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Journal Club
Dr Sidharth Kumar SethiMD, Fellowship [IPNA, ISN, ISPN]
https://www.pediatric-nephrology.com
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Background
• Idiopathic nephrotic syndrome – 40 to 50% show frequent relapses
ISKDC: J Am Soc Nephrol 8: 769–776, 1997
– 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.Pediatr Nephrol 20: 1523–1530, 2005
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Infections and Relapses
• Follow minor infections of the upper respiratory or gastrointestinal tracts J Pediatr 108: 378–382, 1986
• 50 to 70% of relapses of nephrotic syndrome among children in developing countries follow URI
• Mechanism not clear but immunosuppressive agents – attenuate the upregulation of T cells – reduce the risk of infection associated relapses
Arun S, Bhatnagar S, Menon S, Saini S, Hari P, Bagga A: Efficacy of zinc supplements in reducing relapses in steroid-sensitive nephrotic syndrome. Pediatr Nephrol 24: 1583–1586, 2009
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Short term daily steroids during infections
• Two previous studies• Both found an effect on relapse rates, BUT– the first study- small number– the second study- did not examine its long-
term benefit Mattoo TK, Mahmoud MA: Increased maintenance corticosteroidsduring upper respiratory infection decrease therisk of relapse in nephrotic syndrome. Nephron 85: 343–345, 2000Abeyagunawardena AS, Trompeter RS: Increasing thedose of prednisolone during viral infections reduces therisk of relapse in nephrotic syndrome: A randomized controlledtrial. Arch Intern Med 93: 226–228, 2008
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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.
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Aim of the study
To study the effect of short termadministration of small daily doses ofprednisolone during infectious illnesses inreducing annual relapse rates in patients
withfrequently relapsing nephrotic syndrome.
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Study Design
• Design: Randomized controlled trial • Period: September 2006 to October
2009 (Enrollment, 18 months)• Approval: Institutional Ethics Board,• Informed written consent from a
parent before inclusion.
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Inclusion criteria
• Patients aged 1 to 16 yrs • Recently diagnosed frequently
relapsing nephrotic syndrome (at least two relapses in 6 months or more than three relapses in 12 months)
• Eligible for therapy with long term, alternate-day prednisolone with orwithout levamisole.
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Exclusion Criteria
• 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, or
• Steroid threshold exceeding 1 mg/kg on alternate days for maintaining remission and– one or more features of steroid toxicity (body
mass index, 95th percentile for age, cataract, or stage 2 hypertension
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Standard Treatment• Alternate-day prednisolone
– 1.5 mg/kg for 4 weeks,– followed by tapering by 0.25 mg/kg every 2 weeks until a
dose of 0.5 to 0.75 mg/kg on alternate days was reached.
• Patients requiring prednisolone at a dose of 1 mg/kg on alternate days to maintain remission but without the above features of steroid toxicity – combination of levamisole (2 mg/kg on alternate days) and
alternate day prednisolone as above.
• Treatment with long-term, alternate-day prednisolone with or without levamisole was given for 1 year.
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Randomisation
• Allocation concealment–opaque sealed envelopes opened
at inclusion.
• Randomisation–stratified randomization on the
basis of therapy with or without levamisole into intervention and control groups.
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Intervention
• The presence of an infection defined :(1) fever: 38°C-2 measurements axillary temperature at least 1 hr apart(2) rhinorrhea or cough for more than 1 day(3) diarrhea (3 or more semiformed stools/d for 2 days).
• Intervention group Increase the frequency of prednisolone administration from alternate-day to daily treatment for 7 days, without changing the dose of prednisolone.
• Control group Same treatment with alternate-day prednisolone.
• Dose not changed during allergies, insect bites, injuries, immunization, and any presumed noninfectious illness.
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Follow up
• Supplements of calcium carbonate – (250 mg/d <6 yrs; 500 mg/d >6 yrs)
• Parent daily examine the first morning urine specimen by dipstick
• Written record– Details of infections– treatment taken
• Written instructions – therapy, including telephonic advice
followed by a hospital visit within 1 week.
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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.
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Follow up
• Visits – every 2 months for 1 year
• Blood levels of creatinine, albumin, and cholesterol – at enrollment, 6 months, and 12
months.
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Serious Infections
• Lower respiratory tract infection, peritonitis, and cellulitis
• Hospitalized• Both groups– prednisolone (0.5 mg/kg per d orally) or
an equivalent IV hydrocortisone during therapy
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Outcomes
• Primary outcome – comparing the rates of infection-
associated relapses (relapses occurring in the week after the 7-day intervention period) and expressed as episodes/patient per yr.
• Secondary outcomes – frequency and type of infections – cumulative amount of prednisolone
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Premature termination
• Treatment failure. – 2 or more relapses in any 6-month
period – Exit the study – alternative medications.
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Sample Size
• Relapse rate of 4.6+1.4 relapses/yr in patients with frequent relapses
• 70% presumed to follow infections• 50 patients required in each group to
show 50% reduction in frequency of infection-associated relapses
• power of 80%, alpha error of 5%, and dropout rate of 10%.
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Statistical Analysis
• 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
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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.
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Example of Relapse Rates
• Incidence proportion (28 per 1,000) is divided by the number of years (two)
• The Relapse rate is 14 cases per 1000 person-years– 14 relapses would be expected for 1000
children observed for 1 year
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Statistical Analysis
• 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
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Rate Ratio
• Calculated to compare the ratio of events occurring at any given point in time.
• Rate Ratio = Incidence Rate 1/Incidence Rate 2
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Number needed to Treat
• The inverse of the absolute risk reduction or increase and the number of patients that need to be treated for one to benefit compared with a control.
• 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.
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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
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68 patients alternate-day prednisolone alone (strata 1)32 received alternate-day prednisolone and levamisole (strata 2)
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Relapse rates @ 12 months44 relapses (31 infection-associated) intervention group 76 (56 infection-associated) in the controls.
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Infections
• Number of infections– 226 Intervention group– 161 Control Group (P<0.04). – 92% URI– 6% gastroenteritis – 2% fever without any localizing signs
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Infection Relapse Correlation
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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, adjusted for occurrence of infections, 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
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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
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Sub-group Analysis
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Discussion: Salient points of results
• With follow-up over 1 year, showed daily administration during intercurrent 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
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Previous studies• Saudi Arabia, Mattoo et al Nephron 85: 343–345, 2000
• 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 the former.• Limitations– small number– not randomized– did not provide estimates of infections and prednisone dosage in the two
groups.
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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, in the same dose as that
prescribed on alternate days during remission, for 7 days at the first sign of an upper respiratory tract infection.
– Therapy switched during the second infectious illness. • Forty (83.3%) completed the study • Significantly lower relapse rates when receiving daily therapy• Limitations
– Patients observed for two consecutive infections– the effect of the intervention on the long-term unclear.
Arch Intern Med 93: 226–228, 2008
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Infections
• Number of infections– 226 Intervention group– 161 Control Group (P<0.04). – 92% URI– 6% gastroenteritis – 2% fever without any localizing signs
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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
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Critical Appraisal • Randomised controlled Trial• Well defined protocol• Case definitions: Infection• Treatment uniform• Sample size calculation• Randomisation– Allocation concealment– Allocation
• Intervention• Consort statement
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Limitations• Subjects with mild courses of nephrotic syndrome. • Difficult nephrotic syndrome with a prolonged duration of
disease or high steroid threshold or those showing steroidtoxicity 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 cotreated with other
immunosuppressive agents, e.g., MMF or CNI• The effect in patients from developed countries and in
populations where infections dont constitute a major cause for relapses of nephrotic syndrome unclear
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Limitations
• Lack of a placebo arm – adequate allocation concealment before
randomization– subsequently 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.
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Conclusions
• Long-term, alternate-day prednisolone with or without levamisole show reduced relapses during infectious illnesses.
• Recommend consider intervention for reducing infection-associated relapses in selected patients with frequently relapsing nephrotic syndrome.
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Thank You