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Background and objective: Severe edema in children with nephrotic syndrome (NS) may be associated with volume
contraction (VC) or volume expansion (VE). Usually, severe edema in children is treated with intravenous (IV) albumin and
diuretics, which is appropriate for VC patients. However, in VE patients, this can precipitate fluid overload. The objective of
this study was to evaluate treatment of severe edema in NS with diuretics alone.
Design, setting, participants, & measurements: Thirty NS patients with severe edema were enrolled in this prospective study
in two phases. VC was diagnosed based on fractional excretion of sodium (FeNa) <1%. VC patients received IV albumin and
furosemide. VE patients received IV furosemide and oral spironolactone. On the basis of phase 1 observations, FeNa <0.2%
identified VC in 20 phase 2 patients.
Results: All phase 1 patients had FeNa <1%. Phase 1 patients when reanalyzed based on a FeNa cutoff of 0.2%; it was noted
that VC patients had higher BUN, BUN/creatinine ratio, urine osmolality, and lower FeNa and urine sodium compared with
VE patients. Similar results were observed in phase 2. VC patients had significantly higher renin, aldosterone, and antidiuretic
hormone levels. In phase 2, 11 VE patients received diuretics alone and 9 VC patients received albumin and furosemide. There
was no difference in hospital stay and weight loss in VC and VE groups after treatment.
Conclusions: FeNa is useful in distinguishing VC versus VE in NS children with severe edema. The use of diuretics alone
in VE patients is safe and effective.
Clin J Am Soc Nephrol 4: 907–913, 2009. doi: 10.2215/CJN.04390808
I
diopathic nephrotic syndrome (NS) is a common renal excretion leading to sodium/water retention and thereby hy-
disease in children. Children with severe edema are usu- pervolemia and edema (8 –11). The underfill hypothesis is be-
ally hospitalized and treated with intravenous (IV) albu- lieved to be more common (7,12). Also, clinically it is not
min and diuretics. In contrast to adults, children are often more possible to differentiate severely edematous NS patients with
severely hypoalbuminemic and edematous, necessitating hos- intravascular volume expansion (VE) from those with intravas-
pitalization and IV albumin administration. Albumin is rou- cular contraction (VC) (7,12). Hence, the pediatric practitioners
tinely used in children because of (1) low serum oncotic pres- are reluctant to only treat the former group of patients with
sure due to hypoalbuminemia, (2) reports of diuretic resistance diuretics. The objective of this study was to evaluate the use of
and decreased efficacy in NS (1– 4), (3) increased diuresis when diuretics alone for the treatment of severe edema in a subset of
diuretics are given after IV albumin (1,5,6), and (4) a reluctance children with NS, identified as VE.
to treat patients with diuretics only because of concerns about
dehydration and increased risk of thromboembolic complica-
tions. Materials and Methods
This is a prospective cohort study of children admitted to the pedi-
The routine use of albumin for severe edema (7) in children
atric nephrology service at the Children’s Hospital of Michigan with NS
with NS is based on two mutually exclusive hypotheses pro-
and severe edema (October 2003 to August 2006). The study, which was
posed for the pathogenesis of edema (8 –11). According to the approved by the Human Investigation Committee at Wayne State
underfill hypothesis, severe hypoalbuminemia decreases intra- University, was conducted in two phases. The difference between the
vascular oncotic pressure, leading to circulatory volume deple- two phases was the criteria used for differentiating VE and VC patients.
tion and subsequent sodium/water retention (8 –11). The over-
fill mechanism proposes a primary renal defect in sodium
Definitions
NS. NS was defined as the presence of profound proteinuria (ran-
dom urine protein creatinine ratio ⬎3.0) (13), hypoalbuminemia (serum
Received August 28, 2008. Accepted February 23, 2009.
albumin ⱕ2.5 g/dl), and edema.
Published online ahead of print. Publication date available at www.cjasn.org. Severe Edema. Severe edema was defined as evidence of 3⫹ or more
pitting edema and ascites. (Pitting edema graded by study personnel on
Correspondence: Gaurav Kapur, Children’s Hospital of Michigan, Carman and
Ann Adams Department of Pediatrics, 3901 Beaubien Boulevard, Detroit, MI a scale of 0 to 4, with 0 being no edema and 4⫹ being grossly swollen
48201. Phone: 313-745-5604; Fax: 313-966-0039; E-mail: gkapur@med.wayne.edu leg with prolonged pitting upon pressure).
boys) included in phase 2 was 7.6 ⫾ 4.7 yr. The racial distribu-
(ml/min/1.73
tion of phase 2 patients included 9 (45%) black/African Amer-
GFR ican and 11 (55%) caucasian. The main presenting symptoms
124
124
104
109
160
142
165
140
160
149
m2)
were generalized swelling (100%) and decrease in urine output
(100%). None of the patients upon presentation had diarrhea,
vomiting, increased thirst, dizziness, postural hypotension,
FeNa
0.03
0.31
0.02
0.01
0.51
0.05
0.18
0.58
0.58
0.01
muscle cramps, orthostatic hypotension, or delayed capillary
refill. On the basis of FeNa, these patients were grouped as VC
(mg/dl) (mMol/L) (mOsm/kg) Creatinine (mOsm/kg) Creatinine (mMol/L)
5
116
5
5
83
18
87
95
59
5
parison between the two groups before treatment is presented
in Table 2. Noteworthy were statistically significant higher
serum BUN, BUN/creatinine ratio, urine osmolality, and
UOsm/SOsm in the VC group as compared with the VE group.
Protein/
Urine
5.99
5.88
28.0
15.5
54.9
12.1
2.4
13.0
36.7
12.2
Also VC patients had statistically significant lower FeNa and
spot UNa. During both phases, there was no significant differ-
ence in the mean serum albumin and urine protein/creatinine
Osmolality
512
834
900
1270
454
1163
926
581
387
1020
47.5
13.3
45.0
36.6
32.5
31.6
33.3
30.0
30.0
37.5
280
293
281
295
287
305
292
288
294
285
0.40
0.90
0.40
0.60
0.40
0.60
0.30
0.50
0.40
0.40
of FeNa.
SBP/DBP, systolic blood pressure/diastolic blood pressure.
1.5
2.2
1.3
1.3
1.4
1.6
2.0
1.5
1.7
1.9
3/M
14/M
8/M
8/M
15/M
4/M
8/M
5/M
3/F
Table 2. Comparison of laboratory results at admission of VC group (FeNa ⬍0.2%) and VE group (FeNa ⱖ0.2%)
Phase 1a Phase 2b
Laboratory Result
VC VE P VC VE P
New-onset NS 3 3 8 9
Infrequent relapsing NS 0 1 1 2
Frequently relapsing NS 2 1 0 0
Age (years) 6.5 7.4 0.77 5.8 9.1 0.13
HR before treatment (beats/min) 103.2 81.0 0.07 96.8 93.9 0.68
SBP before treatment (mmHg) 111.2 109.8 0.9 108.9 114.3 0.29
BUN (mg/dl) 18.6 12.4 0.00 16.4 11.7 0.05
BUN/creatinine 39.7 27.8 0.03 36.9 21.3 0.01
Hb at admission (gm/dL) 15.2 13.8 0.16 13.5 12.1 0.05
Hct at admission (%) 43.0 40.2 0.31 39.5 36.0 0.06
Sodium (mMol/L) 129.2 135.0 0.05 134.2 136.3 0.19
Albumin (gm/dl) 1.5 1.8 0.23 1.71 1.69 0.97
Serum osmolality (mOsm/kg) 289.2 290.8 0.75 290.7 290.5 0.97
Urine osmolality (mOsm/kg) 973.0 636.4 0.08 1026.0 621.1 0.00
UNa (mMol/L) 7.6 88.0 0.00 7.1 96.1 0.00
Urine protein/creatinine ratio 24.1 13.3 0.33 15.3 15.2 0.33
UOsm/SOsm 3.3 2.2 0.07 3.5 2.1 0.00
FeNa 0.02 0.43 0.00 0.02 0.61 0.01
Admission GFR (ml/min/1.73 m2) 125.6 149.6 0.07 136.8 128.4 0.47
PRA (ng/dl per h) 553 179 0.00
Serum aldosterone (ng/ml) 29.4 3.4 0.01
Serum ADH (pg/ml) 5.9 1.6 0.00
a
Results for phase 1 (VC group, n ⫽ 5; VE group, n ⫽ 5).
b
Results for phase 2 (VC group, n ⫽ 9; VE group, n ⫽ 11).
Table 3. Treatment response of VC patients treated with IV albumin (VC; n ⫽ 9, left panel) and VE patients with
treated with diuretics only (VE; n ⫽ 10a, right panel) during phase 2. The P value represents paired t test
comparison within each group before and after treatment
Patients with FeNa ⬍0.2% Patients withFeNa ⱖ0.2%
and Treated with IV and Treated with Diuretics
Result albumin (n ⫽ 9) Only (n ⫽ 10a)
Mean P Mean P
Table 4. Outcome results of the study patients with FeNa ⱖ0.2% and treated with diuretics alone and of the
patients with FeNa ⬍0.2% treated with IV albumin followed by diuretics
Diuretics
Result IV Albumin followed by Diuretics P
Onlya
Percentage weight loss after day 1 of 4.06 ⫾ 2.60 2.63 ⫾ 1.93 0.13
hospitalization
Percentage weight loss at the end of 7.37 ⫾ 3.47 8.92 ⫾ 4.80 0.37
treatment
Duration of hospitalization 3.30 ⫾ 0.82 4.04 ⫾ 2.34 0.29
a
One patient that was switched from diuretics alone to IV albumin/diuretics was excluded.
(18,19,30). In their studies, mean FeNa in NS patients with early vasoactive hormones supported our hypothesis that avid so-
relapse with hypovolemic symptoms was 0.3%, notably lower dium retention is indicative of hypovolemia and patients not
than that seen in those without hypovolemic (1.1%) symptoms having avid sodium retention are non-hypovolemic. Treatment
(18,30). The difference in the FeNa between their study and trends in the VC and VE group on Hb/Hct, HR, creatinine, and
ours is most likely related to sodium intake of the patients. no side effects in the VE group receiving diuretics alone also
FeNa for patients on a normal home diet (sodium intake 125 to supported study categorization based on FeNa.
150 mEq/d) and normal GFR is 0.2 to 0.3% (17). Therefore, Another study (mean age 5.97 ⫾ 2.9 yr) evaluated volume
phase 1 results were reanalyzed and criteria for VC and VE load in minimal-change NS by measuring inferior vena cava
changed for study phase 2 using a cutoff of 0.2% for FeNa. diameter on echocardiography and treating all patients with
Hormonal evaluation in the study groups coupled with a sig- diuretics alone (furosemide and/or amiloride) (32). These
nificant inverse correlation between FeNa and levels of the patients underwent a starvation period before evaluation
912 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 907–913, 2009
(32), unlike our study cohort who was on a non-restricted nisms in the impaired salt excretion of experimental ne-
home diet. phrotic syndrome. J Clin Invest 71: 91–103, 1983
The suboptimal response to diuretic-only treatment in one 11. Meltzer JI, Keim HJ, Laragh JH, Sealey JE, Jan KM, Chien
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12. Schrier RW, Fassett RG: A critique of the overfill hypoth-
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symptoms of dehydration. It is possible that the patient would Nagajothi N, Racusen LC, Scheel PJ Jr, Brancati FL, Fine
have continued to respond to diuretics alone because the pa- DM: Nephrotic range proteinuria and CD4 count as non-
tient did respond to diuretics alone by losing 2% of the admis- invasive indicators of HIV-associated nephropathy. Am J
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