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Journal Club: Daily Corticosteroids Reduce Infection-associated Relapses in Frequently Relapsing Nephrotic Syndrome: A Randomized Controlled Trial
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Journal Club: Daily Corticosteroids Reduce Infection-associated Relapses in Frequently Relapsing Nephrotic Syndrome: A Randomized Controlled Trial

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Pediatric Nephrology.com Journal Club on a recent article on nephrotic syndrome

Pediatric Nephrology.com Journal Club on a recent article on nephrotic syndrome

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  • 1. Journal Club Dr Sidharth Kumar Sethi MD, Fellowship [IPNA, ISN, ISPN] https://www.pediatric-nephrology.com
  • 2. 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
  • 3. 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
  • 4. 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 corticosteroids
      • during upper respiratory infection decrease the
      • risk of relapse in nephrotic syndrome.
      • Nephron 85: 343–345, 2000
      • Abeyagunawardena AS, Trompeter RS: Increasing the
      • dose of prednisolone during viral infections reduces the
      • risk of relapse in nephrotic syndrome: A randomized controlled
      • trial. Arch Intern Med 93: 226–228, 2008
  • 5. 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.
  • 6. Aim of the study
    • To study the effect of short term
    • administration of small daily doses of
    • prednisolone during infectious illnesses in
    • reducing annual relapse rates in patients with
    • frequently relapsing nephrotic syndrome.
  • 7. 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.
  • 8. 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 or
    • without levamisole.
  • 9. 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
  • 10. 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.
  • 11. 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.
  • 12. 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.
  • 13. 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.
  • 14. 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.
  • 15. Follow up
    • Visits
      • every 2 months for 1 year
    • Blood levels of creatinine, albumin, and cholesterol
      • at enrollment, 6 months, and 12 months.
  • 16. 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
  • 17. 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
  • 18. Premature termination
    • Treatment failure.
      • 2 or more relapses in any 6-month period
      • Exit the study
      • alternative medications.
  • 19. 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%.
  • 20. 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
  • 21. 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 .
  • 22. 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
  • 23. 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
  • 24. Rate Ratio
    • Calculated to compare the ratio of events occurring at any given point in time.
    • Rate Ratio =
    • Incidence Rate 1/Incidence Rate 2
  • 25. 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.
  • 26. 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
  • 27. 68 patients alternate-day prednisolone alone (strata 1) 32 received alternate-day prednisolone and levamisole (strata 2)
  • 28.  
  • 29. Relapse rates @ 12 months
    • 44 relapses (31 infection-associated) intervention group
    • 76 (56 infection-associated) in the controls.
  • 30.  
  • 31. Infections
    • Number of infections
      • 226 Intervention group
      • 161 Control Group (P<0.04).
      • 92% URI
      • 6% gastroenteritis
      • 2% fever without any localizing signs
  • 32. Infection Relapse Correlation
  • 33. 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
  • 34. 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
  • 35. Sub-group Analysis
  • 36. 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
  • 37. 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.
  • 38. 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
  • 39. Infections
    • Number of infections
      • 226 Intervention group
      • 161 Control Group (P<0.04).
      • 92% URI
      • 6% gastroenteritis
      • 2% fever without any localizing signs
  • 40. 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
  • 41. Critical Appraisal
    • Randomised controlled Trial
    • Well defined protocol
    • Case definitions: Infection
    • Treatment uniform
    • Sample size calculation
    • Randomisation
      • Allocation concealment
      • Allocation
    • Intervention
    • Consort statement
  • 42. 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 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
  • 43. 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.
  • 44. 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.
  • 45.
    • Thank You

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