Growth Hormone in Children with Nephrotic Syndrome

Growth Hormone in Children with Nephrotic Syndrome

Minimizing Growth Suppression in Children with Steroid-sensitive Nephrotic Syndrome Alex Constantinescu, MD Director, Pediatric Nephrology Joe DiMaggio Childrens 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 GHRH + - + Somatostatin

Steroids - Pituitary Pulsatile GH secretion - Liver + IGF-1 Growth plate + Connective tissue Adrenal gland -

- GH receptor expression and binding; IGF-1 activity Impact of Short Stature Body image Psychosocial adaptation Bone metabolism Pubertal development Growth in Children with Nephrotic Syndrome 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 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 Ht SDS 2 1 0 -1 -2 -3 -4 -1.8 SD 3m

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

HtSDS in Children with Nephrotic Syndrome 6 5 4 3 2 1 0 -1 -2 -3 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 12 10 Growth Rate SDS 8 6 4 2 0 -2 -4 -6 -8 3m 6m 1y 2y

3y 4y 5y 6y Time 7y 8y 9y 10y 11y 12y Growth Velocity Rate (GVR) in Children with NS

GVR for 3-6-12 mo. 20.0 15.0 p=0.029 10.0 5.0 0.0 GVR - M vs. F >6 yrs. 20.0 3m 6m 12 m 15.0 10.0

GVR - M vs. F <6 yrs. 20.0 p=0.019 15.0 0.0 10.0 5.0 M F M M F F 0.0

5.0 3m 6m 12 m M M M F F 3m 6m 12 m

Long-term Linear Growth in Children with SD or FR Nephrotic Syndrome 56 children (37 M, 19 F) followed-up for 10.53.1 yrs SD = 42, FR = 14 Average growth loss was 0.660.89 SD 2 patients fell below -2SD 23 reached final height with loss of: 0.920.8 HtSDS from the onset of disease (p=0.001) 0.680.7 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 Emma F, et al. Pediatr Nephrol 18:783-8, 2003 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 fr Pdiatrische 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; 29:10391046 66% relapse (129 1 year) male, young age, short time to first relapse predicts FR No. of Patients Distribution Based on Days to Remission 20 18 16 14 12 10 8 6 4 2

0 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 Nr. patients

with hematuria 10 5 0 0-7 FR+SD >7 IR Constantinescu et al, Pediatrics 2000; 105:492-495 Disease Course in Patients without Hematuria Relapse Pattern vs. Days to remission 16 14 12 Nr.

10 Patients 8 without hematuria 6 4 2 0 Predicts infrequent relapsing course * 0-7 >7 IR FR+SD Constantinescu et al, Pediatrics 2000; 105:492-495

* 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 0.4 0.2 IR 4+4 IR 6+6 FR/SD 6+6 (pre-SSA) 5 11 10 * FR/SD 6+6 (on SSA, last) 0 -0.2

Ht SDS -0.4 10 #, -0.6 -0.8 -1 -1.2 -1.4 -1.6 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 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

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