Minimal change nephrotic syndrome

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Minimal change nephrotic syndrome

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  • 5.Immunopathogenesis
  • Brenner
  • 4.IncidenceGN_NDT2011
  • Brenner
  • 6.Rev_MCDadult_WaldmanCJASN2007
  • Brenner
  • Brenner
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • Feehally
  • 7.PredVSplacebo_Black_BMJ1970
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 6. Rev_MCDadult_WaldmanCJASN2007
  • 8.CsA(142)_Eguchi_NDT2010
    Table 20, 21 in Supplement table(KDIGO)
  • POCY 2.5 mg/kg/d 8 wk vs CsA 5 mg/kg/d 9 month
    CsA 0.8 mg/kg/d + P vs P 1 mg/kg/d
  • 9. Tac_Li_NDT2008
  • 10. CVrisk_Lechner_PedNep2004
  • Minimal change nephrotic syndrome

    1. 1. Minimal Change Nephrotic Syndrome 12 February 2013 Amornpan Lertrit , MD.
    2. 2. Outline  Pathogenesis  Etiology  Epidemiology  Clinical manifestation  Pathology  Variants  Differential diagnosis  Natural history  Treatment
    3. 3. Minimal change nephrotic syndrome  Minimal change disease (MCD) is the cause of nephrotic syndrome in about 90% of children younger than 10 years, about 50% - 70% of older children, and 10% - 15% of adults.  MCD is defined by the absence of histologic glomerular abnormalities, other than ultrastructural evidence of epithelial cell foot process fusion, in a patient presenting with nephrotic syndrome who is typically corticosteroid responsive.
    4. 4. Pathogenesis Shao yu Zhang. Contrib Nephrol. 2011, vol 169, pp 94–106
    5. 5. Pathogenesis • Biopsy-proven MCD n = 17 • Biopsy-proven FSGS n = 22
    6. 6. Pathogenesis  CD80 Eduardo H. Garin. International Society of Nephrology,2010 A significant increase in urinary CD80 was found in patients with MCD in relapse compared to those in remission or those with FSGS
    7. 7. Pathogenesis Eduardo H. Garin. International Society of Nephrology,2010 • CD80 was present in the glomeruli of 7/7 MCD patients in relapse. • Minimal in 2/2 subjects with FSGS • Absent in the one subject with MCD in remissionMCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker.
    8. 8. CD80 two hit hypothesis Michiko Shimada. Pediatr Nephrol ,2011,645–649 First hit Direct stimulation of podocyte Viral infection Bacterial infection Allergen T cell cytokine (IL-13,etc) Second hit Ineffective Censoring of podocyte CD80 due to Treg dysfunction or Impaired autoregulation by podocyte Viral infection Reduced CTLA-4, IL-10 or TGF-βresponse Healthy podocyte ↑↑CD80 expression cause Podocyte injury Sustained podocyte injury cause Minimal Change disease
    9. 9. Others markers  Hemopexin  IL-13  IGFBP-1  TRAIL  Angptl4
    10. 10. Mechanism of steroid Changli Wei and Jochen Reiser. Nephrol Dial Transplant,2011
    11. 11. Factors Associated with the Onset of Nephrotic Syndrome in Minimal Change Disease Brenner and Rector’s the kidney,9th edition
    12. 12. Epidemiology • Review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada,Australasia and the Middle East. • Published in 1980– 2010
    13. 13. Epidemiology In children, MCD has been found to cause over 75% of cases of NS •0.23-15.6/100,000/year In Adult •0.6/100,000/year Anita McGrogan, Nephrol Dial Transplant,2011
    14. 14. Epidemiology Brenner and Rector’s the kidney,9th edition
    15. 15. Clinical manifestation  Edema  Gravitational edema  Pleural effusion , Ascites , Pericardial effusion  Hepatomegaly  Diarrhea : edema of the bowel  Microscopic hematuria  Rare in MCD  Hypertension  Hyperlipidemia : Xanthoma
    16. 16. Clinical manifestation  Complication  Infection : sepsis , peritonitis  Increase risk of thromboembolism  Renal function is generally preserved  Serum creatinine concentration is sometimes slightly elevated in adults  Acute kidney injury is a complication particularly seen in adults
    17. 17. Clinical manifestation • Retrospective review • 95 patients who had primary adult-onset MCD • A biopsy-proven MCD • A Single tertiary care center • 1990 to 2005
    18. 18. Clinical manifestation Meryl Waldman. American Society of Nephrology,2007
    19. 19. Clinical manifestation Muehrcke's bandsbandsMuehrcke's bandsbands XanthelasmaXanthelasma Periorbital edemaPeriorbital edema
    20. 20. Thromboembolism Brenner and Rector’s the kidney,9th edition
    21. 21. Acute kidney injury  The development of AKI during the course of MCD, mostly in adults older than age 40.  Marked decrease in glomerular permeability due to extensive foot process effacement  Tubular obstruction from proteinaceous casts  Intrarenal hemodynamic changes : increased endothelin-1 expression  True cause of AKI in MCD remains uncertain and is probably multifactorial.
    22. 22. Acute kidney injury Meryl Waldman. American Society of Nephrology,2007 ARF was defined as a rise in SCr to > 50% above baseline
    23. 23. ↑↑ GlomerularGlomerular PermeabilityPermeability ↑ Hepatic synthesis of lipoprotein Loss of inhibitors of coagulation Loss of hormones and vitamins ↓ IgG ↓ Factor B ↑↑ Risk forRisk for infectionsinfections DeficiencDeficienc y statesy states Thrombo-Thrombo- embolismembolism DyslipideDyslipide miamia EDEMAEDEMA MalnutritiMalnutriti onon Albuminur ia Loss of proteins ↓ Plasma albumin ↓ Oncotic pressure Primary renal salt & water retention Clinical presentation of NS
    24. 24. Pathology  Light microscopy : Normal  Immunofluorescence microscopy : no staining  Electron microscopy: Diffuse foot process effacement
    25. 25. Normal MCD
    26. 26. Variants IgM Nephropathy Some patients presenting with nephrotic syndrome have mesangial deposits of IgM , often with a minor degree of mesangial hypercellularity. Microscopic (and occasionally macroscopic) hematuria Less likely to respond to corticosteroids (50% compared with 90% for MCD).
    27. 27. Differential diagnosis Idiopathic nephrotic syndrome Minimal change disease (MCD) Ig M nephropathy (IgMN) Focal Segmental Glomerulosclerosis (FSGS) Membranous nephropathy (MN) Membranoproliferative glomerulonephritis (MPGN)
    28. 28. Type of glomerulonephritis Nephrotic Nephritis Minimal change ++++ - Membranous GN ++++ + Diabetic GN ++++ + Amyloidosis ++++ + FSGS +++ ++ Fibrilar GN +++ ++ MPGN ++ +++ Crescentic GN + ++++ IgA ++ +++ Nephrotic VS Nephritis
    29. 29. Natural history Younger are more likely to have more relapses and a longer disease course 75% of initial responders who do not relapse within 6 months Nonrelapsing average of 3 years, and 84% are in long-term remission after 10 years. Comprehensive Clinical Nephrology, 4th edition
    30. 30. Treatment
    31. 31. Definition KDIGO,2012
    32. 32. Treatment  Treatment of initial episode of Adult MCD  FR/SD MCD  Corticosteroid-resistance MCD  Supportive therapy
    33. 33. Corticosteroid • A multi-centre controlled trial • Control n = 64 • Prednisolone n = 61 • Dose 20-30 mg/day • Not less than 6 month • More 10 mg/day 12 month • Group A : minimal change • Group B : membranous nephropathy • Group C : proliferative glomerulonephritis.
    34. 34. Corticosteroid D. A. K. Black , BMJ, 1970
    35. 35. Corticosteroid D. A. K. Black , BMJ, 1970 In group A, Prednisone reduced proteinuria to a striking and statistically significant. In groups B and C prednisone did not have any strikingly favourable effect on proteinuria or on renal function
    36. 36. Corticosteroid Conclusion Strong evidence in children (cochrane) Treatment with at least 20 mg/d prednisone for at least 6 months showed an early and rapid decrease in protienuria. By 2.5 yr proteinuria or Serum albumin : no difference Corticosteroid therapy leads to CR in over 80% of adults with MCD. Response rate steroid-free regimen : 75%
    37. 37. Daily vs AD • Complete remission (CR) : a daily urine protein excretion of < 0.3 g/d, urine protein:creatinine ratio of < 0.3, or trace or negative urine albumin dipstick • Partial remission : >50% reduction of proteinuria from baseline. • Time to remission : initiation of therapy - first day on which remission • Relapse : increased protein excretion to > 3 g/d with 3+ or 4+ • Frequent relapse : four or more relapses within 1yr. • Steroid resistance : failure to achieve remission despite at least 16 wk of prednisone • Steroid dependence : relapse upon tapering steroid therapy or within
    38. 38. Daily vs AD • 65 patients received daily steroids • 23 patients received alternate-day steroids.
    39. 39. Daily vs AD Meryl Waldman. American Society of Nephrology,2007
    40. 40. Dairy vs AD Meryl Waldman. American Society of Nephrology,2007
    41. 41. Conclusion KDIGO  Treatment of initial episode of adult MCD 5.1.1: We recommend that corticosteroids be given for initial treatment of NS.(1C ) 5.1.2: We suggest prednisolone be given at a daily single dose of 1 mg/kg (max 80 mg) or alternate-day single dose of 2 mg/kg (max 120 mg). (2C ) 5.1.3: We suggest the initial high dose of corticosteroids be maintained for a minimum period of 4 wks if CR is achieved, and for a maximum period of 16 wks if CR is not achieved. (2C ) 5.1.1: We recommend that corticosteroids be given for initial treatment of NS.(1C ) 5.1.2: We suggest prednisolone be given at a daily single dose of 1 mg/kg (max 80 mg) or alternate-day single dose of 2 mg/kg (max 120 mg). (2C ) 5.1.3: We suggest the initial high dose of corticosteroids be maintained for a minimum period of 4 wks if CR is achieved, and for a maximum period of 16 wks if CR is not achieved. (2C )
    42. 42. Conclusion KDIGO  Treatment of initial episode of adult MCD 5.1.4: We suggest that corticosteroids be tapered slowly over a total period of up to 6 months after achieving remission. (2D ) 5.1.5: For patients with relative contraindications or intolerance to high-dose corticosteroids we suggest oral cyclophosphamide or CNIs as discussed in FR MCD. (2D ) 5.1.6: We suggest using the same initial dose and duration of corticosteroids for infrequent relapses as in Recommendations 5.1.2, 5.1.3,and 5.1.4. (2D ) 5.1.4: We suggest that corticosteroids be tapered slowly over a total period of up to 6 months after achieving remission. (2D ) 5.1.5: For patients with relative contraindications or intolerance to high-dose corticosteroids we suggest oral cyclophosphamide or CNIs as discussed in FR MCD. (2D ) 5.1.6: We suggest using the same initial dose and duration of corticosteroids for infrequent relapses as in Recommendations 5.1.2, 5.1.3,and 5.1.4. (2D )
    43. 43. FR/SD MCD  Relapse of the NS occurred in 73.1% of initial responders  76% treated with at least one additional course of steroids  91.70% achieved a remission  27 (28.6%) patients met criteria for frequent relapsers (mean of 4.1 ± 0.5 /yr)
    44. 44. FR/SD MCD Meryl Waldman. American Society of Nephrology,2007 • oral dosage was 123.6 mg/d, and mean duration of therapy was 11.5± 7.9 wk • Remission was achieved in 11 (55%) patients. • Mean time to remission was 6.4 wk (range 5 to 12 wk) • SD patients had better response rates (no significant) • Mean time to relapse was 18 mo • oral dosage was 123.6 mg/d, and mean duration of therapy was 11.5± 7.9 wk • Remission was achieved in 11 (55%) patients. • Mean time to remission was 6.4 wk (range 5 to 12 wk) • SD patients had better response rates (no significant) • Mean time to relapse was 18 mo
    45. 45. FR/SD MCD Meryl Waldman. American Society of Nephrology,2007 • Daily dosage of 220 mg given in divided doses • Target trough concentration 150 to 200 ng/ml • Mean duration of 49.5±14.8 wk. • Remission was achieved in 24 (61%) patients. • Mean time to remission was 5 wk • Daily dosage of 220 mg given in divided doses • Target trough concentration 150 to 200 ng/ml • Mean duration of 49.5±14.8 wk. • Remission was achieved in 24 (61%) patients. • Mean time to remission was 5 wk
    46. 46. FR/SD MCD Meryl Waldman. American Society of Nephrology,2007 • Dosage 2 - 4 mg twice daily; trough concentrations 5 to 10 ng/ml • 3 remissions (1 CR) • Dosage 2 - 4 mg twice daily; trough concentrations 5 to 10 ng/ml • 3 remissions (1 CR)
    47. 47. FR/SD MCD Meryl Waldman. American Society of Nephrology,2007 • Dosage of MMF was 2 g/d, except in 3 patients who received 1 g/d • Mean duration of therapy was 36.1± 7.9 wk. • 9 (64%) patients responded to MMF • Mean time to remission was 20 ± 2.7 wk. • Dosage of MMF was 2 g/d, except in 3 patients who received 1 g/d • Mean duration of therapy was 36.1± 7.9 wk. • 9 (64%) patients responded to MMF • Mean time to remission was 20 ± 2.7 wk.
    48. 48. Cyclophosphamide  Observational  Significant Remission in adult  The relapse-free interval appears to be longer than with cyclosporine  55% Complete or Partial Remission  Excellent initial response (half relapse)  FR can sustain CR > SD (similar to children)  Add prednisolone  no benefit
    49. 49. Cyclosporine • RCT • Patients with the first relapse of MCNS • CsA (AUC1700–2000 ng/ml) + PSL (0.8 mg/kg/day) group (n = 26) • PSL alone (PSL) (1.0 mg/kg/day) group (n = 26)
    50. 50. Cyclosporine A significant decrease of the urinary protein excretion (P = 0.02) and serum total cholesterol (P = 0.003) was observed at 2 weeks from the first relapse in the CsA + PSL group A significant decrease of the urinary protein excretion (P = 0.02) and serum total cholesterol (P = 0.003) was observed at 2 weeks from the first relapse in the CsA + PSL group
    51. 51. Cyclosporine  70-90% remission rate  FR/SD NS (Adult+Children): RCT (POCY vs CsA)  9 mo CR  same  Maintain remission (At 2 yr) : 63% vs 25%  CsA+P vs P : RCT  Sooner CR  Dose and Duration : uncertained  9 mo  26 mo  CsA < 3 mg/kg/d can maintain remission  Therapeutic level : Insufficient data
    52. 52. Tacrolimus • Open, prospective cohort study • 26 Chinese adults with SD-MCNS • IVCY n = 14 (750 mg/m2 body surface once every 4 weeks for 24 weeks) • Tacrolimus n = 12 (target trough blood level of 4–8 ng/ml for 24 weeks)
    53. 53. Tacrolimus CR after the 24-week therapeutic period •76.9% (10/13) in the IVCY group •90.9% (10/11) in the TAC group. The mean time required for CR in the TAC group was significantly less than in the IVCY group (P = 0.031)
    54. 54. Conclusion (KDIGO)  FR/SD MCD 5.2.1: We suggest oral cyclophosphamide 2–2.5mg/kg/d for 8 weeks. (2C ) 5.2.2: We suggest CNI (cyclosporine 3–5mg/kg/d or tacrolimus 0.05-0.1mg/kg/d in divided doses) for 1– 2 years for FR/SD MCD patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. (2C ) 5.2.3: We suggest MMF 500–1000 mg twice daily for 1– 2 years for patients who are intolerant ofcorticosteroids, cyclophosphamide, and CNIs.(2D ) 5.2.1: We suggest oral cyclophosphamide 2–2.5mg/kg/d for 8 weeks. (2C ) 5.2.2: We suggest CNI (cyclosporine 3–5mg/kg/d or tacrolimus 0.05-0.1mg/kg/d in divided doses) for 1– 2 years for FR/SD MCD patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. (2C ) 5.2.3: We suggest MMF 500–1000 mg twice daily for 1– 2 years for patients who are intolerant ofcorticosteroids, cyclophosphamide, and CNIs.(2D )
    55. 55. Corticosteroid-resistant MCD  No RCT or observational data.  Steroid resistance may be due to undetected FSGS.  A repeat biopsy could be considered 5.3.1: Re-evalulate patients who are corticosteroidresistant for other causes of nephrotic syndrome. (Not Graded ) 5.3.1: Re-evalulate patients who are corticosteroidresistant for other causes of nephrotic syndrome. (Not Graded )
    56. 56. Supportive therapy  AKI during MCD occur 24/95 patients.  17 patients : at initial presentation  7 patients : at relapse  Kidney biopsy 22/24 patients  Tubular injury : 14 patients  Patchy interstitial inflammation : 13 patients  No tubular/interstitial injury : 6 patients  Mean time to recovery 6.4 wk (100%)  Temporary RRT : 4 patients Meryl Waldman. American Society of Nephrology,2007
    57. 57. Supportive therapy  AKI can occur in MCD and sometimes severe enough to require dialysis.  Risk factors include ;  older age , HT , severe NS , and underlying arteriosclerosis of the kidney  Kidney function typically recovers even in the most severely affected patients 5.4.1: We suggest that MCD patients who have AKI be treated with renal replacement therapy as indicated, but together with corticosteroids, as for a first episode of MCD. (2D ) 5.4.1: We suggest that MCD patients who have AKI be treated with renal replacement therapy as indicated, but together with corticosteroids, as for a first episode of MCD. (2D )
    58. 58. Proteinuria and dyslipidemia • 62 patients (age 25-53 years) • Steroid-responsive/dependent NS during childhood
    59. 59. Proteinuria and dyslipidemia At the time of follow-up, 23–46 years after cessation of NS, none of these patients had ESRD or CKD. Brent Lee Lechner, Pediatr Nephrol,2004
    60. 60. Proteinuria and dyslipidemia The data suggest that relapsing NS during childhood does not place patients at increased risk for CVD mortality or morbidity compared with the general population. Brent Lee Lechner, Pediatr Nephrol,2004 The occurrence of events (8%) and mortality from CVD (none) in this cohort of patients is comparable to patients of a similar age in the general population and is lower than that of patients of the same age who are on dialysis.
    61. 61. Supportive therapy  Proteinuria in adult MCD will typically remit with corticosteroids, and statins and RAS blockade to help reduce proteinuria are not necessary if early remission is achieved. 5.4.2: We suggest that, for the initial episode of nephrotic syndrome associated with MCD, statins not be used to treat hyperlipidemia, and ACE-I or ARBs not be used in normotensive patients to lower proteinuria. (2D ) 5.4.2: We suggest that, for the initial episode of nephrotic syndrome associated with MCD, statins not be used to treat hyperlipidemia, and ACE-I or ARBs not be used in normotensive patients to lower proteinuria. (2D )
    62. 62. Take Home Messages  Pathogenesis : CD80  Clinical  Edema, HT  DLP  Proteinuria (Nephrotic range)  Thromboembolism  AKI  Pathology : Normal LM, EM  diffuse foot process effacement
    63. 63.  Corticosteroid  Initial treatment (1C)  Relapse (2B)  Second line drug  Cyclophosphamide (2C)  CyclosporinA (2C)  Tacrolimus (2C)  MMF (2D)  Steroid resistance  Supportive treatment : not use ARB (2B) Take Home Messages
    64. 64. THANK YOU FOR YOUR ATTENTION

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