Journal club presentation, Randomised control trial, nephrotic syndrome, prednisolone

1. JOURNAL CLUB

2. NEPHROTIC SYNDROME
 Glomerular dysfunction
 Characterized by –
Proteinuria >3.5 g/day
hypoalbuminemia
edema
hyperlipidemia
lipiduria

3. Complex disturbances in
immune system
Genetic Mutations /
Mutations in proteins
Extensive effacement of podocyte foot processes
Increased permeability of glomerular capillary
wall
Massive proteinuria
Hypoalbuminaemia
Edema
PATHOPHYSIOLOGY

6. DEFINITIONS
Remission Urine albumin nil or trace for 3 consecutive
early morning specimens
Relapse Urine albumin 3+ or 4+ for 3 consecutive early
morning specimens
Frequent relapses Two or more relapses in initial six months or
more than three relapses in any twelve
months.

7. Daily Corticosteroids Reduce Infection-
associated Relapses in Frequently
Relapsing Nephrotic Syndrome: A
Randomized Controlled Trial
Name of the journal : Clinical journal of the American
Society of Nephrology
Volume : 6
Page No: 63 – 69
Year of publication: 2011
Impact factor = 6.18

8. Ashima Gulati,
Aditi Sinha,
Aparna Math,
Pankaj Hari,
Arvind Bagga
Vishnubhatla Sreenivas
Division of Nephrology,
Departments of Pediatrics,
All India Institute of Medical Sciences,
New Delhi, India
Division of Nephrology,
Departments of Biostatistics,
All India Institute of Medical Sciences,
New Delhi, India

9. OVERVIEW
 Introduction
 Objective
 Methodology
 Intervention
 Outcome
 Results
 Discussion
 Critical appraisal

10. INTRODUCTION
 Idiopathic nephrotic syndrome
 40 to 50% show frequent relapses
 Prolonged course with risks of life threatening infections,
thromboembolic complications
 side effects of therapy
 Need to examine safe and effective treatment regimens for
patients with frequently relapsing nephrotic syndrome.

11. 2 studies found an effect
on relapse rates, BUT
 1st
study- small
number
 2nd
study- did not
examine its long-
term benefit

12. RESEARCH QUESTION
Whether the strategy of short-term administration of small daily doses
of prednisolone during infectious illnesses was effective in reducing
annual relapse rates in patients with frequently relapsing Nephrotic
syndrome.

13. RESEARCH QUESTION
• P- Patients with frequently relapsing Nephrotic Syndrome
• I- Daily prednisolone
• C- Alternate day prednisolone
• O- Rate of infection associated relapse, frequency,
cumulative amount of prednisolone
• S- RCT

14. METHODOLOGY
 Study design: randomized ,non blind, parallel group
 Study site: Tertiary care hospital
 Study subjects: Patients with idiopathic, frequently
relapsing nephrotic syndrome
 Sample size: 100
 Study period: September 2006 to October 2009 (Enrollment,
18 months)
 Ethics committee clearance was taken
 Written informed consent taken

15.  Patients aged 1 to 16 years
 Recently diagnosed frequently
relapsing nephrotic syndrome
(at least two relapses in 6
months or more than three
relapses in 12 months)
 Impaired renal function (serum
creatinine > 1.2 mg/dl confirmed once
over a period of 2 weeks)
 Intake of immunosuppressive
medications other than oral
prednisolone in the preceding 6
months
 Steroid threshold exceeding 1 mg/kg
on alternate days for maintaining
remission and
 one or more features of steroid
toxicity (BMI>95th percentile for
age, cataract, or stage 2
hypertension )
Inclusion criteria Exclusion Criteria

16. Frequently relapsing NS
1.5 mg/kg for 4 weeks,
f/b 0.25 mg/kg every 2 weeks until a dose of 0.5 to
0.75 mg/kg on alternate days was reached.
Prednisolone
STANDARD TREATMENT
If dose > 1mg/day to maintain
remission
If no steroid toxicity
Prednisolone + levamisole=2 mg/kg on alternate days

17. The presence of an INFECTION defined :
(1) fever: >38°C on 2 axillary temperature measurements at
least 1 hour apart
(2) Rhinorrhea or cough for more than 1 day
(3) Diarrhea (3 or more semiformed stools/d for 2 days)
INFECTION
Increase prednisolone
from alternate day to
daily dose for 7 days
Alternate day
prednisolone
Intervention group
Control group

18. RELAPSE DEFINITION AND MANAGEMENT
• Presence of 3 to 4 + proteinuria for 3 consecutive days after 7
days of the onset of an infectious illness
• Treatment:
– Prednisolone - 2 mg/kg per d until remission (trace/negative
protein for 3 consecutive days)
– 1.5 mg/kg; alternate days; 4 weeks and tapered.
Follow ups – Every 2 months for 1 year
Blood levels – (creatinine, albumin, cholesterol)
At enrollment, 6 months & 12 months

19. SERIOUS INFECTIONS
 Lower respiratory tract infection, peritonitis, and
cellulitis - Hospitalized
 Both groups were treated with
prednisolone (0.5 mg/kg per d orally) or an equivalent
IV hydrocortisone during therapy

20. Treatment failure.
2 or more relapses in any 6-month period

21. SAMPLE SIZE
 Relapse rate = 4.6+1.4 relapses/year
 power - 80%
 alpha error - 5%
 dropout rate -10%.
 to show 50% reduction in frequency of infection-associated relapses
n = 50 (each group)

22. STATISTICALANALYSIS
• Stata, version 9.1
• Intention to treat
• Incidence (relapse) density rates and rate differences calculated
• Poisson regression: compare relapse rates
• One-way ANOVA: assess the association between the number
of relapses and infections
• On the basis of the rate ratio, the number needed to be treat to
reduce the frequency of relapses to less than three per year

23. INCIDENCE DENSITY RATES
 The incidence rate is the number of new cases per population
in a given time period.
 When the denominator is the sum of the person-time of the at
risk population, it is also known as the incidence density rate
or person-time incidence rate.

24. EXAMPLE OF RELAPSE RATES
 If a population initially contains 1,000 pts and 14
develop a condition over 1 year of observation
 The Relapse rate is 14 cases per 1000 person-years
 14 relapses would be expected for 1000 children observed for 1
year

25. RATE RATIO
 Calculated to compare the ratio of events occurring at any given
point in time.
 Rate Ratio = Incidence Rate 1/Incidence Rate 2

26. NUMBER NEEDED TO TREAT
 The number of patients that need to be treated for one to
benefit compared with a control.
 1/ARR
 The ideal NNT is 1, where everyone has improved with
treatment and no-one has with control.
 The higher the NNT, the less effective is the treatment.

27. NNT EXAMPLE
Prophylaxis RF No RF Total Risk
Yes 15 285 300 0.05
No 49 251 300 0.16
ARR 0.11
NNT 9

28. RESULTS

29. 68 patients alternate-day prednisolone alone (strata 1)
32 received alternate-day prednisolone and levamisole (strata 2)

31. 44 relapses (31 infection-associated) intervention group
76 (56 infection-associated) in the controls.

34. ADJUSTED ANALYSIS & NUMBER NEEDED TO
TREAT
 Mean numbers of relapses per infection
 Intervention 0.13+0.1
 Control groups 0.35+0.2
 Mean difference 0.22 (95% CI 0.16, 0.28) (P=0.04).
 Poisson regression - daily administration of prednisolone during
infections independently resulted in a 59% reduction in the rate
of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6).
 Reduces frequency of relapses to less than 3 per yr
 For every one out of six patients with frequent relapses

35. TREATMENT FAILURES AND ADD ON THERAPY
• Treatment failures
• 2 intervention group (at 6- and 10-month follow-ups)
• four control group (1 at 6-months & 3 at 9-month follow-up)
• Treated
– cyclophosphamide (n=2) or calcineurin inhibitors (n=4)
• Enalapril for stage 1 hypertension.
– 0.2 mg/kg/d
– 1 patient intervention group & 2 patients control group

36. SUB-GROUPANALYSIS

37. DISCUSSION
 With follow-up over 1 year, showed daily administration
during inter current infections
 reduced relapse rates by almost one-half
 higher proportion of patients with sustained remission.
 1 of every 6 patients receiving intervention showed
infrequent relapses,
 Reduction in relapse rates chiefly due to a reduced number
of infection-associated relapses.
 Seventy percent relapses intervention group and 74%
controls preceded by infections, chiefly URI

38. PREVIOUS STUDIES
• Mattoo et al from Saudi Arabia,
• n=36
– patients with steroid-dependent nephrotic syndrome
– prednisone maintenance dose of 0.5 mg/kg on alternate days
• Alternate patients allocated to either
– receive daily prednisone for 5 days during URI or
– continue on alternate-day prednisone.
• At a 2-year follow-up,
– significant reduction in relapse rates in daily prednisolone.
• Limitations
– small number
– not randomized
– did not provide estimates of infections and prednisone dosage in the two
groups.

39. PREVIOUS STUDIES
 Randomized, placebo-controlled trial from Sri Lanka
 n=48 patients
 steroid-dependent nephrotic syndrome receiving long-term treatment with
low-dose (<0.6 mg/kg), alternate-day prednisolone
 Allocated to
 receive prednisolone or placebo daily, for 7 days at the first sign of an
URTI.
 Therapy switched during the second infectious illness.
 Significantly lower relapse with daily therapy
 Limitations
 Patients observed for two consecutive infections
 The effect of the intervention on the long-term unclear.

40. INFECTIONS
 Number of infections
 226 Intervention group
 161 Control Group (P<0.04).
 92% URI
 6% gastroenteritis
 2% fever without any localizing signs

41. MORE INFECTIONS IN INTERVENTION GROUP!
 Precise reason unclear
 Included four patients, each with 12 to 14 URI episodes
 Mild and self-limiting
 Did not require antibiotic therapy.
 Did not appear to be related to steroids
 Trend toward lower cumulative steroid dose in the
intervention group.
 The risk of serious infections that required hospitalization &
corticosteroid side effects similar in both groups

42.  Lack of a placebo arm
 Although adequate allocation concealment before
randomization
 subsequently physicians aware of the allocation
 potential for bias.
 Diagnosis of infection was clinical
 no efforts for virological or bacteriological
confirmation
 Judgment of excluding allergies on the basis of clinical
presentation, past patient history, and family history.
LIMITATIONS

43. LIMITATIONS
 Subjects with mild courses of nephrotic syndrome.
 Difficult nephrotic syndrome with a prolonged duration of disease
or high steroid threshold or those showing steroid toxicity
excluded.
 Steroid threshold in this study was 0.5 to 0.75 mg/kg every other
day
 Unclear whether this intervention useful in patients with a
lower steroid threshold
 Similar benefits in patients co treated with other
immunosuppressive agents, e.g., MMF or CNI
 Effect in patients from developed countries & in populations where
infections don't constitute a major cause for relapses of nephrotic
syndrome unclear

44. CRITICAL
APPRAISAL
CONSORT checklist

45. Section/topic Checklist item Comment
Title & abstract Identification as a randomised trial in the
title
Mentioned
Structured summary of trial design,
methods, results, and conclusions
Mentioned
Introduction
Background & objective Scientific background and explanation of
rationale
Mentioned
Specific objectives or hypotheses
Mentioned
Methods
Trial design Description of trial design (such as parallel,
factorial) including allocation ratio
Mentioned
Important changes to methods after trial
commencement (such as eligibility criteria),
with reasons
Not applicable

46. Section/topic Checklist item Comment
participants Eligibility criteria for participants
Mentioned
Settings and locations where the data
were collected
Tertiary care hospital
Interventions
The interventions for each group with
sufficient details to allow replication,
including how and when they were
actually administered
Mentioned
Outcomes Completely defined pre-specified primary
and secondary outcome measures,
including how and when they were
assessed
Mentioned
Any changes to trial outcomes after the
trial commenced, with reasons
None
Sample size How sample size was determined
50 in each group.
power-80%, α error-
5%, drop out-10%
When applicable, explanation of any
interim analyses and stopping guidelines
None

47. Section/topic Checklist item Comment
Randomization
Sequence generation
Method used to generate the random
allocation sequence
Mentioned
Type of randomisation; details of any
restriction (such as blocking and block
size)
Stratified
randomisation
Allocation concealment
mechanism
Mechanism used to implement the
random allocation sequence (such as
sequentially numbered containers),
describing any steps taken to conceal the
sequence until interventions were
assigned
Opaque sealed envelops
Implementation Who generated the random allocation
sequence, who enrolled participants, and
who assigned participants to interventions
Not mentioned
Blinding If done, who was blinded after assignment
to interventions (for example, participants,
care providers, those assessing
outcomes) and how
Not done
If relevant, description of the similarity of
interventions
not mentioned
Statistical methods Statistical methods used to compare
groups for primary and secondary
outcomes
Mentioned
Methods for additional analyses, such as
subgroup analyses and adjusted analyses
Subgroup analysis done

48. Section/topic Checklist item Comment
Results For each group, the numbers of
participants who were randomly assigned,
received intended treatment, and were
analysed for the primary outcome
Mentioned
Participant flow For each group, losses and exclusions
after randomisation, together with reasons
Mentioned
Recruitment Dates defining the periods of recruitment
and follow-up
Mentioned
Why the trial ended or was stopped
Not applicable
Baseline data A table showing baseline demographic and
clinical characteristics for each group
Table 1
Number analyzed For each group, number of participants
(denominator) included in each analysis
and whether the analysis was by original
assigned groups
Mentioned
Outcomes & estimation For each primary and secondary outcome,
results for each group, and the estimated
effect size and its precision (such as 95%
confidence interval)
Mentioned
For binary outcomes, presentation of both
absolute and relative effect sizes is
recommended
-

49. CONCLUSION
 Daily administration of maintenance doses of prednisolone,
during intercurrent infections, significantly reduces relapse
rates and the proportion of children with frequently
relapsing nephrotic syndrome.