Hydrochlorothiazide (HCTZ) is a standard therapy for
hypercalciuria, shown to diminish urinary calcium excretion and prevent
stone recurrence. However the hypertension literature has long debated the
clinical significance of side effects attributed to thiazides. These side
effects are not often given much attention in the literature describing the
drug class' use for therapy of stones. Young normotensive stone formers may
be limited in taking thiazides due to the development of hypotension or
orthostasis. Few alternatives are available. Treatment with oral phosphate
preparations or restriction of calcium intake may both be associated with
negative calcium balance (resulting in worsening of osteoporosis frequently
noted in stone formers), as well as increased urinary oxalate excretion.
These two papers examined the effects of indapamide as an alternative
therapy for calcium stones. Indapamide is a mild thiazide-like diuretic
with hypotensive effect, and supposedly fewer metabolic derangements. Its
efficacy as an anti-hypertensive in dialysis patients has led to the
suggestion (as with thiazides) that the drug's action as a vasodilator is
more important than its diuretic effect.
I recently saw a patient with recurrent stone disease and
dysautonomia, treated for a tendency to volume depletion with
fludrocortisone. The suggestion that indapamide would be a better
hypo-calciuric agent for him led to a review of the (scanty) relevant
literature.
Borghi, L., Meschi, T., Guerra, A., Novarini, A. Randomized prospective
study of a non-thiazide diuretic, indapamide, in preventing calcium stone
recurrences.
J Cardiovasc Pharmacol 22 (S6): S78-S86, 1993.
75 patients with hypercalciuria and recurrent stone formation (with
at least 1 stone in the previous 3 years), but stone-free before therapy,
were selected, and randomized into 3 groups of 25: a) diet and fluid
therapy; b) diet and fluid therapy with indapamide 2.5 mg qd; c) diet and
fluid therapy, indapamide 2.5 mg and allopurinol 300 mg qd. Patients were
followed at least yearly for up to 3 years.
Over this period there were significant decrements in blood
pressure in groups b and c, taking indapamide, as well as decreases in
serum K from 4.4 mEq/L to 3.9 mEq/L and 4.0 mEq/L respectively. Only 1
patient had to discontinue indapamide due to hypotension. Uric acid rose
from 4.9 mg/dl to 5.6 mg/dl in group b but not in group c, the one treated
with allopurinol. Urinary calcium fell in all 3 groups in the first 12
months, but by more, and for a prolonged period, in the indapamide groups.
At 3 years UCaV was 330 mg, 201 mg and 203 mg in the 3 groups, having
started at similar values. With no decline in urinary citrate despite the
decline in serum K, the net result was a fall in relative supersaturation
of calcium oxalate of 55% in the indapamide groups.
The stone rate in all 3 groups fell, but by more in the groups
treated with indapamide. There was no additional effect of allopurinol. As
compared to the rate of stones per year in the 3 previous years, the rate
in the 3 study years fell from 0.79 to 0.28 in group a, from 1.41 to 0.06
and from 1.2 to 0.04 in groups b and c respectively. The proportions of
patients stone-free at the end of the study in the 3 groups were 57% (group
a); 84% (group b) and 87% (group c).
In summary, indapamide appeared to effectively reduce urinary
calcium and diminish the rate of stone recurrence. It was well-tolerated
but claims that the drug was better tolerated and more effective, with
fewer metabolic derangements than thiazide are not possible without a
thiazide group for comparison.
Martins et al.
Martins, M.C., Meyers, A.M., Whalley, N.A., Margolius, L.P., and Buys, M.E.
Indapamide (Natrilix): the agent of choice in the treatment of recurrent
renal calculi associated with idiopathic hypercalciuria.
British J Urol 78:176-180, 1996.
This paper attempted to compare the hypocalciuric potential of indapamide
as compared to hydrochlorothiazide (HCTZ). 12 patients were studied before
and during 3 month periods of treatment with either HCTZ 50 mg qd, or
indapamide 2.5 mg qd, separated by 3 week washout periods. Both groups had
similar declines in urinary calcium excretion. There were no significant
differences in any serum parameter during the 2 drug study periods except K
which fell from 4.01 to 3.76 mEq/L for HCTZ and from 4.20 to 3.56 with
indapamide.Urinary citrate fell from 1.41 to 1.00 mmol/24h with HCTZ, and
did not fall with indapamide. No investigation of the relative natriuretic
effects of the 2 drugs was performed.
In summary these 2 papers provide interesting data suggesting that
indapamide may be effective for the management of recurrent stone disease
with hypercalciuria. The only basis for concluding that indapamide is
superior to thiazide is that in both studies indapamide caused no decline
in urinary citrate excretion, a potentially important advantage. But since
both drugs cause hypokalemia of similar magnitude, K supplementation will
be required for both groups.
Other papers, not reviewed here, purport to show fewer metabolic
complications with indapamide as compared to thiazide. The long-term
significance of other metabolic effects associated with thiazides such as
hyperglycemia, hyperuricemia, and changes in lipid profiles continues to be
debated in the hypertension literature. Their importance in a stone-forming
population which may not have the other risk factors for cardiovascular
disease relevant to the treatment of hypertensive patients is more unclear
still. I think there is no basis for thinking that indapamide is less
natriuretic, particularly if any data claiming to show this examine urinary
Na excretion after 3 months of therapy. In fact, the consistent
similarities in the hypokalemic effects of the 2 drugs would seem to
reflect on the similarities of the effects on Na. Lastly indapamide is much
more costly than thiazides.
(David S. Goldfarb, M.D., NYU School of Medicine)
(August, 1997)