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

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

Clinical manifestation

Edema Gravitational edema Pleural effusion , Ascites , Pericardial effusion Hepatomegaly Diarrhea : edema of the bowel

Microscopic hematuria Rare in MCD

Hypertension Hyperlipidemia : Xanthoma

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

• Retrospective review • 95 patients who had primary adult-onset

MCD • A biopsy-proven MCD • A Single tertiary care center• 1990 to 2005

Meryl Waldman. American Society of Nephrology,2007

Muehrcke's bands bandsMuehrcke's bands bands

XanthelasmaXanthelasma

Periorbital edema

Thromboembolism

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

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

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

Dairy vs AD

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

• 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

• 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

• 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

• 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

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 )

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

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 )

Proteinuria and dyslipidemia

• 62 patients (age 25-53 years) • Steroid-responsive/dependent NS during childhood

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

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 )

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

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