TREATMENT
OF
THE
NEPHROTIC
SYNDROME
WITH
TRIAMCINOLONE
By Leon Hellman, M.D., Barnett Zumoff, M.D., Arnold Minsky, M.D.,
Norman Kretchmer, M.D., and Benjamin Kramer, M.D.
Sloan-Kettering Institute for Cancer Research, and Departments of Pediatrics, New York
Hospital-Cornell Medical Center and Maimonides Hospital
(Accepted September 29, 1958; submitted July 15.)
This work was supported by grants (H-2157 and A-1323) from the National Institutes of Health, Public Health Service, and a contract (A.T(30-1)-910) with the U. S. Atomic Energy Commission.
ADDRESS: (L.H.) Sloan-Kettering Institute, 410 East 68th Street, New York 21, New York.
PEDIATRICS, April 1959
688
T
RIAMCINOLONE#{176}(9-alpha-fiuoro-16-al-pha-hydroxy-&-hydrocortisone), a syn-thetic steroid, is a recent product of the search for corticosteroids which are more potent and have fewer undesirable
side-effects than hydrocortisone. It differs from hydrocortisone by having a fluorine atom at C-9, a double bond between C-i and C-2, and a hydroxyl group at C-16. The com-pound is of particular interest because the parent substances, fluorohydrocortisone and 1fluorohydrocortisone, are potent “salt-retainers,” whereas the addition of the
hy-droxyl group at C-16 abolishes the salt-retention without interfering with the
anti-inflammatory and glucocorticoid properties
of the compound. Metabolic and clinical studies have shown that triamcinolone has no salt-retaining or hypertensive effects in
doses of 10 to 20 mg/day, which are suffi-cient to produce desirable therapeutic re-sponses in a variety of diseases.’4
These features should make triamcinolone an excellent agent for the treatment of the nephrotic syndrome. Accordingly, the
com-pound was administered to 15 children with the nephrotic syndrome.
SUBJECTS AND PROCEDURE
Of the 15 children (Table I), 4 were fe-males, ranging in age from 1-9 years; ii were
males, ranging in age from 2-5 years. Two of
the children had hypertension; one of these
(BLA) had normal concentration of urea nitro-gen in the blood and normal urea clearance,
* Aristocort#{174} brand used in this study supplied
by Lederle Laboratories Division of the American Cyanamid Company.
whereas the other (DEC) had azotemia. The remaining 13 patients in this series had the nephrotic syndrome in its characteristic form, with all the typical clinical and laboratory
findings, but without stigmata of renal in-sufficiency. The duration of the nephrotic syn-drome in these patients ranged from 0.5 to 36 months.
All patients were hospitalized for preliminary studies, which included history and physical examination, blood count and absolute eosino-phil count, urinalysis, roentgenogram of the chest, electrocardiogram, and determination in the blood of urea nitrogen, sodium, potassium,
CO, content, chlorides, free and esterified cholesterol, and total protein and albumin : glob-ulin ratio.
Following the control period, treatment with triamcinolone was carried out in the hospital, with frequent repetition of clinical examination and biochemical determinations during and after treatment.
The usual course of treatment was 20 mg of triamcinolone daily in five oral doses of 4 mg each. Treatment was continued until all
find-ings in the blood and urine had returned to normal or, if no improvement occurred, for 6 weeks. At the conclusion of the treatment period, the dose of steroid was gradually re-duced over 3 to 4 days and then discontinued. In the cases in which complete remission oc-curred during treatment with triamcinolone, about 30 days were required for all biochemical findings to revert to normal. Four patients in-itially received courses of treatment with
tn-amcinolone of only 15-20 days in duration, and all four experienced partial remission; they were retreated for 30-45 days, and all had a
complete remission. Therefore it is believed
ARTICLES 687
TABLE I
CLINICAL DATA ON PATIENTS TREATED WITH TRIAMCINOLONE*
.
Patient Age
(inS)
Sex
Duration
of
.
D?sease (mo)
BUN
(mg/100 1) m
Serum
Chol. (mg/V%1
ml)
Serum
Alb. (gm/ffxi
ml)
Blood Pressure
Protein-.
urza Result
NIC 9 F 24 9 550 1.2 104/70 4+ Complete remission
PES 35 M 10 13 1192 1.9 110/80 4+ Complete remission
MER 5 M 12 16 766 1 .4 120/70 4+ Complete remission
DOR 4 M 13 13 415 1 .3 96/60 4+ Complete remission
CAS 5 M 23 13 595 1 .0 100/80 4+ Complete remission
DUN 24 M 3 17 596 1 .9 100/60 4+ Complete remission
KAL 14 0.5 10 620 1 .5 110/60 4+ Complete remission
BOE 5 F 10 13 410 1.1 110/70 4+ Completeremission
KLE 1 F 2 15 327 1 .5 90/60 4+ Complete remission
GRA 3 M 0.5 16 440 1.3 110/78 4+ Partialremission
DON 44 M 32 17 620 1 .8 100/70 4+ Partial remission
BIA 84 F 36 15 387 0.9 128/90 4+ Partial remission
DUE 2 M 9 12 511 1.1 110/60 4+ Partial remission
BLA 3 M 18 17 542 1.8 150/112 4+ Partial remission
DEC 4 M 18 20-0 385 1.8 160/100 4+ Failure
* All values were obtained prior to treatment, except for patients PES and MER who were receiving prednisone,
10 and 5 mg/day, respectively.
RESULTS (Table II)
Of the 15 patients treated, 10 had com-plete remission (defined as the induction of a complete diuresis, and return of all
find-ings in the blood and urine to normal). Four patients developed partial remissions (the induction of partial or complete diuresis, with variable improvement in findings in blood and urine, but failure to return corn-pletely to normal). One of the four with partial remissions (BLA, Table I), who had hypertension without azotemia, received two complete courses of triarncinolone
then-apy; the first course was a failure, the see-ond produced a partial remission. In
an-other patient (DEC), with hypertension and azoternia, treatment was a failure and was
not repeated.
The clinical courses of the patients who obtained a complete remission were fairly similar to those observed with other
ster-oids. However, there were some features
worthy of comment:
Duration of Treatment before Diuresis
The typical response was an abrupt
diuresis beginning 10-12 days after the start
of treatment, and resulting in complete dis-appearance of retained fluid in the next 3-4
days. In three patients diuresis was gradual,
TABLE II
RESULTS OF TREATMENT WITH TRIAMCINOLOYE
I. Patients treated: 15
II. Complete remissions: 10
Average age: 4.0 years (range 1-9)
Sex : 7 males, 3 females
Average duration of disease: 9 months (range 0.5-24)
Per cent with duration of disease 12 months or less: 80%
Number with signs of renal failure: 0
III. Partial remissions: 4
Average age: 4.5 years (range 2-8.5) Sex :3 males, 1 female
Average duration of disease: 24 months (range
9-36)
Per cent with duration of disease 12 months or
less: 25%
Number with signs of renal failure: 1
IV. Failures:1
Age: 4
Sex: male
688
At the onset of diuresis, albumin began to beginning slowly between 5 and 10 days after the start of therapy. There were no
clinical or biochemical findings which dis-tinguished patients who responded with a more gradual diuresis from those with an abrupt diuresis.
Two patients who had received 5 and 10
mg/day, respectively, of prednisone and had relapsed while having this therapy, were changed to 20 mg/day of
triamcino-lone; an abrupt diuresis began on the fifth
day of therapy and both proceeded to corn-plete remission. Although the low dose of prednisone was inadequate to prevent
re-lapse, it may have facilitated the
subse-quent response to effective doses of tn-amcinolone. However, it should be em-phasized that delayed effect or “lag period” of steroid therapy in the nephrotic syn-drome is quite variable in duration.
Sodium and Potassium Balance
There were no systematic changes in
serum concentrations of sodium or
potas-sium, and potassium supplements were neither given nor required. In one patient,
in whom quantitative urinary excretion of sodium and potassium was followed, there was no sodium retention and no potassium
loss during therapy. Diuresis was accom-panied by massive increase in urinary ex-cretion of sodium, but little change in excre-tion of potassium. None of the patients showed significant weight gain during the “lag period” prior to diuresis.
The absence of weight gain during the “lag period” suggests that initial expansion
of the total extracellular fluid volume is
not a necessary prerequisite for the induc-tion of diuresis with steroids.
Urinary Abnormalities
During the period of diuresis, the urinary
excretion of protein decreased rapidly and by the time diuresis was complete (in 3-4 days) the urinary findings were usually within normal limits.
Albumin and Globulin in the Serum
increase and globulin to decrease in the serum. Determinations were not obtained
frequently enough to demonstrate the slight increase in serum albumin prior to the on-set of diuresis noted by others.5 It usually
required 3-5 weeks of triarncinolone
then-apy before these values became normal. The return of serum globulin to normal fre-quently lagged behind the improvement in albumin levels.
Cholesterol in the Serum
A small but significant increase in serum cholesterol was often observed during the
“lag period.” This effect is often seen in corticosteroid therapy of many diseases. Co-incident with the onset of diuresis, the
serum cholesterol began to decrease slowly, and it frequently took 4-6 weeks to reach normal (i.e., less than 250 mg/100 ml).
Side-effects
No psychic effects were noted. There was neither exaggeration nor depression of
ap-petite. Acne was not seen. Slight moon facies developed after 4 weeks of therapy in some, but not all, patients. No patient
de-veloped hypertension. In general, triarncino-lone was exceedingly well tolerated.
Duration of Disease and Effect of
Therapy
The patients in whom complete
remis-sions occurred had the nephrotic syndrome for an average of 9 months (range 0.5-24 months), whereas those who obtained only partial remission had had the disease for an
average of 24 months (range 9-36 months). There was no other obvious point of distinc-tion between the two groups. Of the nine patients with disease of less than 1 year in duration and without hypertension, eight
obtained a complete remission as a result of tniamcinolone therapy, while the ninth obtained a partial remission.
Relapses
Of the 10 patients who obtained a com-plete remission during triamcinolone
re-ARTICLES 689
lapses occurred 1-4 months after treatment. Three of these patients responded to a see-ond complete course of triamcinolone
ther-apy with a second complete remission, and a fourth obtained a partial remission. The
fifth has not yet been retreated. At the time of submission of this report, 8 of the original 15 patients were in complete
re-mission. In four of these, the remission was less than 4 months in duration. Four
pa-tients had been in remission for 6, 7, 16 and 21 months. It has not been the authors’
prac-tice to give maintenance doses of steroid following the completion of the course of treatment of 4-6 weeks.
Of the four patients who developed par-tial remission, most had a relapse within 1-2 months. Partial remission should be
con-sidered as essentially a failure because rapid relapse is the rule. The ultimate prognosis
in this group is poor, although occasional complete recoveries are observed.
SUMMARY AND CONCLUSIONS
In this report, only acute remissions of
the nephrotic syndrome following tn-arncinolone therapy are considered. No
con-clusions are drawn regarding the effects of
this treatment on the ultimate fate of these children. With these reservations kept clearly in mind, this experience with 15
chil-dren with the nephrotic syndrome indicates that triamcinolone is a highly effective ther-apeutic agent.
With the 20 mg/day dose employed for 30-45 days in this series, side-effects were
absent except for the occasional appearance
of slight moon facies.
The incidence of complete remission in the entire series was 10 out of 15 patients
(67%). Of patients whose disease was less than 12 months in duration, and who did not have hypertension, eight out of nine patients (89%) had a complete remission.
These results compare favorably with the
experience reported in the literature with
other steroids.#{176} S
The mere induction of acute remissions, no matter how readily or reproducibly, should not be the chief concern in therapy of nephrosis. The ultimate prognosis is still
pessimistic, despite regimens of therapy with currently available steroids.7 A recent report5 suggests that the long-term results of ster&d therapy in the nephrotic
syn-drome might be improved by earlier, more intensive, and more prolonged treatment. It is the present authors’ impression that tn-amcinolone is a useful steroid for such a
program, because of its high potency and minimal side-effects. The doses employed did not cause hypertension or retention of sodium.
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