Minimal change nephrotic syndrome

1. Minimal Change
Nephrotic Syndrome
12 February 2013
Amornpan Lertrit , MD.

2. Outline
 Pathogenesis
 Etiology
 Epidemiology
 Clinical manifestation
 Pathology
 Variants
 Differential diagnosis
 Natural history
 Treatment

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. Pathogenesis
Shao yu Zhang. Contrib Nephrol. 2011, vol 169, pp 94–106

5. Pathogenesis
• Biopsy-proven MCD n = 17
• Biopsy-proven FSGS n = 22

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. 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. 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. Others markers
 Hemopexin
 IL-13
 IGFBP-1
 TRAIL
 Angptl4

10. Mechanism of steroid
Changli Wei and Jochen Reiser. Nephrol Dial Transplant,2011

11. Factors Associated
with the Onset of
Nephrotic Syndrome in
Minimal Change
Disease
Brenner and Rector’s the kidney,9th
edition

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. 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. Epidemiology
Brenner and Rector’s the kidney,9th
edition

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. 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. 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. Clinical manifestation
Meryl Waldman. American Society of Nephrology,2007

19. Clinical manifestation
Muehrcke's bandsbandsMuehrcke's bandsbands
XanthelasmaXanthelasma
Periorbital edemaPeriorbital edema

20. Thromboembolism
Brenner and Rector’s the kidney,9th
edition

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. Acute kidney injury
Meryl Waldman. American Society of Nephrology,2007
ARF was defined as a rise in SCr to > 50% above baseline

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. Pathology
 Light microscopy : Normal
 Immunofluorescence microscopy : no staining
 Electron microscopy: Diffuse foot process
effacement

28. Normal
MCD

29. 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).

30. Differential diagnosis
Idiopathic nephrotic syndrome
Minimal change disease (MCD)
Ig M nephropathy (IgMN)
Focal Segmental Glomerulosclerosis (FSGS)
Membranous nephropathy (MN)
Membranoproliferative glomerulonephritis (MPGN)

31. Type of
glomerulonephritis
Nephrotic Nephritis
Minimal change ++++ -
Membranous GN ++++ +
Diabetic GN ++++ +
Amyloidosis ++++ +
FSGS +++ ++
Fibrilar GN +++ ++
MPGN ++ +++
Crescentic GN + ++++
IgA ++ +++
Nephrotic VS Nephritis

32. 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

33. Treatment

34. Definition
KDIGO,2012

35. Treatment
 Treatment of initial episode of Adult MCD
 FR/SD MCD
 Corticosteroid-resistance MCD
 Supportive therapy

36. 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.

37. Corticosteroid
D. A. K. Black , BMJ, 1970

38. 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

39. 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%

40. 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

41. Daily vs AD
• 65 patients received daily steroids
• 23 patients received alternate-day steroids.

42. Daily vs AD
Meryl Waldman. American Society of Nephrology,2007

43. Dairy vs AD
Meryl Waldman. American Society of Nephrology,2007

44. 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 )

45. 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 )

46. 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)

47. 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

48. 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

49. 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)

50. 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.

51. 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

52. 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)

53. 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

54. 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

55. 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)

56. 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)

57. 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
)

58. 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 )

59. 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

60. 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 )

61. Proteinuria and dyslipidemia
• 62 patients (age 25-53 years)
• Steroid-responsive/dependent NS during childhood

62. 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

63. 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.

64. 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 )

65. Take Home Messages
 Pathogenesis : CD80
 Clinical
 Edema, HT
 DLP
 Proteinuria (Nephrotic range)
 Thromboembolism
 AKI
 Pathology : Normal LM, EM  diffuse foot
process effacement

66.  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

67. THANK YOU FOR YOUR
ATTENTION