Download patologias del sistema nervioso

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Case Reports
Arch. Esp. Urol. 2014; 67 (3): 284-287
CALCIUM NEPHROLITHIASIS INDUCED BY
TOPIRAMATE
Sergio Merino-Salas1, Miguel Angel Arrabal-Polo2,
Maria del Carmen Cano-Garcia3, Miguel ArrabalMartin2.
Urology Department. Hospital de Poniente. El Ejido. Almería
Urology Department. Hospital Universitario San Cecilio.
Granada.
3
Urology Department. Hospital Universitario Morales
Meseguer. Murcia. España.
1
2
Summary.- Topiramate is an approved drug to treat
seizures, but its indications have been extended to other
diseases of the nervous system and as an adjuvant to
chronic pain.
We present four cases of topiramate-induced nephrolithiasis
from 2006-2012 in women whose treatment was
prescribed for pain control and as a mood stabilizer at
doses of 250-300 mg/day. In two cases, the lithiasis was
caused by calcium phosphate (apatite) and in the other
two cases by oxalate and calcium phosphate. The most
common metabolic alteration was an alkaline pH, followed
by hypocitraturia. The drug was discontinued in two
patients; it was reduced in one and was maintained in the
fourth. An increase in fluid and potassium citrate intake was
prescribed. In patients starting treatment with topiramate, an
adequate control and prevention of nephrolithiasis should
be performed due to the risk of mixed tubular acidosis and
hypocitraturia. to the risk of mixed tubular acidosis and
hypocitraturia.
Keywords: Topiramate. Chronic pain. Nephrolithiasis.
Resumen.- El topiramato es un fármaco aprobado para
el tratamiento de crisis convulsivas, pero cuya indicación
se ha extendido a otras patologías del sistema nervioso
y como adyuvante del dolor crónico. En el periodo de
2006-2012 presentamos 4 casos de litiasis renal inducida
por topiramato en mujeres cuyo tratamiento fue prescrito
para control del dolor y como estabilizador del ánimo en
dosis entre 250-300 mg/día. En dos casos la litiasis fue
de fosfato cálcico (apatita) y otros dos casos de litiasis de
oxalato y fosfato cálcico. La alteración metabólica más frecuente fue pH urinario alcalino seguido de hipocitraturia.
Se retiró el fármaco en 2 pacientes, en 1 se redujo la dosis
y en otro se mantuvo. Se indicó aumento de ingesta hídrica
y citrato potásico. En pacientes que inician tratamiento con
topiramato debe realizarse un control y profilaxis adecuada de litiasis renal por riesgo de acidosis tubular mixta e
hipocitraturia.
Palabras clave: Topiramato. Dolor crónico. Nefrolitiasis.
@
INTRODUCTION
CORRESPONDENCE
Miguel Angel Arrabal-Polo
Camino de Ronda, 143 - 4ºF.
18003 Granada (Spain)
[email protected].
Accepted for publication: November 21st, 2013
Topiramate is a sulfamate-substituted monosaccharide
that was approved in 1996 by the FDA for monotherapy
or in combination with other drugs in the treatment
of generalized tonic-clonic or partial seizures; this
medication is also used in the treatment of Lennox–
Gastaut syndrome, bipolar disorder, post-traumatic
psychiatric disorders and alcohol dependence; in
migraine prophylaxis; and as an anti-obesity agent;
moreover, it may be useful in the treatment of bulimia,
obsessive-compulsive disorder, idiopathic intracranial
hypertension, neuropathic pain and smoking cessation
(1).
The therapeutic targets of topiramate are multiple: this
molecule acts as a sodium channel blocker, GABAergic
activity enhancer, glutamate receptor antagonist,
calcium channel modulator, carbonic anhydrase
285
S. Merino-Salas, M. A. Arrabal-Polo, M. C. Cano-Garcia, et al.
isoform inhibitor and proton excretion inhibitor in the
distal tubule of the nephron. These last two actions
can cause a lack of urinary acidification due to a
loss of the action of carbonic anhydrase types II and
IV (2) and of proton excretion, which leads to a 10fold increase in the lithogenic risk (1). The inhibition
of carbonic anhydrase produces metabolic acidosis
and the inability to achieve urinary pH acidification,
along with hypocitraturia and hypercalciuria, which
are lithogenic risk factors (3).
The aim of this study is to present the incidence of
nephrolithiasis in our center caused by topiramate after
its administration for different pathologies.
CASES DESCRIPTION
In the 2006-2012 period, we received four patients in
the urolithiasis and endourology units of our hospital
treatment center, all of them with nephrolithiasis treated
with topiramate with no history of nephrolithiasis
previously known or studied.
We retrospectively collected the clinical and metabolic
features that patients showed at the time of lithiasis
diagnosis when they were taking the aforementioned
drug and were diagnosed with nephrolithiasis by
clinical and radiological studies.
The main variables analyzed in the study were the cause
for topiramate prescription, daily dose, time from the
onset of treatment until the diagnosis of lithiasis, type
of treatment performed to solve the lithiasic episode,
necessary ancillary procedures, main metabolic
alterations encountered, lithiasic composition and
subsequent recommendations given to patients. The
main demographic and clinical features of the patients
are shown in Table I.
The four patients received at our center were women
aged between 30 and 72 years whose main cause of
drug prescription was as an adjuvant in the treatment
of chronic pain. The main composition of the lithiasis
was calcium phosphate (carbonate apatite) in three
cases, whereas in the fourth case, the composition
was mixed (oxalate and calcium phosphate). The
most frequently encountered urinary disorder was
hypocitraturia, which in certain cases was associated
with hypercalciuria (Table II). In three cases, the lithiasis
was solved by extracorporeal shock wave lithotripsy
(ESWL), and in one case, it was necessary to perform
a nephrectomy due to sepsis and an absence of renal
function observed in a diuretic renogram. In two cases,
the drug was discontinued and in all cases, different
dietary recommendations were provided (Table II).
DISCUSSION
Since its introduction and FDA approval, topiramate has
become a widely used drug with very different purposes,
including use as a mood and impulse stabilizer, pain
adjuvant, anticonvulsant and antimigraine agent, among
others. In phase III studies, topiramate was shown to
produce nephrolithiasis, increasing the risk by two- to
fourfold in these patients (1, 3). The etiopathogenesis
of calculus formation is not completely known. Multiple
Table I. Cases description in patients treated with topiramate.
Case 1
Case 2
Case 3
Case 4
Woman
Woman
Woman
Woman
Age (years)
54
72
49
30
Previous history of stones
No
No
No
No
Time first episode
10
24
8
12
Chronic head pain
Adjuvant treatment
Fibromialgia and
Personality
(migraña)
chronic pain
estabilizador del
trastorn
Sex
(months)
Cause of
prescription
ánimo
Doses (mg/day)
300
250
300
300
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CALCIUM NEPHROLITHIASIS INDUCED BY TOPIRAMATE
factors are assumed to play causative roles, such as
the inhibition of carbonic anhydrase isoforms II and
IV, simulating the action of acetazolamide (4), which
causes a hyperchloremic acidosis with a normal anion
gap (1), with a decrease in the blood levels of the
HCO3- anion, and, importantly, a decrease in urinary
citrate and urinary alkalinization (2), a mechanism
similar to a mixed renal tubular acidosis (1,5). Theses
effects are reversible upon discontinuation of the
drug, although the metabolic alteration it produces,
particularly hypocitraturia, may persist for a time (16).
The most common lithiasis is calcium phosphate (7),
which can sometimes be associated with oxalate, as
was observed in certain of our patients (1, 2). However,
in other studies it has been observed that oxaluria
may decrease, and therefore, the presence of calcium
oxalate may be more related to the hypercalciuria that
can occur (3).
The frequency of nephrolithiasis formation secondary
to drugs is quite low, comprising approximately 0.5%
of all cases of lithiasis, and occurs primarily for two
reasons: a) Due to the precipitation of the drug or
its metabolite in the urinary tract and b) Because of
impaired urinary mineral composition due to the
drug. The latter mechanism applies to topiramate (8),
which produces a loss of bicarbonate and sodium
in the urine. This alteration causes a mild metabolic
acidosis and leads to the renal reabsorption of citrate,
thus decreasing the levels of this ion in the urine and
reducing its inhibitory effect on the precipitation of
crystals of calcium phosphate and oxalate (9). Action
on the distal tubules has also been attributed to
topiramate, inhibiting proton excretion and leading to
an alkaline urine (1), especially in circumstances that
cause acidemia (10).
Although the incidence of this adverse side effect of
topiramate occurs in a small percentage of patients
(1), a major lithogenic risk associated with the drug
has been observed in patients with a family history
of nephrolithiasis, urinary anatomic abnormalities
or urinary mineral excretion anomalies. In general,
lithogenic risk groups should be identified and a
prophylactic treatment and clinical follow-up should be
instituted for these groups (2-3).
Table II. Description of characteristics of stones, metabolic alterations, and treatment performed in patients with
lithiasis induced by topiramate.
Case 1
Case 2
Case 3
Case 4
Stone composition
Calcium oxalate and
phosphate
Calcium phosphate
Calcium
phosphate
Calcium oxalate
and phosphate
Principal urinary
alteration
Hypocitraturia
Hypercalciuria
Urinary alkaline pH
Hypocitraturia
Urinary alkaline pH
Hypocitraturia
Urinary alkaline
pH
Hypercalciuria
Urinary alkaline
pH
5 SWL sessions
Nephrectomy
1 SWL session
1 SWL session
Auxiliary procedures
No
Yes (Percutaneous
nephrostomy)
No
No
Suspend Topiramate
Yes
Yes
No (decrease the
dose to 50mg/
day)
No
Definitive treatment
Reccomendations
· Hydric ingestion
· Normocalcic diet
(1000 mg/day of
calcium)
· Potassium citrate
· Hydric ingestion · Hydric ingestion · Hydric ingestion
· Potassium citrate · Potassium citrate
· Normocalcic
· Pregabalina instead
diet (1000 mg/
topiramate
day of calcium)
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S. Merino-Salas, M. A. Arrabal-Polo, M. C. Cano-Garcia, et al.
In the four cases presented, we observed abnormalities
in the urine metabolic and mineral analysis, highlighting
the presence of alkaline pH in the four women, along
with hypocitraturia and hypercalciuria in certain
of them. In three cases, it was necessary to perform
instrumental treatment by ESWL due to the size and
morphology of the lithiasis; moreover, nephrectomy
was necessary in one case due to kidney failure and
terminal hydronephrosis. Although this change was not
always possible, topiramate was discontinued in two
cases; in another case, the same dose was maintained,
and the dose was reduced in the fourth case. It is often
difficult to determine at what drug dose the lithogenic
risk increases in a significant manner or the duration of
treatment that induces a higher prevalence of lithiasic
disease because the available data in the literature are
sometimes scarce and heterogeneous; in certain studies,
even the prevalence of asymptomatic lithiasis is very
high with respect to other studies (11). In the literature,
there are no defined criteria that indicate a forced
withdrawal of the drug; rather, this option depends on
the adequate control of the epileptic disease or pain
for which the topiramate was prescribed (1, 3, 12).
In the case of increased lithiasic risk with inability to
withdraw the drug, potassium citrate is recommended
to prevent recurrence (1,-2, 10); we prescribed this
treatment in three patients. In addition to continuation
or discontinuation of the drug, follow-up is essential,
and prophylaxis must be performed, increasing water
intake and limiting sodium intake, as the relapse rate is
greater than 25% (1, 3, 10).
However, prospective studies are needed, with an
extended follow-up period, including a basal study
before the onset of drug intake to assess the actual
prevalence and incidence of topiramate in the
development of nephrolithiasis as well as the dose
and time elapsed between the onset of treatment and
development of the calculus.
CONCLUSION
The occurrence of nephrolithiasis produced by
topiramate is typically caused by a mixed mechanism
of tubular acidosis that mainly produces hypocitraturia
and alkaline pH, thus favoring the precipitation of
calcium phosphate salts and to a lesser extent, calcium
oxalate. It is necessary to monitor and control patients
starting treatment with this drug, especially if they
have a family or personal history of nephrolithiasis. In
general, we recommend an increase in water intake
and supplementation with potassium citrate as a
standard prophylaxis.
REFERENCES AND RECOMMENDED READINGS
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