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Evolution of Therapies for Idiopathic Nephrotic Syndrome

Evolution of Therapies for Idiopathic Nephrotic Syndrome. The history of pediatric nephrology is the history of idiopathic nephrotic syndrome. Milestones. Cytoxan for Frequent Relapses. CyA for SDNS / SRNS. Steroids proven effective. Antibiotics. 1940s. 1950s. 1960s. 1980s. 1990s.

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Evolution of Therapies for Idiopathic Nephrotic Syndrome

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  1. Evolution of Therapies for Idiopathic Nephrotic Syndrome

  2. The history of pediatric nephrology is the history of idiopathic nephrotic syndrome

  3. Milestones Cytoxan for Frequent Relapses CyA for SDNS / SRNS Steroids proven effective Antibiotics 1940s 1950s 1960s 1980s 1990s 2000s 1970s Renal Biopsy “4x4” Steroids (ISKDC) MMF for SDNS/SRNS “6x6” Steroids

  4. The Pre-Modern Eraof Nephrotic Syndrome Only case reports and series prior to 1950s Most nephrotic children succumbed to infections

  5. State of the art in childhood nephrotic syndrome (Arneil, 1961) • 50% got better spontaneously • ~ 50 % died • “ a few survived with continued proteinuria”

  6. Nephrotic Syndrome Treatments of the Pre-Modern Era Thyroxine 1910s Epstein Diet 1910s-1920s Inducing Infection 1920s-1940s Antibiotics 1940s

  7. 1951Corticosteroids Enter the Picture • Cortisone & ACTH used with some success • Efficacy based on edema resolution • Sodium retention confused efficacy

  8. 1956 Steroids Become Established • Gavin Arneil, The Lancet • Case Series, 5 children • Prelone daily • 100% remission* within 6 days • * Remission defined

  9. 1950sNephrology Organizes Around Nephrotic Syndrome • National Nephrosis Foundation • Founded by wealthy parents of Robert Lee DeBold, an infant with nephrotic syndrome • Died around age 2 years

  10. 1958The National Nephrosis Foundation becomes the NKF Ada U. DeBold

  11. International Study of Kidney Disease in Children(ISKDC) Henry Barnett, 1974, founder of the ISKDC

  12. What ISKDC Did • Established Definitions • Clinicopathologic correlation • Defined Natural History • Established treatment regimens • Tested treatment regimens with RCTs • 1st RCT in pediatrics

  13. ISKDC Researchers Trendsetting in more ways than one – Dr. Cameron and Dr. Habib, 1970

  14. ISKDC Definitions Nephrotic Syndrome Edema, Albumin < 2.5, Proteinuria > 40 mg/m2/hr Remission Negative or trace proteinuria for 3 consecutive days Relapse > 2+ proteinuria for 3 consecutive days when previously negative

  15. More ISKDC Definitions Steroid-Responsive No proteinuria within 8 wks on steroids Steroid-Resistant Failure to achieve Remission within 8 wks on steroids Steroid-Dependent Relapse while tapering, OR Within 2 wks of steroid discontinuation Frequent Relapser 2 relapses in 6 months, OR 3 relapses in 12 months

  16. Acute Management • Use albumin infusions and diuretics cautiously – most patients don’t need them • Think about thrombosis risk • Think about infectious complications

  17. ISKDC Pathology • 1st Percutaneous renal biopsy – 1954 • Our current pathological framework established on first 127 patients enrolled in ISKDC Churg J, Habib R, White R.H.R., Pathology of the nephrotic syndrome in children: report of the ISKDC, Lancet 1:1299-1302, 1970.

  18. ISKDC pathology still widely referenced today Distribution of Pathology in Nephrotic Syndrome by AgeNash, Edelman, Bernstein et al, 1992

  19. ISKDC Natural History of Nephrotic Syndrome * Non-ISKDC Data

  20. Why ISKDC wasn’t the ASKDC • 1st proposed trial • “Is imuran and prednisone superior to prednisone alone for • Steroid resistant patients • Frequently relapsing patients • U.S. nephrologists thought it was unethical not to give imuran – a “proven” therapy

  21. 1st ISKDC Misstep • Much argument over 1st line steroid therapy • Started with compromise • High dose steroids until protein-negative for 3 days, • Then taper • Miserable Failure

  22. The Birth of the Gold Standard Initial Therapy Prednisone 60 mg/m2 div BID 28 days Prednisone 40 mg/m2 QOD 28 days Taper 28 days Relapses Prednisone 60 mg/m2 div BID Until Urine neg x 3 d Prednisone 40 mg/m2 QOD 28 days Taper 28 days

  23. Study Arms of 1st ISKDC Study • Separate trials for • Frequent Relapsers (90 days) • Non-responders (180 days) IMURAN 60 mg/m2/day PLACEBO daily Vs. PREDNISONE QOD PREDNISONE QOD

  24. ISKDC saved by Luck • “Imuran” Believers still grumbling, so one successful pilot patient unmasked • A frequently relapsing 3 y/o boy who went into remission chosen • PLACEBO arm

  25. Results of 1st ISKDC Study • No difference in partial or complete response between PLACEBO and IMURAN arms in either frequent relapsers or non-responders Abramowicz M., Arnel G.C., Barnett H.L., Controlled trial of azathioprine in children with nephrotic syndrome: A report f the ISKDC, Lancet 1:959-961, 1970.

  26. The 2nd ISKDC Study • Can Cytoxan sustain remission in frequent relapsers or induce remission in steroid-resistant patients? • 90 day study CYTOXAN 5 mg/kg/day PREDNISONE QOD Vs.

  27. 2nd ISKDC Study Results • Cytoxan patients also relapsed less frequently • Subsequent studies established that cytoxan + Steroid QOD gave even better response • No difference in steroid-resistant patients

  28. ISKDC Results and Treatment Regimens Have Held for ~ 40 years Minor adjustments over time Newer treatments with newer agents

  29. ISKDC “Tweaked” over the years • The “6x6” Regimen • Longer Regimens for Younger Children

  30. 1988The “6x6” Regimen Arbeitsgemeinschaft für Pädiatrische Nephrologie 4x4 6x6 Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Lancet 1988; 1:380.

  31. 2003Longer Taper in Younger Kids • Japanese Prospective and randomized Study • 73 kids • “6x6” regimen vs. “4x4” with 28 week taper • Longer tapers gave more sustained remissions and less frequently relapsing courses in kids < 4 y Long Taper “6x6” Hiraoka, M, Tsukahara, H, Matsubara, K, Tsurusawa, M. A randomized study of two long-course prednisolone regimens for nephrotic syndrome in children. Am J Kidney Dis 2003; 41:1155.

  32. Newer Agents for Difficult Cases New Drugs • Cyclosporine • MMF • Rituximab • Old Drugs • Chlorambucil • Nitrogen Mustard • Levamisole

  33. Rituximab • Chimeric anti-CD20 monoclonal antibody • For steroid resistant or dependent patients • 1-4 injections of 375mg/m² • 72% relapse free • Better results in minimal change disease Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F. Pediatr Nephrol. 2008 Aug;23(8):1269-79

  34. Chlorambucil • An alternate to cytoxan • Used in Europe • 0.2 mg/kg for 2 months • Similar efficacy to cytoxan Grupe, WE, Makker, SP, Ingelfinger, J. Chlorambucil treatment of frequently relapsing nephrotic syndrome. N Engl J Med 1976; 295:746.

  35. Cyclosporine • For Steroid Resistant or Dependent Patients • French Society of Pediatric Nephrology • Open study of 65 children • 42% remitted, half within 1 month • Remission seen with Minimal Change and FSGS Niaudet, P, for the French Society of Pediatric Nephrology. Treatment of childhood steroid resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. J Pediatr 1994; 125:981.

  36. Nitrogen Mustard(Mechlorethamine) • Induces rapid remission • Usually within 7 days • Indications • When steroids are contraindicated • Useful when thrombophilia needs to be rapidly corrected • Two 4 daily injections, one month apart Broyer M; Meziane A; Kleinknecht C; Niaudet P, Nitrogen mustard therapy in idiopathic nephrotic syndrome of childhood. Int J Pediatr Nephrol 1985 Jan-Mar;6(1):29-34.

  37. Levamisole • British Association for Paediatric Nephrology • 61 children • levamisole (2.5 mg/kg QOD or placebo • More remission in levamisole group (14/30 vs 4/31) 4 months after steroid withdrawal • most patients relapsed within 3 months after stopping levamisole

  38. MMF • Barletta, Bunchman, Flynn and others • Retrospective case-crossover14-child study, FRNS or SDNS • Almost all had seen CSA or Cytoxan • Minimal decrease in yearly relapse rate (1.07 vs 2.85) • Moudgil and others • Case-crossover, 19 SDNS kids, all had seen Levamisole or Cytoxan • MMF + Prelone • Decreased yearly relapse rate from 6.6 to 2

  39. Summary • Management of pediatric nephrotic syndrome • is what made pediatric nephrology a specialty • gave pediatrics randomized controlled trials • Still, in 2012, uses ISKDC protocols and definitions • Gave birth to the National Kidney Foundation • Is the “bread-and-butter” of pediatric nephrology

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