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.
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
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
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
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
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).
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
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.
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.
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 )
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