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Minimizing Growth Suppression in
Children with Steroid-sensitive
Nephrotic Syndrome
Alex Constantinescu, MD
Director, Pediatric Nephrology
Joe DiMaggio Children’s Hospital
Hollywood, Florida
Outline
• Define steroid-sensitive nephrotic syndrome• Define steroid-sensitive nephrotic syndrome
• Disease course – relapse pattern
• Side effects of steroids
• Growth suppression data
• Strategies to prevent growth-suppression
Definition
• “Nephrotic Syndrome = clinical entity having
multiple causes, characterized by high glomerular multiple causes, characterized by high glomerular
membrane permeability, manifested by massive
proteinuria and lipiduria, …in the absence of
depressed GFR.” (G. Schreiner, 1963)
• Upr excretion rates are usually >40 mg/m2/hr in
children, or >1 g protein/g creatinine (random
sample)
Childhood Nephrotic
Syndrome (NS)
• Most common
cause: minimal
change disease
(MCD)(MCD)
• First line of
therapy:
corticosteroids –
daily followed by
alternate day
• Many protocols ISKDC – 1978, 1981
Types of Nephrotic
Syndrome
• Based on steroid sensitivity:
– steroid-responsive (protein-free)
• Infrequent relapsers (<2 in a year)
• Frequent relapsers (2 in 6 months, or >3 in a year)
• Steroid-dependent (within 1 month after steroids stopped or while on alternate day therapy)
– steroid-resistant (no response after 4-6 weeks)
Systems Affected by
Steroid Therapy
• Gastro-intestinal (gastritis)
• Cardio-vascular (hypertension)
• Hematological (leukocytosis, immunosuppression)
• Neuro-psychological (psychosis, depression)
• Bone metabolism (osteoporosis)
• Skin and Eye (striae, cataracts)
• Glucose metabolism (diabetes, cushingoid body habitus)
• Growth – suppression, leading to short stature
Steroid-induced Growth Suppression -
Mechanisms
Hypothalamus
Pituitary
GHRH Somatostatin+ -Steroids
+
-Pituitary
Liver
Growth plate
Connective tissue
Adrenal gland
Pulsatile GH secretion
+
IGF-1
+
↓↓↓↓ GH receptor
expression and
binding;
↓↓↓↓ IGF-1 activity-
-
-
Impact of Short Stature
• Body image• Body image
• Psychosocial adaptation
• Bone metabolism
• Pubertal development
• Single center - Robert Wood Johnson Medical School, New Brunswick, NJ
• We sought to identify:– Degree of growth suppression caused by steroid therapy in children with NS, presumed
Growth in Children with
Nephrotic Syndrome
– Degree of growth suppression caused by steroid therapy in children with NS, presumed to have MCD
– Moment of “maximum impact”
– Frequency of this adverse effect
– Is this long-lasting?
• Patients with focal segmental sclerosis on biopsy, as well as those with other steroid-resistant forms of NS were excluded
• Data entered in GrowTrack v 1.0.6 Software (Genentech, Inc.)
• Standard deviation scores (SDS) for Ht (HtSDS) and GR (GRSDS), were calculated and compared with normal values for age and gender
Cederbaum N, Constantinescu A. J Investigative Medicine 50:187, 2002.
Results
• 69 children with complete growth data• 69 children with complete growth data
• 44 boys, 25 girls, M:F=1.8:1
• Age range 1-17.8 years
• Younger than 6 yrs of age 75.4%
• Older than 6 yrs of age 24.6%
Ht SDS in Children
with Nephrotic Syndrome
1
2
3
4
Ht
SD
S
-4
-3
-2
-1
0
Time
Ht
SD
S
3m 6m 1y 2y 3y 4y 5y 6y 7y 8y 9y 10y 11y
-1.8 SD
HtSDS in Children with Nephrotic Syndrome
23456
HtS
DS
HtSDS in M<6y (n=31)
HtSDS in F<6y (n=21)
-3-2-1012
HtS
DS
HtSDS in F<6y (n=21)
HtSDS in M>6y (n=13)
HtSDS in F>6y (n=4)
3 mos 6 mos 12 mos
Growth Rate SDS in Children with Nephrotic
Syndrome
4
6
8
10
12
Gro
wth
Ra
te S
DS
-8
-6
-4
-2
0
2
4
Time
Gro
wth
Ra
te S
DS
3m 6m 1y 2y 3y 4y 5y 6y 7y 8y 9y 10y 11y 12y
Growth Velocity Rate (GVR) in
Children with NS
10.0
15.0
20.0
p=0.029
GVR for 3-6-12 mo.
0.0
5.0
3 m 6 m 12 m
0.0
5.0
10.0
15.0
20.0
3 m 6 m 12 m
MF
M F M F
GVR - M vs. F <6 yrs.
p=0.0190.0
5.0
10.0
15.0
20.0
3 m 6 m 12 m
MF
M
F
M
GVR - M vs. F >6 yrs.
Long-term Linear Growth in Children
with SD or FR Nephrotic Syndrome
• 56 children (37 M, 19 F) followed-up for 10.5±3.1 yrs
• SD = 42, FR = 14
Emma F, et al. Pediatr Nephrol 18:783-8, 2003
• SD = 42, FR = 14
• Average growth loss was 0.66±0.89 SD
• 2 patients fell below -2SD
• 23 reached final height with loss of:
• 0.92±0.8 HtSDS from the onset of disease (p=0.001)
• 0.68±0.7 HtSDS from predicted target height (p=0.001)
• Correlated with steroid dose – higher risk if more than 6 months
• Growth velocity rate lower in younger children, <4 yrs
So far …
• Reviewed the impact of steroids on growth
• How can we minimize exposure to steroids?
– Lower the frequency of relapse
– Lower the initial dose of steroids
• Can we tailor the therapy?
Tailor Therapy
• Arbeitsgemanschaft für Pädiatrische Nephrologie published in 1998, in Lancet, the finding that 6 weeks of daily steroids + 6 weeks of alternate day published in 1998, in Lancet, the finding that 6 weeks of daily steroids + 6 weeks of alternate day steroids appear to reduce the relapse rate – larger cumulative steroid dose
• Niaudet and Habib in 1994 introduced cyclosporine in the treatment of NS, as steroid-sparing agent.
• No sustained remission, additional side effects
• Segregate according to “days to remission” ?
Predictors of Frequent
Relapses in NS
• Mishra et al. J Trop Pediatr 2013; 59:343-349
– 60% relapse (150 – 1 year) – young age and longer time to – 60% relapse (150 – 1 year) – young age and longer time to
remission predicts frequent relapsing course
• Harambat et al. Pediatr Nephrol 2013; 28:631-638
– 70% FR/SD (120 – 6.7 years) – longer time to remission
predicts use of steroid-sparing agents
• Sureshkumar et al. Pediatr Nephrol 2014; 29:1039–1046
– 66% relapse (129 – 1 year) – male, young age, short time to
first relapse predicts FR
Distribution Based on
Days to Remission
14161820
No
. o
f P
ati
en
ts
02468
101214
No
. o
f P
ati
en
ts
1 wk 2 wks 4 wks >4 wks
Days to Remission
IR FR+SD
Constantinescu et al, Pediatrics 2000; 105:492-495
Disease Course in Patients
with Hematuria
Relapse pattern vs. Days to
remission
0
5
10Nr.
patients
with
hematuria
remission
0-7 >7 IR
FR+SD
Constantinescu et al, Pediatrics 2000; 105:492-495
Disease Course in Patients
without Hematuria
Relapse Pattern vs. Days to remission
Predicts
0
2
4
6
8
10
12
14
16
Nr.
Patients
without
hematuria
0-7
>7
IRFR+SD
Constantinescu et al, Pediatrics 2000; 105:492-495
*
Predicts
infrequentrelapsing
course
* p<0.05
MDR-1 Gene Polymorphism
• MDR-1 encodes for P-glycoprotein-170, a biological barrierbiological barrier
• Up-regulated MDR-1 gene expression correlates with a poor response to steroids
• MDR-1 polymorphism studies – in NS, TT genotype associated with a delayed response to steroids and a FR course
Wasilewska, A, et al. Pediatr Nephrol 22:44-51, 2007
Our Approach to Minimize
Exposure to Steroids
• Establish the diagnosis of nephrotic syndrome
• Determine if hematuria is present at the onset• Determine if hematuria is present at the onset
• Start steroid therapy
• Parents call first day urine is protein-free
• With hematuria, steroids 6 wks QD + 6 wks QOD
• Without hematuria AND response in >1 wk, therapy for 6 wks QD + 6 wks QOD
• Without hematuria AND response in <1 wk, therapy only for 4 wks QD + 4 wks QOD
• No response in 4 wks - kidney biopsy
Our Data
• 2006 – present: 60 children with steroid-sensitive NS
• 26 with complete growth records• 26 with complete growth records
• 34 – either recently diagnosed, incomplete records, or lost to follow-up
• Relapse pattern noted (IR, FR/SD)
• Initial steroid course (4+4 or 6+6)
• Ht SDS at the last visit
Ht SDS - A Function of Relapse
Pattern and Steroid DoseHt SDS in Children with NS
-0.4
-0.2
0
0.2
0.4
IR 4+4 IR 6+6 FR/SD 6+6
(pre-SSA)FR/SD 6+6
(on SSA, last)
5 11 10
*10
#,¶
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
Ht S
DS
SSA = patient receiving steroid-sparing agent (tacrolimus or cyclosporine)
* p = 0.039 between IR 4+4 and pre-SSA
# p = 0.0000133 between pre-SSA and last visit on SSA
¶ p = 0.29 between IR 4+4 and FR/SD 6+6 at last visit on SSA
Conclusions
• Steroids have growth-suppression potential
• Attempts needed to minimize the exposure• Attempts needed to minimize the exposure
• Change in daily dose is not recommended
• Cumulative dose can be decreased by predicting
the infrequent relapsing pattern based on:
– response within one week and,
– the absence of hematuria.
• Prospective studies needed