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

• 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 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)

• 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

Liver

Growth plate

Connective tissue

Adrenal gland

GHRH Somatostatin+ -

Pulsatile GH secretion

+IGF-1

+ GH receptorexpression andbinding; IGF-1 activity

Steroids+

-

-

-

-

Impact of Short Stature

• 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 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

Growth in Children with Nephrotic Syndrome

Cederbaum N, Constantinescu A. J Investigative Medicine 50:187, 2002.

Results

• 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

-4

-3

-2

-1

0

1

2

3

4

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

-3-2-10123456

HtS

DS

HtSDS in M<6y (n=31)

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

-8

-6

-4

-2

0

2

4

6

8

10

12

Time

Gro

wth

Rat

e S

DS

3m 6m 1y 2y 3y 4y 5y 6y 7y 8y 9y 10y 11y 12y

Growth Velocity Rate (GVR) in Children with NS

0.0

5.0

10.0

15.0

20.0

p=0.029

3 m 6 m 12 m

GVR for 3-6-12 mo.

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

FM

GVR - M vs. F >6 yrs.

Long-term Linear Growth in Children with SD or FR Nephrotic Syndrome

Emma F, et al. Pediatr Nephrol 18:783-8, 2003

• 56 children (37 M, 19 F) followed-up for 10.5±3.1 yrs• 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 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

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

02468

101214161820

No.

of

Pat

ient

s

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 Patientswith Hematuria

0

5

10Nr.

patients with

hematuria

Relapse pattern vs. Days to remission

0-7 >7 IR

FR+SD

Constantinescu et al, Pediatrics 2000; 105:492-495

Disease Course in Patients without Hematuria

02468

10

1214

16

Nr. Patients without

hematuria

Relapse Pattern vs. Days to remission

0-7

>7

IRFR+SD

Constantinescu et al, Pediatrics 2000; 105:492-495

*

Predictsinfrequent

relapsing course

* p<0.05

MDR-1 Gene Polymorphism

• MDR-1 encodes for P-glycoprotein-170, a biological 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• 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• 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 Dose

Ht SDS in Children with NS

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

Ht

SD

S

IR 4+4 IR 6+6 FR/SD 6+6(pre-SSA)

FR/SD 6+6(on SSA, last)

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

5 11 10*

10#,¶

Conclusions

• Steroids have growth-suppression potential• 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