4-2. SRNS. Rosanna Coppo (eng)

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4-2. SRNS. Rosanna Coppo (eng)

  1. 1. Rosanna Coppo Torino Steroid resistant nephrotic syndrome: still a therepeutic challenge
  2. 2. Idiopathic Nephrotic Syndrome minimal change GN IgMGN mesangial proliferative GN focal segmental glomerulosclerosis In all these cases steroid resistance is the most strong predictor of progression
  3. 3. corticosteroids Nakayama, 2002
  4. 4. Clinical Practice Guideline for Glomerulonephritis WWW.KDIGO.ORG
  5. 5. CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN 4.1: EVALUATION OF CHILDREN WITH SRNS 4.1.1: We suggest a minimum of 8 weeks treatment with corticosteroids to define steroid resistance. (2D) 4.1.2: The following are required to evaluate the child with SRNS (Not Graded): • a diagnostic kidney biopsy; • evaluation of kidney function by GFR or eGFR; • quantitation of urine protein excretion. Kidney Disease: Improving Global Outcomes WWW.KDIGO.ORG
  6. 6. Podocytopathies
  7. 7. 14 types Genetically determined steroid –resistant Idiopathic NS 2-5% of all the cases
  8. 8. Treatment of children and adults with idiopathic steroid-resistant NS ALKYLATING AGENTS
  9. 9. Cochrane Database Syst Rev 2010 Alkylating agents in idiopathic steroid-resistant NS in children 9 RCTs involving 449 children: RR of persistent NS • Oral Cyclophosphamide+P vs Prednisone RR 1.01 (0.74-1.36) • IV CPA vs oral CPA RR 0.09 (0.01-1.39) • Azathioprine+P vs Prednisone RR 1.01 (0.77-1.32) no significant effect of alkylating drugs on RR of persistent NS
  10. 10. Treatment and outcome of children and adults with idiopathic steroid-resistant NS ALKYLATING AGENTS CYCLOSPORIN
  11. 11. CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN 4.2: TREATMENT RECOMMENDATIONS FOR SRNS 4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for children with SRNS. (1B) 4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. (2C) 4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. (2C) 4.2.1.3: We suggest that low-dose corticosteroid therapy be combined with CNI therapy. (2D) Kidney Disease: Improving Global Outcomes WWW.KDIGO.ORG
  12. 12. Cyclosporin treatment decreases glomerular utrafiltration coefficient 15 3,4 10 8,60 5 1,8 4,2 2,1 Saline 0 2,40 CyA Glomerula volume nl Kl (ul/min mmHg cmH20) Kf (nl/min mmHg)
  13. 13. CyA Meyrier’s hypothesis: CyA is lipophilic and bind sto a lipidic complex associated to the slit diaphragm, limiting the protein leak
  14. 14. Synaptopodin (protein which stabilyzes cytosckeletal actin and is co-localyzes with calcineurin)
  15. 15. Synaptopodin is instable and undergoes lysis due to cathepsin with disappearance of cytoskeleton actin stress fibers
  16. 16. The interaction between synaptopodin and serine/treonine binding protein maintains F-actin stability, normal cytoskeleton structure and absence of proteinuria F actin ser / treo BP Dephosphorylation synactopodin synactopodin P ser / treo binding protein sin Cyclosporin sin sin
  17. 17. Cochrane Database Syst Rev 2010 Cyclosporin in idiopathic steroid-resistant NS in children 3 RCTs: 49 children: RR of persistent NS Cyclosporin (CyA) vs PL RR 0.64 (0.47-0.88)
  18. 18. Treatment of steroid-resistant NS Cyclosporin A Evidence-based recommendations Treatment MCGL Level of evidence Grade Comments 4 D Possible benefit from pooled case series; no significant benefit in RCT – small numbers 1 A Beneficial Cyclosporin (at least 6 months) FSGS Cyclosporin (at least 6 months)
  19. 19. An example of CyA nephrotoxicity. Francois H, et al Am J Kidney Dis. 2007;49:158-61. Renal tolerability of CyA is reasonably good when the dosage is low Meyrier A, Expert Opin Pharm 2005
  20. 20. Long Term CyA treatment in SRNS GE-ITALIAN STUDY Adult and Children Ghiggeri 2004 • 55 steroid –resistant NS treated with CyA NS remission (partial or total): 20 patients Mean follow-up: 81 months Renal biopsy after 5 years of treatment: no tubular or interstitial fibrosis
  21. 21. CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN 4.2: TREATMENT RECOMMENDATIONS FOR SRNS 4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for children with SRNS. (1B) 4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6 months and then stopped if a partial or complete remission of proteinuria is not achieved. (2C) 4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months. (2C) 4.2.1.3: We suggest that low-dose corticosteroid therapy be combined with CNI therapy. (2D) Kidney Disease: Improving Global Outcomes WWW.KDIGO.ORG
  22. 22. CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN 4.2.2: We recommend treatment with ACE-I or ARBs for children with SRNS. (1B) 4.2.3: In children who fail to achieve remission with CNI therapy: 4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose corticosteroids (2D), or a combination of these agents (2D) be considered in children who fail to achieve complete or partial remission with CNIs and corticosteroids. 4.2.3.2: We suggest that cyclophosphamide not be given to children with SRNS. (2B) Kidney Disease: Improving Global Outcomes WWW.KDIGO.ORG
  23. 23. Steroid-, cytotoxic- and cyclosporin-resistant desperate NS: rescue therapy Steroid therapy : different doses, different forms  Cyclosporin late response late and sustained effect, cyclosporin dependancy, risk of toxicity  Other calcineurin-inhibitors: Tacrolimus
  24. 24. 22 children with steroid-resistant NS (9 MCD, 11 FSGS, 2 MP) TAC 0.1 mg/Kg/day (5-10 μg/ml TL) Total remission10/13 resistant also to Cyclophosphamide(CP) 2/4 resistant also to Cyclosporine (CyA) Side effects:diarrhea and hypertension (3 withdrawn) TAC is an effective therapeutic modality for SRNS, including children non responsive to CP and CyA
  25. 25. Mean time to remission : 60 days
  26. 26. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus Roberti I, Vyas S. Pediatr Nephrol 2010, 25: 1117-24 19 children with steroid-resistant NS (10 FSGS, 5 other forms) Complete remission:11/19 (58%) , partial in 6 Mean time to remission : 8 weeks Remission sustained during follow-up in 58%. Among FSGF remission 50% , in 40% non responders, ESRF.
  27. 27. 41 children with steroid-resistant NS TAC 0.1-0.2 mg/Kg or CsA 5-6 mg/Kg for 1 year Alternative day steroids and ACE-i (10 FSGS, 5 other forms) At 6 mo Complete remission:TAC 85%, CsA 80% RR for relapse after 1 year : OR 4.5 (TAC better) Cosmetic negative effects in CsA only
  28. 28. Steroid-, cytotoxic- and cyclosporin-resistant desperate NS: rescue therapy  Steroid therapy : different doses, different forms  Cyclosporin late response late and sustained effect, cyclosporin dependancy, risk of toxicity  Other calcineurin-inhibitors: Tacrolimus  Purine synthesis inhibitors: Mycophenolate
  29. 29. MMF and prednisone in steroid-dependent NS Bagga A Am J Kidney Dis 2003 19 Children previously treated with P, oral CP, and still cortico-dependent NS: MMF 30 mg/Kg/day for 2 years associated with low tapering doses of Prednisone. FU: 18 months Frequency of relapses from 6.6 to 2 each year p<0.0001: MMF was effective as steroid-sparing agent 75% reduction of relapses After withdrawal relapse in 68% of the cases
  30. 30. MMF in steroid-resistant NS Author N cases Regimen Efficacy Day CJ (Wolverhampt, UK, NDT 2002) 7 adults MMF (1 gx2) Complete remission 6/7 1/7 partial r. MP pulses (15 mg/kg/week x 4-8) ACE-i/ARB MMF (250-500 mg/m2) Proteinuria (6-24 months) 72% below baseline p<0.01 Montané (Miami, 9 US, Ped Nephrol childr. 2003) Mendizabal S (Spain, Ped Nephrol 2005) Ulinski (Lyon, Ped Nephrol 2005) no response to CP and CyA 27 5 SRNS MMF (1200 mg/m2) 1/5 remission Relapse after withdrawal. CyA with GFR impairment: 2g/1.73 m2 0/4 remissions 9 4SRNS
  31. 31. In FSGS MMF should be used for > 6 months, No RCT is available. The rate of relapse is high.
  32. 32. CHAPTER 4: STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN 4.2.2: We recommend treatment with ACE-I or ARBs for children with SRNS. (1B) 4.2.3: In children who fail to achieve remission with CNI therapy: 4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose corticosteroids (2D), or a combination of these agents (2D) be considered in children who fail to achieve complete or partial remission with CNIs and corticosteroids. 4.2.3.2: We suggest that cyclophosphamide not be given to children with SRNS. (2B) Kidney Disease: Improving Global Outcomes WWW.KDIGO.ORG
  33. 33. Steroid-, cytotoxic- and cyclosporin-resistant desperate NS: rescue therapy sporadic case reports Permeability factor (PF) V.Savin 1993 PF is a small anionic protein that binds to Prot A and has analogies with Immunoglobulins Plasmapheresis
  34. 34. Plasmapheresis and protein A immunoadsorption Dantal et al (N Engl, 1994) In native and in recurrent FSGS in grafted kidneys: • Effect often limited in time, with relapse at withdrawal • High cost / often limited benefits • In cases with antiproteinuric response the progression to ESRF is only partially limited
  35. 35. Recurrence of FSGS on transplanted kidney Plasmapheresis or Immunoadsorbance on A Protein + cyclophosfamide: 70% reduction in proteinuria Lyon and Miami Protocol
  36. 36. Steroid-, cytotoxic- and cyclosporin- resistant NS: sporadic case reports of rescue therapy B cells as new target for NS treatment? Anti-CD 20 chimeric MoAb Rituximab
  37. 37. Rituximab is a Chimeric Monoclonal Ab: Mouse IgG variable region directed against CD20 Ag + Human IgG1 constant region
  38. 38. A review of the current use of rituximab in autoimmune diseases Gurvan HM Int Immunopharmacol 2008 Nov Pharmacological effects: B lymphocytes depletion Reduced expression of activated T cell markers
  39. 39. B and T collaboration T lymphocytes and NS Hodgkin’s disease Allergy Viral infections In vitro evidences Shaloub’s hypothesis: permeabilizing T lymphokine Permeability Factor (Ig part?) B cells activated in relapse
  40. 40. Francois H, Daugas E, Bensman A, Ronco P. Unexpected efficacy of rituximab in multirelapsing minimal change nephrotic syndrome in the adult Am J Kidney Dis. 2007;49:158-61. Rituximab 375 mg/m2 x4 persistent remission
  41. 41. Results • Always effective in 15/15 proteinuria-free patients • Remission was induced in 3/7 NS • In 19/22( 85%) one or more concomitant immunosuppressive treatment was stopped
  42. 42. RTX was repeated in 12 patients who responded, when CD19 count was >1% of total lymphocytes
  43. 43. Collaborative study (London, Tokyo, Toronto, Turin) G1) steroid-dependent NS : (28 cases) Complete remission: 61% G 2) steroid-resistant NS (27 cases) Complete remission: 22% G3 post transplant recurrrence (15 cases) Complete remission: 40% Side effects 26% Skin rash,bronchospasm, hypotension
  44. 44. Rituximab used in > 500.000 subjects Adverse events: Allergic reactions, anti chimeric Antibodies. 35 30 % HACA positive - 25 20 15 10 5 0 0 3 6 9 12
  45. 45. Rituximab toxicity and adverse events: progressive multifocal leukoencephalopathy (PML) in 2 cases of SLE and one of RA treated with multiple drugs , including Rituximab
  46. 46. 2 SLE, 1 RA, 2 autoimmune pancytopenia/thrombocytopenia 7 stem cells Tx, 26 purine analogues, 39 alkylating agents 52 lymphoproliferative disorders
  47. 47. The emerging role of podocytes
  48. 48. The interaction between synaptopodin and serine/treonine binding protein maintains F-actin stability, normal cytoskeleton structure and absence of proteinuria F actin ser / treo BP Dephosphorylation synactopodin synactopodin P ser / treo binding protein sin sin sin
  49. 49. New treatments for Nephrotic syndrome protease inhibitors?
  50. 50. PROTEASE INHIBITORS HIV ANTI-RETROVIRAL DRUGS transcription viral proteins viral capsids PROTEASE INHIBITORS
  51. 51. 8 patients in treatment with saquinavir 30 mg/Kg/day • 6 males, 2 females • Previous history of NS: 7.2 4.2 years 3 primary SRNS, 3 secondary SRNS 2 SDNS • Previous treatments: – Steroids, ACTH (8/8) – Cyclophosphamide (4/8) – Cyclosporine A (7/8), Tacrolimus (5/8), MMF (3/8) – Plasma exchange (3/8) – Rituximab (4/8) • Median age at SAQ start-up : 13.5 (7-38) years • Median duration of treatment: 14.7 (6-68) months
  52. 52. drug interaction between saquinavir and calcineurin inhibitors Pharmacokinetic interactions pGp MDR2/3 CyP450 SAQ is substrate and inhibitor Increase in Cyclosporine A and tacrolimus blood levels SAQ is metabolyzed by isoenzyme CYP3A4: modifies CyA and TAC metabolism
  53. 53. Medium dosage of calcineurin inhibitors administered together with saquinavir • Cyclosporine A: 2 mg/kg/day (vs 5 mg/kg/day before SAQ) to maintain a blood levels of 100 ng/ml • Tacrolimus: 0.01-0.06 (median 0.018) mg/kg/day (vs 0.1 mg/kg/day before SAQ) to maintain a blood levels of 3-5
  54. 54. Significant decrease in cumulative steroid dosage Medium dosage of prednisone: 25.2 mg/kg/month Prednisone mg/kg/month 35 Pre-saquinavir Mean mean reduction reduction of 63% of 56% Post-saquinavir 100 30 75 25 p=0.03 20 50 % 15 10 25 5 0 0 12 months before SAQ Last 12 months with SAQ Medium dosage of prednisone: 8.4mg/kg/month Pre-SAQ Post-SAQ
  55. 55. Nuclear binding of NF-kB p50- p65 in immortalized human podocytes activated by LPS without or with addition of SAQ 10 and 20 µM. Nuclear binding of NF-kB p50, p65 in immortalized human podocytes activated by TNFα with or without addition of SAQ10 and 20 µM.
  56. 56. Conclusions • The protease inhibitor SAQUINAVIR provided with proteasome inhibitor activity: 1/2 primary SRNS 5/5 SDNS or secondary SRNS Infrequent relapsers • This drug was active when associated with calcineurin inhibitors, which had to be reduced to less than one third of the original dose to obtain safe blood levels.
  57. 57. saquinavir benefits: hypotheses Proteasome-inhibitor activity: NF-kB hyperactivity inhibition of in circulating mononuclear cells with decrease synthesis of a permeability factor (IPS downregulation) Proteasome-inhibitor activity: NF-kB hyperactivity inhibition in podocytes with foot process rearrangement. Direct impact on podocyte protein synthesis
  58. 58. saquinavir benefits: hypotheses Combined effect with low doses of CNI and prednisone NF-kB target for Saquinavir (protease inhibitor) Glucocorticoids (GCR binding to p65) CNI (non competitive inhibitors of proteasome & ubiquitinylation)
  59. 59. saquinavir benefits: hypotheses anti retroviral drug: antiviral beneficial effect in NS?
  60. 60. A rescue therapy may be tried even in steroid resistant NS CsA, TAC (MMF) PE Rituximab new approaches : Protease inhibitors Antifibrotic drugs?
  61. 61. Thank you Grazie СПАСИБО

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