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Selective effects of thiazide on intestinal absorption of calcium in absorptive and renal hypercalciurias
Metabolism Clinical and Experimental VOL.
XXVII,
FEBRUARY
NO. 2
1978
Selective Effects of Thiazide on Intestinal Absorption of Calcium in Absorptive and Renal Hypercalciurias D. E. Barilla,
R. Tolentino,
R. A. Kaplan,
The effect of long-term thiazide therapy on the intestinal Ca absorption was measured in 10 well-defined cases of absorptive hypercalciuria with intestinal hyperabsorption of Co and 8 with renal hypercalciuria (“renal leak’ of Ca), many of whom had hyperabsorption of Ca. In most cases of absorptive hypercalciuria, the intestinal hyperabsorption of Ca persisted during treatment, despite restoration of normal urinary Ca. In contrast, the in-
and C. Y. C. Pak
testinal Ca absorption decreased significantly during thiazide therapy in 7 of 8 patients with renal hypercalciuria commensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. The results support the hypothesis that the intestinal hyperabsorption of Ca in absorptive hypercalciuria may be primary, whereas that in renal hypercalciuria may be associated with the hyperparathyroid state.
A
BSORPTIVE HYPERCALCIURIA (AH)lm3 and renal hypercalciuria (RH)4 probably represent two major subtypes of idiopathic hypercalciuria.’ The hypercalciuria in AH is believed to result from an enhanced intestinal absorption of Ca, whereas that in RH is thought to be the consequence of a primary defect in the renal tubular reabsorption (renal leak) of Ca. Parathyroid function in AH is normal or suppressed, unlike in RH, where it is stimulated. The intestinal Ca absorption, which is invariably high in AH,’ may also be increased in RH.396 It has been postulated that the cause for the increased Ca absorption in RH is the promotion of the renal synthesis of la,25-dihydroxycholecalciferol (1,25-DHCC) associated with secondary hyperparathyroidism.‘** Coe et al. have shown that the hypercalciuria and the secondary hyperparaFrom the Section on Mineral Metabolism, Department of Internal Medicine. University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Tex. Received for publication October 21, 1976. Supported by USPHS Grants ROI-AM 16061. MOI-RROO633, and POI-HLl1662. Reprint requests should be addressed to D. E. Barilla. M.D., Department of Internal Medicine. University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd.. Dallas, Tex. 75235. 0 1978 by Grune & Stratton, Inc. W260495/78/2702-0001$01.00/0 Metabolism, Vol. 27, No. 2 (February), 1978
125
126
BARILLA
ET Al.
thyroidism of RH may be corrected or ameliorated by treatment with thiazide.4 It is therefore possible that this therapy may restore normal intestinal Ca absorption in RH. In contrast, thiazide may not significantly alter the intestinal absorption of Ca in AH, in which there is no parathyroid stimulation. In this study, the preceding hypothesis was tested by a careful measurement of intestinal Ca absorption in well-defined cases of AH and RH. MATERIALS
AND METHODS
Clinical Data Eighteen adult patients. Clinical
Research
Center.
IO with AH
consent. As shown previously,’
or ~1 > 0.61),
(iPTH)
and
CAMP
fasting
state (~0.1 I mg/mg
of 1 g Ca (>0.20
mg/mg
normal
(~5.4 Cr),
aration.
type 1, and 5 had AH
urinary
urinary
with RH
stimulatiq;
was above the normal
tients. However,
urinary
Ca
(frac-
hormone during
following
type II, urinary
the
oral
load
Ca on a constant
whereas it was high in AH
range.
antiserum
of Arnaud,’
characteristics: Ca/Cr
of Ca
and high
hypercalciuria.
following
normal
an oral
in the
Ca
the assay of serum iPTH
21 l-32 or 21 l-41.
All patients
patients.
During
Ca, urinary in all the pa-
by the technique
et al..* or the procedure
had endogenous
Ca 24-hr
had to be modi-
was utilized
in fasting serum were found of Kaplan
The
by absorbed
no single assay procedure
prep-
fractional
load.’
remaining
Unfortunately,
the method
dietary
here had an increased
not compensated
Thus,
high serum
after an adequate
was probably
elevated values of iPTH
antiserum
Wellcome
normal
mg/day).
who were evaluated
renal excretion
tied during the course of the study. CH14M
(~200
fasting urinary
was high in four patients
the fast, when parathyroid CAMP
parathyroid
Ca excretion
type 11.9 In AH
was normal
and elevated
and an exaggerated
CAMP
[Cr]),
written
Ca absorption
immunoreactive
urinary
was made from the following
CAMP,
Most of the patients
absorption
gave informed
intestinal
features were the same.
The diagnosis of RH and/or
creatinine
and an exaggerated
diet of 400 mg Ca and 100 meq Na/day
iPTH
had elevated
or suppressed
rmoles/g
in this study at the General
all patients
Cr13
Five patients had AH type I. Otherwise
participated
of the study.
the patients with AH
tional Ca absorption urinary
and 8 with RH,
Prior to the initiation
utilizing
using Burroughs-
creatinine
clearance
greater
than 80 ml/min.
Outline of Protocol All patients throughout initially
underwent
modification synthetic
were maintained
the period
on
of study,
of a previously
described
Doyle
refrigeration
least and
I
yr
of
avoidance
preceding
parathyroid were
Minn.),
pools and were analyzed
daily without
a venous stasis before a 12-hr fast, a 2-hr
for Ca and Cr. On day 2, IL2 PCi of 47Ca mixed
Urine for
Ca,
breakfast
fasting
urine
in 250 ml of the
daily
specimens Cr,
synthetic
liquid 400
mg
were col-
P. and
meal for Ca, sample
They
to a slight
on a constant
containing
l-3).
products
treatment.
according
maintained
days (days
of dairy
thiazide
function,
Minneapolis,
for 3 consecutive
of day 4, following
consisting
They
method.’
daily in 24-hr
Venous blood was obtained
diet.
at
Pharmaceutical,
Ca, 800 mg P, and 100 meq Na,
Cr. On the morning
for
studies of Ca metabolism
diet (Calcitest,
lected under
a low-Ca and
CAMP. P. and
was obtained
diet
containing
100 mg Ca was given orally to measure a. After with AH
the initial evaluation,
all patients
was given chlorthalidone.
were begun on diuretic
50 mg orally each day. Others
50 mg twice a day orally.
All patients
and reevaluated according
to the same protocol
was conducted
HCTZ
was withheld
received
3 mo after
as in the initial
after 6, 12, 18, and 24 mo of therapy
In some patients, studied again.
were readmitted
(HCTZ)
18-24
One patient
hydrochlorothiaride.
the initiation
evaluation.
in those in whom
for 3 mo after
therapy.
of treatment
Similar
treatment
mo of treatment;
evaluation
was continued. they were then
Ip
< 0.001.
tp < 0.01.
*Significant
Abbreviations:
as mean
HCTZ,
9.86
zt 0.34
* 0.03$
* 1.12 & 1.70
zk 0.46
0.589
0.719
Cr;3 24-hr
from control
period,
Co,
obtained
by paired
zt 0.037
zt 0.67
* 0.68
patients.
0.552
0.699
134
Co absorption.
t test, p < 0.05.
01, fractional
-
f f
1.58 1.16*
f 0.069
0.772
In normal
4.02
0.0597 CAMP,
i
+ 0.085
114+201
0.486 urinary
zk 0.021
* 0.02
* 0.87 i 0.40*
f 0.12
f 0.32
18
149+31*
0.03
0.07
4.49 4.00
9.83
9.67
far a is 0.61.’
subjects:
f 0.064’
control
0.560
0.669
111 + 40t
limit of normal
in normal
* 0.50 f 0.27
139 l 40*
0.07
3.45 3.85
9.70
9.40
Months of HCTZ Treatment 12
The upper
Values
zk 0.103
127 zt 58*
0.06
0.04
3.41 6.71
108 & 42 (SD) mg/day.’
or chlorthalidone;
urinary
different
* 0.108*
* 0.059
92 zt 32i
9.85 10.01
6
Effectsof Thiazide in Absorptive and Renal Hypercalciurios
117 * 56*
0.04
0.06
3.49 5.69
9.65
3
+ SD of mean values from
0.104
zt 0.064
i
hydrochlorothiazide
(SD) mg/mg
difference
=t 0.027
Values are presented
0.695
0.701
AH
248 f 66
RH
204 + 57
* 0.07
+ 0.02
+ 0.76 f- 1.53
RH
Co, 0.057
a
* 0.45
+ 0.41
AH
Urinary
0.21
3.21 5.54
0.08
Co (mg/day)
9.53
9.76
RH
Cl)
Cr)
ml)
AH
Ca (mg/mg
Fasting urinary
AH RI-I
Urinary CAMP @male/g
RH
Serum Ca (mg/lOO AH
Control
Table 1.
9.79
0.725
subjects,
257
0.031
o.os7t
(Y is reproducible
(SD) pmoles/g
i
f 0.107
83 k 321
0.499 -I: 0.70
f
zt 0.03
+z 1.33 f 0.777
0.14
zt 0.29 f
149 f
0.06
0.06
4.20 3.50
9.74
24
Cr;’
f
0.21
f
f 0.046
19
0
to within
fasting
5%.
urinary
0.6 13 + 0.059
0.733
240 f
0.04
z!.z0.38 + 3.23
230 f
0.18
0.07
3.14 6.43
9.5 f 0.28
9.65
Off
E ID z 0 P
2
z ;;I
g
2 6 E Fi
2
BARILLA
128
ET
AL.
Analytical Procedures Ca was determined
by atomic
by the protein-binding
absorption
assay of Gilman.”
spectrophotometry. Cr was analyzed
sured from the fecal recovery of orally administered
Urinary
CAMP
by,;utoanalyzer,
was measured
and a was mea-
radiocalcium.
RESULTS
Serum Ca and Urinary CAMP (Table 1 I In both AH and RH, serum concentration of Ca was normal initially and did not change significantly during treatment with HCTZ. Before treatment, urinary CAMP was significantly higher in RH than in AH (p < 0.05). In RH, urinary CAMP decreased during later periods of treatment and returned toward pretreatment levels when therapy was stopped. In AH, urinary CAMP levels remained in the normal range throughout the treatment period. Fasting Urinary Ca/Cr (Figs. 1 and 2 and Table 1 I Fasting urinary Ca was normal (co.1 1 mg/mg Cr), both in the control period and during HCTZ treatment phase in all patients with AH in whom it was measured. In contrast, fasting urinary Ca was high initially in every case of RH. It decreased to the normal range during treatment, and returned to the high pretreatment range when therapy was stopped. 030 FASTING
0.20
URINARY
cam
w/w
0.10
:.---
t
OL 400 r 300 URINARY CO
mq/day
t 200 t
1.0 r 0.8 -
FRACTIONAL CO
Q6-
ABSORPTION
0.4 -
0.2 0 L
, 0 +-MONTHS
,
6
OF
12
I8
HCTZ
THERAPY+
I
24 OFF
Fig. 1. Effect of HCTZ on fasting urinary Cct. 24-hr urinary Ca, and fractional Co absorption in absorptive hypercalciuria. Each line represents a study in a separate patient.
EFFECTS
OF THIAZIDE
ON INTESTINAL
129
ABSORPTION
FASTING
020
URINARY
corn
w/w
0.10
0
URINARY CO
200
mq/day 100
FRACTIONAL
0.6 -
Co ABSORPTION
0.4 -
0.2 -
Fig. 2. Effect of HCTZ in renal hypercalciurio. Origin of horizontal broken line indicates the time when HCTZ was discontinued.
0-
0 k-MONTHS
6
12 OF HCTZ
I8 THERAPY+
24 OFF
24-hr Urinary Ca (Figs. 1 and 2) Before treatment, hypercalciuria was found in both AH and RH. During treatment with HCTZ, urinary Ca decreased significantly in virtually every patient in both groups. When treatment was stopped, urinary Ca returned toward control values. These changes were also significant when urinary Ca was calculated for the whole group (Table 1). Fractional Ca Absorption (Figs. 1 and 2) Fractional Ca absorption was high or high normal initially in both AH and RH patients. The mean values for both groups were significantly elevated (p < 0.001). In patients with AH, (Yremained high both during and following treatment with HCTZ, except in one in whom it was high normal after 24 mo of treatment. Values for the whole group did not change significantly during HCTZ treatment, and remained elevated (Table 1). In contrast, seven of eight patients with RH had a fall in (Y during HCTZ treatment. In six patients who had high Q initially, cy decreased to the normal range in every case. In one patient, however, CYdid not decrease during treatment, but remained high normal. The mean value for (Yfor the whole group of RH patients decreased significantly to normal during HCTZ treatment; it returned toward pretreatment values when therapy was stopped.
BARILLA
130
ET Al.
DISCUSSION
Thiazide diuretic was effective in ameliorating hypercalciuria in both AH and RH. In RH, it corrected the renal leak of Ca and probably restored normal parathyroid function.4 Thus, fasting urinary Ca and urinary CAMP decreased during treatment. The effect of thiazide on intestinal Ca absorption was distinct in the two conditions. In RH, thiazide typically reduced the fractional Ca absorption, commensurate with the “correction” of renal leak of Ca and secondary hyperparathyroidism. It is recognized that PTH may play an important role in the with potent action regulation of the synthesis of 1,25-DHCC,8S’37’4 a metabolite on intestinal Ca transport. The results therefore suggest that the increased intestinal Ca absorption in RH may be secondary to an enhanced synthesis of 1,25-DHCC associated with the hyperparathyroid state.’ The reduction in intestinal Ca absorption during thiazide therapy may then be explained by the reduced synthesis of the vitamin D metabolite consequent to restoration of normal parathyroid function. In contrast, thiazide did not correct the intestinal hyperabsorption of Ca in AH, even though it caused a fall in total renal Ca excretion. The results support the primacy of intestinal hyperabsorption of Ca in AH. Assessment of thiazide response by a direct analysis of circulating concentration of I ,25-DHCC and of iPTH may provide further clarification. Other workers have reported varying effects of thiazide on intestinal Ca absorption in patients with idiopathic hypercalciuria.‘5.‘6 However, they did not segregate the group into AH and RH. REFERENCES I. Pak CYC. Ohata M. Lawrence EC, et al: The hypercalciurias: Causes, parathyroid functions and diagnostic criteria. J Clin Invest 54: 387-400, 1974 2. Nordin BEC, Peacock M, Wilkinson R: Hypercalciuria and calcium stone disease, in McIntyre I (ed): Clinics in Endocrinology and Metabolism, vol I. Philadelphia, Saunders, 1972. pp 169~ml83 3. Pak CYC, Kaplan R, Bone H. et al: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med 292:497 500, 1975 4. Coe FL. Canterbury JM. Firpo JJ, et al: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 52: I34142. 1973 5. Henneman PH. Benedict et al: idiopathic hypercalciuria. 259:8022807, 1958
PH. Forbes AP, N Engl J Med
6. Pak CYC, Barilla D, Bone H. et al: Medical management of renal calculi, in Rose (ed): Symposium on Advances in Endocrinology and Metabolism. New York, Grune & Stratton, 1977, pp 97-106
7. Pak CYC, Kaplan R. Bone H. et al: A simple test for hypercalciuria? N Engl J Med 292:1134~1136, 1975 8. Kaplan RA, Haussler MR, Deftos LJ. et al: The role of In.25dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Invest 59: 756 760. 1977 9. Pak CYC. Holt K: Nucleation and growth of brushite and calcium oxalate in urine of stone-formers. Metabolism 25:665 673. 1976 IO. Pak CYC: Idiopathic hypercalciuria, in Massry S. Ritz E (eds): Phosphate Metabolism. New York, Plenum, 1977, pp 3099317 I I. Gilman AC: A protein binding assay for adenosine 3’5’-cyclic monophosphate. Proc Natl Acad Sci USA 67:3055312. 1970 12. Pak CYC. East DA, Sanzenbacher LJ, et al: Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab 35: 261-270, 1972 13. Garabedian M, Holick MF. DeLuca HF, et al: Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 69:167331676, 1972
EFFECTS
OF THIAZIDE
ON INTESTINAL
ABSORPTION
14. Haussler MR. Bursac KM, Bone H, et al: Increased circulating la,25dihydroxy vitamin Ds in patients with primary hyperparathyroidism. Clin Res 23:322A, 1975
IS. Ehrig U, Harrison feet of long-term thiazide
JE, Wilson DR: Eftherapy on intestinal
131
calcium absorption in patients with recurrent renal calculi. Metabolism 23:139-147, 1974 16. Curse1 E: Effects of diuretics on renal and intestinal handling of calcium. NY State J Med 70:399-405, 1970
XXVII,
FEBRUARY
NO. 2
1978
Selective Effects of Thiazide on Intestinal Absorption of Calcium in Absorptive and Renal Hypercalciurias D. E. Barilla,
R. Tolentino,
R. A. Kaplan,
The effect of long-term thiazide therapy on the intestinal Ca absorption was measured in 10 well-defined cases of absorptive hypercalciuria with intestinal hyperabsorption of Co and 8 with renal hypercalciuria (“renal leak’ of Ca), many of whom had hyperabsorption of Ca. In most cases of absorptive hypercalciuria, the intestinal hyperabsorption of Ca persisted during treatment, despite restoration of normal urinary Ca. In contrast, the in-
and C. Y. C. Pak
testinal Ca absorption decreased significantly during thiazide therapy in 7 of 8 patients with renal hypercalciuria commensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. The results support the hypothesis that the intestinal hyperabsorption of Ca in absorptive hypercalciuria may be primary, whereas that in renal hypercalciuria may be associated with the hyperparathyroid state.
A
BSORPTIVE HYPERCALCIURIA (AH)lm3 and renal hypercalciuria (RH)4 probably represent two major subtypes of idiopathic hypercalciuria.’ The hypercalciuria in AH is believed to result from an enhanced intestinal absorption of Ca, whereas that in RH is thought to be the consequence of a primary defect in the renal tubular reabsorption (renal leak) of Ca. Parathyroid function in AH is normal or suppressed, unlike in RH, where it is stimulated. The intestinal Ca absorption, which is invariably high in AH,’ may also be increased in RH.396 It has been postulated that the cause for the increased Ca absorption in RH is the promotion of the renal synthesis of la,25-dihydroxycholecalciferol (1,25-DHCC) associated with secondary hyperparathyroidism.‘** Coe et al. have shown that the hypercalciuria and the secondary hyperparaFrom the Section on Mineral Metabolism, Department of Internal Medicine. University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Tex. Received for publication October 21, 1976. Supported by USPHS Grants ROI-AM 16061. MOI-RROO633, and POI-HLl1662. Reprint requests should be addressed to D. E. Barilla. M.D., Department of Internal Medicine. University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd.. Dallas, Tex. 75235. 0 1978 by Grune & Stratton, Inc. W260495/78/2702-0001$01.00/0 Metabolism, Vol. 27, No. 2 (February), 1978
125
126
BARILLA
ET Al.
thyroidism of RH may be corrected or ameliorated by treatment with thiazide.4 It is therefore possible that this therapy may restore normal intestinal Ca absorption in RH. In contrast, thiazide may not significantly alter the intestinal absorption of Ca in AH, in which there is no parathyroid stimulation. In this study, the preceding hypothesis was tested by a careful measurement of intestinal Ca absorption in well-defined cases of AH and RH. MATERIALS
AND METHODS
Clinical Data Eighteen adult patients. Clinical
Research
Center.
IO with AH
consent. As shown previously,’
or ~1 > 0.61),
(iPTH)
and
CAMP
fasting
state (~0.1 I mg/mg
of 1 g Ca (>0.20
mg/mg
normal
(~5.4 Cr),
aration.
type 1, and 5 had AH
urinary
urinary
with RH
stimulatiq;
was above the normal
tients. However,
urinary
Ca
(frac-
hormone during
following
type II, urinary
the
oral
load
Ca on a constant
whereas it was high in AH
range.
antiserum
of Arnaud,’
characteristics: Ca/Cr
of Ca
and high
hypercalciuria.
following
normal
an oral
in the
Ca
the assay of serum iPTH
21 l-32 or 21 l-41.
All patients
patients.
During
Ca, urinary in all the pa-
by the technique
et al..* or the procedure
had endogenous
Ca 24-hr
had to be modi-
was utilized
in fasting serum were found of Kaplan
The
by absorbed
no single assay procedure
prep-
fractional
load.’
remaining
Unfortunately,
the method
dietary
here had an increased
not compensated
Thus,
high serum
after an adequate
was probably
elevated values of iPTH
antiserum
Wellcome
normal
mg/day).
who were evaluated
renal excretion
tied during the course of the study. CH14M
(~200
fasting urinary
was high in four patients
the fast, when parathyroid CAMP
parathyroid
Ca excretion
type 11.9 In AH
was normal
and elevated
and an exaggerated
CAMP
[Cr]),
written
Ca absorption
immunoreactive
urinary
was made from the following
CAMP,
Most of the patients
absorption
gave informed
intestinal
features were the same.
The diagnosis of RH and/or
creatinine
and an exaggerated
diet of 400 mg Ca and 100 meq Na/day
iPTH
had elevated
or suppressed
rmoles/g
in this study at the General
all patients
Cr13
Five patients had AH type I. Otherwise
participated
of the study.
the patients with AH
tional Ca absorption urinary
and 8 with RH,
Prior to the initiation
utilizing
using Burroughs-
creatinine
clearance
greater
than 80 ml/min.
Outline of Protocol All patients throughout initially
underwent
modification synthetic
were maintained
the period
on
of study,
of a previously
described
Doyle
refrigeration
least and
I
yr
of
avoidance
preceding
parathyroid were
Minn.),
pools and were analyzed
daily without
a venous stasis before a 12-hr fast, a 2-hr
for Ca and Cr. On day 2, IL2 PCi of 47Ca mixed
Urine for
Ca,
breakfast
fasting
urine
in 250 ml of the
daily
specimens Cr,
synthetic
liquid 400
mg
were col-
P. and
meal for Ca, sample
They
to a slight
on a constant
containing
l-3).
products
treatment.
according
maintained
days (days
of dairy
thiazide
function,
Minneapolis,
for 3 consecutive
of day 4, following
consisting
They
method.’
daily in 24-hr
Venous blood was obtained
diet.
at
Pharmaceutical,
Ca, 800 mg P, and 100 meq Na,
Cr. On the morning
for
studies of Ca metabolism
diet (Calcitest,
lected under
a low-Ca and
CAMP. P. and
was obtained
diet
containing
100 mg Ca was given orally to measure a. After with AH
the initial evaluation,
all patients
was given chlorthalidone.
were begun on diuretic
50 mg orally each day. Others
50 mg twice a day orally.
All patients
and reevaluated according
to the same protocol
was conducted
HCTZ
was withheld
received
3 mo after
as in the initial
after 6, 12, 18, and 24 mo of therapy
In some patients, studied again.
were readmitted
(HCTZ)
18-24
One patient
hydrochlorothiaride.
the initiation
evaluation.
in those in whom
for 3 mo after
therapy.
of treatment
Similar
treatment
mo of treatment;
evaluation
was continued. they were then
Ip
< 0.001.
tp < 0.01.
*Significant
Abbreviations:
as mean
HCTZ,
9.86
zt 0.34
* 0.03$
* 1.12 & 1.70
zk 0.46
0.589
0.719
Cr;3 24-hr
from control
period,
Co,
obtained
by paired
zt 0.037
zt 0.67
* 0.68
patients.
0.552
0.699
134
Co absorption.
t test, p < 0.05.
01, fractional
-
f f
1.58 1.16*
f 0.069
0.772
In normal
4.02
0.0597 CAMP,
i
+ 0.085
114+201
0.486 urinary
zk 0.021
* 0.02
* 0.87 i 0.40*
f 0.12
f 0.32
18
149+31*
0.03
0.07
4.49 4.00
9.83
9.67
far a is 0.61.’
subjects:
f 0.064’
control
0.560
0.669
111 + 40t
limit of normal
in normal
* 0.50 f 0.27
139 l 40*
0.07
3.45 3.85
9.70
9.40
Months of HCTZ Treatment 12
The upper
Values
zk 0.103
127 zt 58*
0.06
0.04
3.41 6.71
108 & 42 (SD) mg/day.’
or chlorthalidone;
urinary
different
* 0.108*
* 0.059
92 zt 32i
9.85 10.01
6
Effectsof Thiazide in Absorptive and Renal Hypercalciurios
117 * 56*
0.04
0.06
3.49 5.69
9.65
3
+ SD of mean values from
0.104
zt 0.064
i
hydrochlorothiazide
(SD) mg/mg
difference
=t 0.027
Values are presented
0.695
0.701
AH
248 f 66
RH
204 + 57
* 0.07
+ 0.02
+ 0.76 f- 1.53
RH
Co, 0.057
a
* 0.45
+ 0.41
AH
Urinary
0.21
3.21 5.54
0.08
Co (mg/day)
9.53
9.76
RH
Cl)
Cr)
ml)
AH
Ca (mg/mg
Fasting urinary
AH RI-I
Urinary CAMP @male/g
RH
Serum Ca (mg/lOO AH
Control
Table 1.
9.79
0.725
subjects,
257
0.031
o.os7t
(Y is reproducible
(SD) pmoles/g
i
f 0.107
83 k 321
0.499 -I: 0.70
f
zt 0.03
+z 1.33 f 0.777
0.14
zt 0.29 f
149 f
0.06
0.06
4.20 3.50
9.74
24
Cr;’
f
0.21
f
f 0.046
19
0
to within
fasting
5%.
urinary
0.6 13 + 0.059
0.733
240 f
0.04
z!.z0.38 + 3.23
230 f
0.18
0.07
3.14 6.43
9.5 f 0.28
9.65
Off
E ID z 0 P
2
z ;;I
g
2 6 E Fi
2
BARILLA
128
ET
AL.
Analytical Procedures Ca was determined
by atomic
by the protein-binding
absorption
assay of Gilman.”
spectrophotometry. Cr was analyzed
sured from the fecal recovery of orally administered
Urinary
CAMP
by,;utoanalyzer,
was measured
and a was mea-
radiocalcium.
RESULTS
Serum Ca and Urinary CAMP (Table 1 I In both AH and RH, serum concentration of Ca was normal initially and did not change significantly during treatment with HCTZ. Before treatment, urinary CAMP was significantly higher in RH than in AH (p < 0.05). In RH, urinary CAMP decreased during later periods of treatment and returned toward pretreatment levels when therapy was stopped. In AH, urinary CAMP levels remained in the normal range throughout the treatment period. Fasting Urinary Ca/Cr (Figs. 1 and 2 and Table 1 I Fasting urinary Ca was normal (co.1 1 mg/mg Cr), both in the control period and during HCTZ treatment phase in all patients with AH in whom it was measured. In contrast, fasting urinary Ca was high initially in every case of RH. It decreased to the normal range during treatment, and returned to the high pretreatment range when therapy was stopped. 030 FASTING
0.20
URINARY
cam
w/w
0.10
:.---
t
OL 400 r 300 URINARY CO
mq/day
t 200 t
1.0 r 0.8 -
FRACTIONAL CO
Q6-
ABSORPTION
0.4 -
0.2 0 L
, 0 +-MONTHS
,
6
OF
12
I8
HCTZ
THERAPY+
I
24 OFF
Fig. 1. Effect of HCTZ on fasting urinary Cct. 24-hr urinary Ca, and fractional Co absorption in absorptive hypercalciuria. Each line represents a study in a separate patient.
EFFECTS
OF THIAZIDE
ON INTESTINAL
129
ABSORPTION
FASTING
020
URINARY
corn
w/w
0.10
0
URINARY CO
200
mq/day 100
FRACTIONAL
0.6 -
Co ABSORPTION
0.4 -
0.2 -
Fig. 2. Effect of HCTZ in renal hypercalciurio. Origin of horizontal broken line indicates the time when HCTZ was discontinued.
0-
0 k-MONTHS
6
12 OF HCTZ
I8 THERAPY+
24 OFF
24-hr Urinary Ca (Figs. 1 and 2) Before treatment, hypercalciuria was found in both AH and RH. During treatment with HCTZ, urinary Ca decreased significantly in virtually every patient in both groups. When treatment was stopped, urinary Ca returned toward control values. These changes were also significant when urinary Ca was calculated for the whole group (Table 1). Fractional Ca Absorption (Figs. 1 and 2) Fractional Ca absorption was high or high normal initially in both AH and RH patients. The mean values for both groups were significantly elevated (p < 0.001). In patients with AH, (Yremained high both during and following treatment with HCTZ, except in one in whom it was high normal after 24 mo of treatment. Values for the whole group did not change significantly during HCTZ treatment, and remained elevated (Table 1). In contrast, seven of eight patients with RH had a fall in (Y during HCTZ treatment. In six patients who had high Q initially, cy decreased to the normal range in every case. In one patient, however, CYdid not decrease during treatment, but remained high normal. The mean value for (Yfor the whole group of RH patients decreased significantly to normal during HCTZ treatment; it returned toward pretreatment values when therapy was stopped.
BARILLA
130
ET Al.
DISCUSSION
Thiazide diuretic was effective in ameliorating hypercalciuria in both AH and RH. In RH, it corrected the renal leak of Ca and probably restored normal parathyroid function.4 Thus, fasting urinary Ca and urinary CAMP decreased during treatment. The effect of thiazide on intestinal Ca absorption was distinct in the two conditions. In RH, thiazide typically reduced the fractional Ca absorption, commensurate with the “correction” of renal leak of Ca and secondary hyperparathyroidism. It is recognized that PTH may play an important role in the with potent action regulation of the synthesis of 1,25-DHCC,8S’37’4 a metabolite on intestinal Ca transport. The results therefore suggest that the increased intestinal Ca absorption in RH may be secondary to an enhanced synthesis of 1,25-DHCC associated with the hyperparathyroid state.’ The reduction in intestinal Ca absorption during thiazide therapy may then be explained by the reduced synthesis of the vitamin D metabolite consequent to restoration of normal parathyroid function. In contrast, thiazide did not correct the intestinal hyperabsorption of Ca in AH, even though it caused a fall in total renal Ca excretion. The results support the primacy of intestinal hyperabsorption of Ca in AH. Assessment of thiazide response by a direct analysis of circulating concentration of I ,25-DHCC and of iPTH may provide further clarification. Other workers have reported varying effects of thiazide on intestinal Ca absorption in patients with idiopathic hypercalciuria.‘5.‘6 However, they did not segregate the group into AH and RH. REFERENCES I. Pak CYC. Ohata M. Lawrence EC, et al: The hypercalciurias: Causes, parathyroid functions and diagnostic criteria. J Clin Invest 54: 387-400, 1974 2. Nordin BEC, Peacock M, Wilkinson R: Hypercalciuria and calcium stone disease, in McIntyre I (ed): Clinics in Endocrinology and Metabolism, vol I. Philadelphia, Saunders, 1972. pp 169~ml83 3. Pak CYC, Kaplan R, Bone H. et al: A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med 292:497 500, 1975 4. Coe FL. Canterbury JM. Firpo JJ, et al: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 52: I34142. 1973 5. Henneman PH. Benedict et al: idiopathic hypercalciuria. 259:8022807, 1958
PH. Forbes AP, N Engl J Med
6. Pak CYC, Barilla D, Bone H. et al: Medical management of renal calculi, in Rose (ed): Symposium on Advances in Endocrinology and Metabolism. New York, Grune & Stratton, 1977, pp 97-106
7. Pak CYC, Kaplan R. Bone H. et al: A simple test for hypercalciuria? N Engl J Med 292:1134~1136, 1975 8. Kaplan RA, Haussler MR, Deftos LJ. et al: The role of In.25dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Invest 59: 756 760. 1977 9. Pak CYC. Holt K: Nucleation and growth of brushite and calcium oxalate in urine of stone-formers. Metabolism 25:665 673. 1976 IO. Pak CYC: Idiopathic hypercalciuria, in Massry S. Ritz E (eds): Phosphate Metabolism. New York, Plenum, 1977, pp 3099317 I I. Gilman AC: A protein binding assay for adenosine 3’5’-cyclic monophosphate. Proc Natl Acad Sci USA 67:3055312. 1970 12. Pak CYC. East DA, Sanzenbacher LJ, et al: Gastrointestinal calcium absorption in nephrolithiasis. J Clin Endocrinol Metab 35: 261-270, 1972 13. Garabedian M, Holick MF. DeLuca HF, et al: Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 69:167331676, 1972
EFFECTS
OF THIAZIDE
ON INTESTINAL
ABSORPTION
14. Haussler MR. Bursac KM, Bone H, et al: Increased circulating la,25dihydroxy vitamin Ds in patients with primary hyperparathyroidism. Clin Res 23:322A, 1975
IS. Ehrig U, Harrison feet of long-term thiazide
JE, Wilson DR: Eftherapy on intestinal
131
calcium absorption in patients with recurrent renal calculi. Metabolism 23:139-147, 1974 16. Curse1 E: Effects of diuretics on renal and intestinal handling of calcium. NY State J Med 70:399-405, 1970