Nephrotic syndrome: What’s new, what’s not?

Presentation on theme: "Nephrotic syndrome: What’s new, what’s not?"— Presentation transcript:

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