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Allergology International. 2013;62:381-383
DOI: 10.2332!
allergolint.12-LE-0531
Dear Editor
A Puzzling Cause of Relapsing
Proteinuria:When Treatment Causes
the Disease
Nephrotic syndrome is one of the most common renal diseases and is associated with heavy proteinuria
and hypoalbuminemia. 1 These patients are treated
mainly with prednisolone (PSL). However, several patients with chronic renal disease have been reported
to develop PSL-induced proteinuria. 2 In this report,
we present the case of a 10-year old girl with steroidsensitive nephrotic syndrome who developed proteinuria during PSL treatment.
CASE PRESENTATION
A 10-year-old girl first developed steroid-sensitive
nephrotic syndrome at the age of 3 years and suffered from frequent relapses thereafter. She was admitted to our hospital at the twelfth relapse. In addition, she suffered from food allergies (allergy to eggs,
milk, shrimp, and salmon roe), bronchial asthma, and
atopic dermatitis ( treated with topical betamethasone). Physical examination was unremarkable other
than mild pitting edema on both lower extremities. At
the time of admission, her blood pressure was 89!
59
mmHg; heart rate, 72 beats!min; and temperature,
36.7℃. Laboratory investigations revealed blood urea
nitrogen, 18.9 mg!
dL; serum creatinine, 0.43 mg!
dL;
total protein, 5.1 g!
dL; albumin, 1.5 g!dL; total cholesterol, 277 mg !dL ; and C-reactive protein, < 0.01
mg !dL. Dipstick urinalysis was negative for occult
blood but was 4 + for protein. The urinary proteincreatinine ratio (u-TP!Cr) in early morning sample
was 8.6 g!
g Cr. These findings were typical of relapsing nephrotic syndrome. The regimen specified by
the International Society of Kidney Disease in Childay for 3 days after the urine is
dren (60 mg!
m2 PSL!
found to be protein-free, followed by the administration of 40 mg!
m2 PSL on alternate days for 4 weeks)
was followed for treating her relapse.3 Proteinuria decreased to a u-TP !Cr value of 3-4 g !gCr, but she
could not achieve complete remission even after administering 60 mg!
m2 PSL daily for 4 weeks. The patient was considered to be suffering from steroidresistant nephrotic syndrome. 1 We reduced the dosage of PSL to 40 mg!
m 2 every alternate day. 3 Thereafter, proteinuria decreased to 0.3-0.5 g!
g Cr, but she
did not achieve remission. However, we observed
that proteinuria was not present on the morning after
the day PSL was not administered. This led us to suspect PSL-induced proteinuria, and we discontinued
PSL. Thereafter, the patient promptly achieved complete remission (Fig. 1).
We performed drug-induced lymphocyte stimula-
Allergology International Vol 62, No3, 2013 www.jsaweb.jp!
LETTER TO THE EDITOR
tion test (DLST) with only PSL without any additives
such as cornstarch ; PSL formulation in which the
cornstarch excipient is present; and methylprednisolone ( mPSL ) , a formulation that does not contain
cornstarch, to identify the cause of these puzzling relapses that occurred following PSL administration.
The test was negative with both only PSL and mPSL,
whereas cornstarch yielded a positive DLST ( Table
1 ) , confirming that cornstarch was the causative
agent for the PSL-induced proteinuria. During subsequent relapses, she achieved prompt remission with
mPSL, and this confirmed that she was in fact steroidresponsive.
DISCUSSION
This report presents the case of a 10-year-old girl with
steroid-sensitive nephrotic syndrome who developed
proteinuria with PSL treatment. We first suspected an
allergic reaction to PSL itself. There have been some
previous reports on the acute effects of PSL on proteinuria. Using an alternate-day regimen, a typical fluctuating pattern of protein excretion was noted, with
an increase of protein excretion on PSL days and a
decrease on non-prednisolone days. 4,5 Wetzels et al.
reported that, after PSL administration, urinary total
protein excretion increased in all patients from a
mean of 4.89 ± 0.59 mg!min to 9.09 ± 0.99 mg!min
significantly. 6 They concluded that this increase cannot be explained by changes in renal hemodynamics
or tubular protein reabsorption, and which therefore
must be the result of a change in glomerular permselectivity characteristics. Moreover, Reichert et al. reported that, after PSL administration, total proteinuria
increased from 6.66 ± 4.42 to 9.37 ± 6.07 mg!min in
26 patients with nephrotic syndrome. 7 By analyzing
the excretion of proteins with different charge and
weight (albumin, transferrin, IgG, IgG 4, and beta2microglobulin), it became apparent that the increase
of proteinuria was the result of a change in size selectivity rather than a change in glomerular charge selectivity or tubular protein reabsorption. Neither the
renin-angiotensin axis nor prostaglandins seem to be
involved in these effects of PSL on proteinuria. However, in our patient, DLST demonstrated that the adverse effect was not caused by the steroid itself but
by the cornstarch present in the PSL formulation.
Substituting PSL with cornstarch-free mPSL led to
rapid resolution of proteinuria. It is true that PSL
could increase proteinuria transiently in some nephrotic syndrome patients as previously reported. However, this mechanism may be completely different
from our case because our case showed DLST positivity to cornstarch and some allergic reaction is supposed to be involved in the onset mechanism of proteinuria. We speculated that this effect is due to modification of the glomerular basement membrane permselectivity due to permeability factor secreted by T-
381
Kanai H et al.
PSL 60 mg/m2/day
Proteinuria
(3+)
(2+)
(+)
(±)
(−)
4/4 4/5
4/6 4/7
4/8
4/9 4/10
4/11 4/12 4/13 4/14 4/15 4/16
PSL 40 mg/m2/every other day
PSL free
Proteinuria
(3+)
(2+)
(+)
(±)
(−)
4/17 4/18 4/19 4/20 4/21 4/22 4/23 4/24 4/25 4/26 4/27 4/28 4/29
Fig. 1 Proteinuria levels during administration of 60 mg/m2 prednisolone (PSL)
daily (upper panel) and 40 mg/m2 PSL every alternate day (lower panel). Proteinuria persisted in the former case but decreased in the latter case. Moreover, proteinuria appeared only on mornings after the days she received PSL. Complete remission was achieved when PSL was discontinued. Proteinuria was measured by
dipstick.
Table 1 Result of drug-induced lymphocyte stimulation test
Prednisolone
Methylprednisolone
Corn-starch
Control
Measurements
(cpm)
S.I.
(%)
Result†
345
273
554
221
156
123
250
Negative
Negative
Positive
S.I., Stimulation Index.
†S.I. (%) <180 was considered as a negative result, while S.I.
(%) >180 was considered as a positive result.
lymphocytes. Because cornstarch was positive in
DLST, a type IV allergic reaction to cornstarch was
inferred. Shalhoub et al. proposed that minimalchange nephrotic syndrome is caused by abnormal Tcell function resulting in the secretion of a circulating
chemical mediator toxic to glomerular basement
membrane. 8 We speculated that the allergic reaction
involved only kidney because she developed relapse
of nephrotic syndrome, and T-cell was activated that
secreted the cytokine that increased the permeability
of the glomerular basement membrane. We thought
that the other allergic symptoms were suppressed by
PSL itself. Moreover, the rapid appearance and disappearance of proteinuria was probably because of the
small amount of cornstarch in the PSL formulation,
382
the short half-life of PSL, and the rapid removal of
permeability factors from the body.
In addition to an allergic reaction to an excipient,
such as cornstarch in our case, an allergy to corticosteroids should also be considered in patients who
develop systemic allergic reactions to steroids. Several reports on such untoward effects with topical, inhaled, oral, and parenteral steroids have been published.9,10 Considering the various symptoms of allergic reactions to PSL, identifying the real cause is difficult. An allergic reaction is generally diagnosed
based on the patient’s history by observing the clinical manifestation and by performing skin prick or
patch tests and more elaborate laboratory tests, including DLST. DLST is a highly specific method that
has a potential to identify a specific allergen. Past reports have not identified a specific allergen nor have
they used DLST to confirm whether the allergy is
caused by corticosteroid itself or by an additive in the
formulation.11,12 In this study, we determined that the
cause of proteinuria was the excipient, not the steroid, as mPSL showed a rapid effect.
There is a limitation of this case report. It is well
known that the diagnostic gold standard for allergy is
an antigen challenge test. A careful medical history
paired with in vivo testing such as skin patch testing
often can provide a reliable diagnosis. We also tried
to perform skin patch test in addition to DLST. Unfor-
Allergology International Vol 62, No3, 2013 www.jsaweb.jp!
Puzzling Cause of Relapsing Proteinuria
tunately, we did not get an approval from the patient
and her parents. However, from her clinical course, it
is apparent that she suffered from PSL-induced proteinuria. This observation has a clinical significance
similar to the antigen oral challenge test.
In conclusion, this is the first report that has identified cornstarch as a cause of PSL-induced proteinuria.
This report also addresses three important points.
First, clinicians should be aware of the possibility of
adverse reactions to PSL even when its previous use
has not resulted in any adverse reaction. Second, if
the patient is allergic to the drug, DLST should be
performed to confirm whether the allergen is an additive or the steroid itself. Finally, if patients with
steroid-sensitive nephrotic syndrome become resistant to PSL, proteinuria induced by PSL or an excipient in its formulation should be considered, and they
should be treated with another steroid such as mPSL.
Hiroaki Kanai1, Emi Sawanobori1, Anna Kobayashi1,
Kyoko Matsushita1, Kanji Sugita1 and Kosuke Higashida1
1 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Email: hkanai@kind.ocn.ne.jp
Conflict of interest: No potential conflict of interest
was disclosed.
REFERENCES
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children: Clinical aspects. In: Avener ED, Harmon WE,
Niaudet P, Yoshikawa N (eds). Pediatric Nephrology, 6th
edn. Heidelberg: Springer, 2009;667-702.
2. Heymann W, Grupe WE. Increase in proteinuria due to
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steroid medication in chronic renal disease. J Pediatr
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3. International Study of Kidney Disease in Children. The
primary nephrotic syndrome in children. Identification of
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4. Wetzels JF, Gerlag PG, Sluiter HE, Hoitsma AJ, Koene
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6. Wetzels JF, Sluiter HE, Hoitsma AJ, van Munster PJ,
Koene RA. Prednisolone can increase glomerular permeability to proteins in nephrotic syndrome. Kidney Int 1988;
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7. Reichert LJ, Koene RA, Wetzels JF. Acute haemodynamic
and proteinuric effects of prednisolone in patients with a
nephrotic syndrome. Nephrol Dial Transplant 1999;14:917.
8. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder
of T-cell function. Lancet 1974;2:556-60.
9. Kounis NO. Untoward reactions to corticosteroids: intolerance to hydrocortisone. Ann Allergy 1976;36:203-6.
10. Peng YS, Shyur SD, Lin HY, Wang CY. Steroid allergy: report of two cases. J Microbiol Immunol Infect 2001;34:1504.
11. Nahum A, Garty BZ, Marcus N, Shoenfeld T, Levy Y. Severe hypersensitivity reactions to corticosteroids in children. Pediatr Emerg Care 2009;25:339-41.
12. Baeck M, Marot L, Nicolas JF, Pilette C, Tennstedt D,
Goossens A. Allergic hypersensitivity to topical and systemic corticosteroids: a review. Allergy 2009;64:978-94.
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