mcd

1. MINIMAL CHANGE DISEASE
Dr Prateek Singh
PGY2 Medicine
IOM,TUTH

2. introduction
 First described in 1913 by Munk , who called it lipoid
nephrosis due to lipids in tubular epithelial cells and urine.
 More common in children
-70-90% cause of nephrotic synd. In kids <10 yrs
- 50 % of nephrotic synd in kids 10-18 yrs
-10-25 % primary nephrotic synd in adults , 3rd most
common after FSGS and MN
 Boys > girls

3.  More common in asia then in europe and america.
 MCD usually presents as a primary renal disease but can
be associated with several other conditions
- Hodgkin’s disease
- allergies
- use of nonsteroidal anti-inflammatory agent

4. Pathophysiology
 Shalhoub, in 1974, proposed that MCD is caused by a
circulating factor, thought to be a cytokine, that
increases the permeability of the glomerular basement
membrane (GBM) to plasma proteins

6.  MCD might represent aT cell disorder based on
-the lack of immune deposits,
-the rapid response to corticosteroids,
-the association with Hodgkin disease (aT cell neoplasm),
- and the observation that remission often occurred during
resolution of measles infection, which is associated with a
transient inhibition of cell-mediated immunity

7.  B cell disorder
initially thought to be uninvolved but recent studies
showing response to Rituximab (B20 monoclonal antibody)
suggest Bcell involvement producing permeability factors
in circulation.

8.  Circulating Factor(s)
1. Cytokines - IL-8 , IL-13 . podocytes possess IL- 13R and
stimulation of cultured monolayer podocytes with IL-13
lead to decreased transepithelial electrical resistance.
IL13 expression is upregulated inT cells in children with
steroid sensitive nephrotic synd. in relapse.

9. 2. Hemopexin- synthesized in the liver and is present in
human plasma of patients with MCD which, when
infused into the isolated rat kidney, induced proteinuria
by increased glomerular permeability.
patients with relapse shows increased level hemopexin
proteinase activity.

10. 3. Microbial Products- 70% of MCD patients with relapse
have documented viral or bacterial respiratory infections.
-TwoToll-like receptor (TLR) ligands
- lipopolysaccharide (LPS)
- a component of the outer membrane of gram-negative
bacteria
- polyinosinic-polycytidylic acid (poly IC)
- viral-like particle

11.  Bind toTLR-4 andTLR-3 on podocytes, respectively, and
cause proteinuria in animals with podocyte expression of
CD80 and increased urinary CD80 excretion, mimicking
findings observed in MCD patients during relapse.

12. Mechanisms of proteinurea
 Loss of Anionic Charges in the Glomerular Filtration
Barrier as a Cause of Minimal Change Disease –
Heparan sulfate proteoglycans, which are the major
source of anionic sites in the GBM, are reported to be low
or normal in the GBM of MCD patients.

13.  Podocyte Dysfunction as a Cause of Minimal Change
Disease –
- Alteration of slit diaphragm proteins such as reduced
nephrin phosphorylation 19 & alteration in integrin-mediated
podocyte adhesion .
-Podocyte expression of two molecules, CD80 (also known as
B7.1) andangiopoietin-like-4 (Angptl-4) also have been
proposed .

15. 1. CD80
CD80 is a co-stimulatory molecule present on antigen-
presenting cells that was found to be expressed on podocytes
in children with MCD. It also can be induced in podocytes both
byTLR ligands, with the development of transient proteinuria
and focal foot process effacement. High levels of CD80 also can
be found in the urine of children with steroid-sensitive MCD

16.  CD80 is regulated by cytotoxicT lymphocyte–associated
antigen 4 (CTLA-4) (expressed by podocytes)
 viral components stimulateTLR-3 podocyte receptors,
resulting in overexpression of podocyte CD80. Because of an
inadequate CTLA4 response by the podocyte, the increased
expression of CD80, by interfering with phosphorylation of
nephrin, could lead to changes in podocyte shape affecting
the “size barrier “

17. 2. Angiopoietin-like-4 (Angptl-4) –
-glomerular over expression of angptl4 and podocin
marked loss of GBM heparan sulfate proteoglycans,
podocyte foot process effacement, and albuminuria .

18.  MCD is the most common type of nephrotic syndrome in
patients with Hodgkin disease <1%.
-C-MIP is overexpressed in Reed-Steinberg cells and
podocytes. C-MIP appears to mediate podocyte injury by
preventing the interaction of nephrin with the tyrosine
kinase
-decreased phosphorylation of nephrin
-cytoskeleton rearrangement and proteinuria

19. Etiology

20. Clinical features
 Most frequently the presenting symptom of MCD is
nephrotic syndrome characterized by edema, periorbital, of
the scrotum or labia, and of the lower extremities.
Nephrotic Syndrome
-Edema
-Massive proteinuria (.40 mg/m2 per h in children, .3.5 g/d in
adults)
-Hypoalbuminemia (,2.5 g/dl)
- Hyperlipidemia

21.  Anasarca may develop with ascites and pleural and
pericardial effusion (serum albumin levels below 2 g/dl),
leading to abdominal pain because of hypoperfusion
and/or thrombosis, dyspnea (rarely), and cold extremities
with low BP.

22.  Intravascular volume depletion and oliguria are also present,
and concomitant factors (sepsis, diarrhea, diuretics) can lead
to AKI (common in adolescents and young adults )
 Gross hematuria –rare (3%)
 HTN (50% in adults)
 Abdominal pain and nausea

23.  AKI with MCD
-Mostly in adults older than age 40
-Marked decrease in glomerular permeability due to
extensive foot process effacement, tubular obstruction
from proteinaceous casts, and intrarenal hemodynamic
change and increased endothelin-1 expression in the
kidneys
-AKI with gross hematuria followed by anuria can also be
secondary to bilateral renal vein thrombosis.

24. Lab findings
 Nephrotic range proteinuria is defined as greater than 3.5
g/24 h
 Hypoalbuminemia serum level of albumin below 2.5 g/dl
 Hyperlipidemia (elevated total cholesterol and low-density
lipoprotein[LDL] cholesterol)
 acute kidney injury (AKI) with oliguria secondary to
reduction of intravascular compartment
 Mild hyponatremia

25.  Low serum calcium and vitamin D levels
 Elevated hemoglobin and hematocrit levels and
thrombocytosis
 Elevated srum c3 level.

26. Diagnosis
 Renal biopsy

27. Light microscopy
 Usually normal
 Sometime minimal focal segmental prominence limited
to 3-4 cells in matrix of segment may be seen
 This mesangial prominence should have no more than
three or four cells embedded in the matrix of a segment,
and the matrix should not be expanded to the extent that
capillary lumens are compromised

28.  Lipid and protien deposits in tubular cells stain with PAS stain
 Areas of interstitial fibrosis and tubular atrophy raise possibilty
of FSGS
 Focal proximal tubular epithelial flattening (simplification),
which is histologically identical to that seen with ischemic AKI,
occurs in patients who have the syndrome of MCD with AKI

30. Immunoflourance
 No staining with IgG , IgM, IgA, C3, C4 or C1q
 Low level mesangial staining for IgM can be seen but
without mesangial electron dense deposits on EM
 Effacement of foot process seen in EM which diminish as
diseases remits.
 Due to increased lipid absorption intracytoplasmic
densities can be seen.
 Findings non specific and seen in nephrotic range
protienuria.

31. Electron microscopy
 During active nephrosis, the effacement often is very
extensive, with only a few scattered intact foot
processes. As the patient enters remission, the extent of
foot process effacement diminishes.
 MCD is a diagnosis by exclusion that is made only when
there is no evidence by light, immunofluorescence, and
electron microscopy for any other glomerular disease

33. MCD vs FSGS
 Primary FSGS diagnosis requires biopsy findings of
segmental glomerusclerosis in at least 1 glomerulus in
addition to diffuse foot process effacement
 Sclerotic changes appear first at the juxtamedullary
glomeruli, which may not be seen in a biopsy sample
containing only outer cortex or with <8 glomeruli on biopsy .
 Patients responding poorly to steroids and progressing to
ESRD are thought to have been missed FSGS at initial
diagnosis.

36. Treatment
 General considerations
-low sodium diet
- Avoid bed rest because of the increased risk for
thromboembolic events.
- diuretics are often used to control extracellular fluid
volume
- thrombosis prophylaxis
-statins for hyperlipidemia (rarely used)

37.  MCD is highly steroid responsive and carries an
excellent prognosis
 Steroid therapy leads to complete remission in 80-85 %
of adults with MCD
 Corticosteroid exert direct protection of podocytes from
injury and/or promotion of repair

38.  Adults are not considered steroid-resistant until after 4
months
 The time course to a complete remission is prolonged,
with 50 % responding by four weeks and 10 to 25 %
requiring more than three to four months of therapy
 relapses occurring in about 56%–76% of patients

40.  Steroid dependence is seen in 25 to 30 %
 Remissions are typically abrupt, with the patient being
free of proteinuria within two to three weeks from the
time of initial response .
 10%–20% of adults with MCD are resistant, and a repeat
renal biopsy in these patients may show FSGS

42.  Studies failed to show a significant benefit of intravenous
methylprednisolone (20 mg/kg per day for 3 days)
followed by reduced-dose oral steroids (prednisone 0.5
mg/kg per day) versus full-dose oral steroids alone
(prednisone 1 mg/kg per day).

43.  Yeung et al
- of intravenous methylprednisolone (20 mg/kg per day
for 3 days followed by a 2-week steroid-free period and
oral prednisolone at 0.5 mg/kg)
- oral prednisolone (1 mg/kg per day for 4–6 weeks
followed by a taper).

44.  N 18 @ 2 weeks
- IV methyl pred * 3day - 3 of 10 remission
- oral prednisolone – 5 of 7 remission
 nonresponders in the iv m-pred- received oral
prednisolone (1 mg/kg per day) ---5 of 7 remission.
 1 mth all patients on oral prednisolone – remission.

45.  controversial issue for therapy since slow tapering may
increase cumulative steroid doses, but rapid tapering may
expose patients to the risk of relapses .
 taper prednisone by 5–10 mg/wk after remission over 8
weeks for a total 24-week period of exposure to prednisone

46. Steroid response pattern in MCD

48.  The rate of dose tapering and total length of treatment
of the initial episode may need to be reduced in
individual patients if steroid toxicity is significant (e.g.,
uncontrolled diabetes, psychiatric complications, patient
with severe osteoporosis)

49. frequent replapsing/ steroid dependent
 Rituximab may be effective therapy in adults
with frequently relapsing or glucocorticoiddependent
MCD. Its suggested rituximab therapy be attempted in
such patients who have also failed to attain a durable
remission with cyclophosphamide or calcineurin
inhibitors.

50. Steroid resistant MCD
 Approx 10-20% of patients
-Re-evaluate patients who are corticosteroid resistant for
other causes of nephrotic syndrome
-IV steroid can be tried
-Cyclosporine can be started in combination
with steroid

51. Other Immunomodulatory Treatments for FR,
SD, orSteroid-Responsive Disease
 use of levimasole not reported in adults
 In MCD with AKI
- dialysis
-Albumin infusion may be considered if there is evidence
of severe intravascular volume depletion with severe
hypoalbuminemia

52. Take home message
 MCD is a histologic picture than does not correspond to a
single disease entity
 MCD is highly steroid responsive and carries an
excellent prognosis
 With longer treatment duration and slower tapers
required compared with children to attain remission and
minimize relapses
 Adults with MCD that are steroid resistant repeat renal
biopsy in these patients may show FSGS

53.  Thank you

54. Refrence
 TheTreatment of Minimal Change Disease in Adults Jonathan Hogan and Jai
Radhakrishnan Division of Nephrology, Columbia University Medical Center, New
York, NewYork
 Minimal Change Disease
MarinaVivarelli,* Laura Massella,* Barbara Ruggiero,† and Francesco Emma*
 Harrison 20°
 Comprehensive Clinical Nephrology 6e
 KDIGO guidelines