1. Nephrotic syndrome: What’s new, what’s not?
Rodney D Gilbert

2. I know all I need to know about nephrotic syndrome (if not all I’d like to know)
Yes No

3. Prolonged, slow taper of steroids for the initial episode of nephrotic syndrome
Is evidence based, state of the art treatment, increases time to 1st relapse + reduces the number of frequent relapsers
Is of no benefit

4. Nephrotic Syndrome Steroid Sensitive 90% Steroid Resistant 10%
Frequently Relapsing
Drug responsive
Drug non-responsive
Steroid Dependent
Long term remission
2° Steroid Resistance
ESRD
No Recurrence 70%
Transplant
Recurrence 30%

5. Can we reduce the frequency of relapses?
Yes No
Don’t know

6. Can we reduce the frequency of steroid dependence?
Yes No
Don’t know

7. Can we reduce the frequency of secondary steroid resistance?
Yes No
Don’t know

8. Can we avoid toxic and expensive drugs in patients who will not benefit?
Yes No
Don’t know

9. 225 children with newly presenting SSNS
PREDNOS
225 children with newly presenting SSNS
£0.9m funding
ISKDC regimen
Total 8 weeks steroids
Then placebo to 16 weeks
Prednisolone 60mg/m2/d 4w
Then alternate days 60mg/m2 2w
50mg/m2 2w
40mg/m2 2w
30mg/m2 2w
20mg/m2 2w
10mg/m2 2w
Total 16 weeks steroids
Set up data safety monitoring board etc

10. Results: participants
237 randomised in 86 centres
237 randomised
Standard Course Therapy
N = 118
4 weeks
9 participants steroid resistant
N = 109
Extended Course Therapy
N = 119
5 participants steroid resistant
N=114
24 study sites – largest NIHR paediatric study in terms of number of study sites
ITT population 213

11. Primary end point: No difference in time to first relapse
HR 0.87, 95%CI , log-rank p=0.3

12. Results: secondary end-points

13. Adverse effects No difference in SAEs: SC 39 vs. EC 28, p=0.1
No difference in height, weight, BMI or blood pressure SDS
No difference in Achenbach CBC scores

14. Cochrane meta-analysis
Number of patients developing frequently relapsing SSNS by 12-24m

15. Prednos Conclusions No benefit in prolonged initial steroid therapy
Time to first relapse
Number of relapses
Incidence of frequent relapsers
Some increase in behaviour problems but not significant on Achenbach testing

16. Conclusion (Part 1)
Initial episode of nephrotic syndrome should be treated according to the ISKDC protocol:
60 mg/m2/day as a single, early morning dose until urine shows neg or trace for protein for 3 days
40 mg/m2 on alternate days for 4 weeks then stop

17. Can we change the incidence of secondary steroid resistance?
No hard evidence, but…

18. RAC1 in nephrotic syndrome
RAC1 is a small GTPase involved in maintaining podocyte cytoskeleton
Several mutations known to cause nephrotic syndrome involve negative regulators of RAC1 (TRPC5, ARHGAP24)
Steroids down-regulate RAC1 in podocytes

19. RAC1 and nephrotic syndrome
Mouse model with conditional over-expression of RAC1 causes nephrotic syndrome
Increased RAC1 for short duration: remission
Prolonged upregulation of RAC1: FSGS, progressive renal failure

20. Conclusion (2)
Prolonged or frequent relapses of nephrotic syndrome may be a risk factor for secondary steroid resistance

21. Can we offer more informed management?
Kidney International 2017; 91(4):

22. Summary Findings 187 patients with SRNS underwent WES
12% had family history
Focus on 53 genes associated with nephrotic syndrome
Monogenic cause found in 26.2% (mostly NPHS1, NPHS2 and WT1)
30.8% monogenic cause in primary steroid resistance, 0% in secondary

23. Summary Findings Genetic SRNS did not respond the drug treatment*
Genetic SRNS progressed faster to ESRD but no recurrences post transplant
Primary steroid resistance with no identified genetic cause had 47.8% recurrence

24. Implications All SRNS patients should undergo genetic testing
No drug treatment for those with monogenic disease*
Very low risk of recurrence with monogenic disease
Almost 50% risk of recurrence with primary steroid resistance but no genetic cause

25. After this talk I am
Better informed on the management of nephrotic syndrome
More confused about the management of nephrotic syndrome
Both better informed and more confused

26. After this talk I am
Better informed on the management of nephrotic syndrome
More confused about the management of nephrotic syndrome
Both better informed and more confused

27. The incidence of bilateral renal agenesis is 1:3000
True
False

28. The incidence of bilateral renal agenesis is 1:3000
True
False

29. The incidence of unilateral renal agenesis is 1:100
True
False

30. The incidence of unilateral renal agenesis is 1:100
True
False 1:1000

31. The incidence of duplicated kidney is 1:200
True
False

32. The incidence of duplicated kidney is 1:200
True
False

33. The incidence of duplicated kidney is 1:200
True
False 1:125

34. The incidence of horseshoe kidney is 1:1000
True
False

35. The incidence of horseshoe kidney is 1:1000
True
False 1:500

36. Abnormally positioned kidneys have a high Incidence of obstruction and / or VUR
True
False

37. Abnormally positioned kidneys have a high Incidence of obstruction and / or VUR
True
False Most are absolutely normal in function

38. In a duplex kidney vesico-ureteric is likely in :
The upper moiety
The lower moiety
Both upper and lower moieties
Neither moiety

39. In a duplex kidney vesico-ureteric is likely in :
The upper moiety
The lower moiety
Both upper and lower moieties
Neither moiety

40. In a duplex kidney obstruction is likely in :
The upper moiety
The lower moiety
Both upper and lower moieties
Neither moiety

41. In a duplex kidney obstruction is likely in :
The upper moiety
The lower moiety
Both upper and lower moieties
Neither moiety

42. In a duplex kidney both moieties are likely to be ectopic :
True
False

43. In a duplex kidney both moieties are likely to be ectopic :
True
False