 mmoH1 GF)
n'etait pas statistiquement differente de la TmCa moyenne dans
le groupe des sujets sains (2.18±0.23 mmol·t1 GF). La TmCa
corrigce pour le sodium urinaire, a ete affectee de fa~on
similaire dans les deux groupes. Notre etude dcmontre pour la
premiere fois que chez les patients atteints de sarcoi:dose
thoracique chronique active, il n'y a pas d'augmentation de
TmCa. L'hypercalcemie n'est done pas la consequence d'une
augmentation de TmCa.
Eur Respir J., 1990, 3, 447-449
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