Minimal change nephrotic syndrome
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Transcript of Minimal change nephrotic syndrome
Minimal Change Nephrotic Syndrome
12 February 2013
Amornpan Lertrit , MD.
Outline
Pathogenesis Etiology Epidemiology Clinical manifestation Pathology Variants Differential diagnosis Natural history Treatment
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.
Pathogenesis
Shao yu Zhang. Contrib Nephrol. 2011, vol 169, pp 94–106
Pathogenesis
• Biopsy-proven MCD n = 17
• Biopsy-proven FSGS n = 22
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
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 remission
MCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker.
CD80 two hit hypothesis
Michiko Shimada. Pediatr Nephrol ,2011,645–649
First hitDirect stimulation of podocyte
Viral infectionBacterial infection
AllergenT cell cytokine (IL-13,etc)
Second hitIneffective Censoring of podocyte CD80 due to
Treg dysfunction or Impaired
autoregulation by podocyte
Viral infectionReduced CTLA-4, IL-10
or TGF-βresponse
Healthy podocyteCD80 expression cause
Podocyte injury
Sustained podocyte injury cause Minimal
Change disease
Others markers
Hemopexin IL-13 IGFBP-1 TRAIL Angptl4
Mechanism of steroid
Changli Wei and Jochen Reiser. Nephrol Dial Transplant,2011
Factors Associated with the Onset of
Nephrotic Syndrome in Minimal Change
Disease
Brenner and Rector’s the kidney,9th edition
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
Epidemiology
In children, MCD has been found to cause over 75% of cases of NS•0.23-15.6/100,000/yearIn Adult•0.6/100,000/year
Anita McGrogan, Nephrol Dial Transplant,2011
Epidemiology
Brenner and Rector’s the kidney,9th edition
Clinical manifestation
Edema Gravitational edema Pleural effusion , Ascites , Pericardial effusion Hepatomegaly Diarrhea : edema of the bowel
Microscopic hematuria Rare in MCD
Hypertension Hyperlipidemia : Xanthoma
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
Clinical manifestation
• Retrospective review • 95 patients who had primary adult-onset
MCD • A biopsy-proven MCD • A Single tertiary care center• 1990 to 2005
Clinical manifestation
Meryl Waldman. American Society of Nephrology,2007
Clinical manifestation
Muehrcke's bands bandsMuehrcke's bands bands
XanthelasmaXanthelasma
Periorbital edema
Periorbital edema
Thromboembolism
Brenner and Rector’s the kidney,9th edition
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.
Acute kidney injury
Meryl Waldman. American Society of Nephrology,2007
ARF was defined as a rise in SCr to > 50% above baseline
Glomerular Glomerular PermeabilityPermeability
Hepatic synthesis of lipoprotein
Loss of inhibitors of coagulation
Loss of hormones and vitamins
IgG Factor B
Risk for Risk for infectionsinfections
DeficiencDeficiency statesy states
Thrombo-Thrombo-embolismembolism
DyslipideDyslipidemiamia
EDEMAEDEMA
MalnutritiMalnutritionon
Albuminuria
Loss of proteins
Plasma albumin
Oncotic pressure
Primary renal salt &
water retention
Clinical presentation of NS
Pathology
Light microscopy : Normal Immunofluorescence microscopy : no
staining Electron microscopy: Diffuse foot
process effacement
Normal
MCD
Variants
IgM NephropathySome 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).
Differential diagnosis
Idiopathic nephrotic syndrome
Minimal change disease (MCD)
Ig M nephropathy (IgMN)
Focal Segmental Glomerulosclerosis (FSGS)
Membranous nephropathy (MN)
Membranoproliferative glomerulonephritis
(MPGN)
Type of glomerulonephritis
Nephrotic Nephritis
Minimal change ++++ -Membranous GN ++++ +Diabetic GN ++++ +Amyloidosis ++++ +FSGS +++ ++Fibrilar GN +++ ++MPGN ++ +++Crescentic GN + ++++IgA ++ +++
Nephrotic VS Nephritis
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
Treatment
Definition
KDIGO,2012
Treatment
Treatment of initial episode of Adult MCD FR/SD MCD Corticosteroid-resistance MCD Supportive therapy
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.
Corticosteroid
D. A. K. Black , BMJ, 1970
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
Corticosteroid
ConclusionStrong 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 differenceCorticosteroid therapy leads to CR in over 80% of adults with MCD.Response rate steroid-free regimen : 75%
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 4 wk of discontinuing steroids
Daily vs AD
• 65 patients received daily steroids• 23 patients received alternate-day steroids.
Daily vs AD
Meryl Waldman. American Society of Nephrology,2007
Dairy vs AD
Meryl Waldman. American Society of Nephrology,2007
Conclusion KDIGO
Treatment of initial episode of adult MCD5.1.1: 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 )
Conclusion KDIGO
Treatment of initial episode of adult MCD5.1.4: 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 )
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)
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
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
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)
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.
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
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)
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
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
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)
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)
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 )
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 )
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
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 )
Proteinuria and dyslipidemia
• 62 patients (age 25-53 years) • Steroid-responsive/dependent NS during childhood
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
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.
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 )
Take Home Messages
Pathogenesis : CD80 Clinical
Edema, HT DLP Proteinuria (Nephrotic range) Thromboembolism AKI
Pathology : Normal LM, EM diffuse foot process effacement
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
THANK YOU FOR YOUR ATTENTION