Minimal Change Disease

Minimal Change Disease

A. Brad Farris, III, MD

A biopsy with minimal change disease shows a normal glomerulus on PAS stain without GBM thickening or inflammatory cells and with minimal mesangial hypercellularity.

Prominent foot process effacement image is present in this case of minimal change disease. The glomerular basement membrane has a normal thickness, and no electron-dense deposits are present.



  • Minimal change disease (MCD)


  • Lipoid nephrosis

  • Nil disease

  • Minimal change nephrotic syndrome

  • Minimal change glomerulopathy


  • Idiopathic glomerular disease that causes nephrotic syndrome, with little or no light or immunofluorescent microscopic abnormalities and podocyte foot process effacement on electron microscopy

  • Occurs as primary (idiopathic) disease, especially in children, and secondary to drugs, allergic reactions, and neoplasia at all ages


Idiopathic (Primary)

  • Classified as disease of podocytes, a “podocytopathy”

  • Loss of podocyte negatively charged glycocalyx a central feature

    • Cause unknown; possibilities include

      • Enzymatic cleavage (e.g., neuraminidase)

      • Neutralizing positively charged molecule

      • Decreased synthesis

    • Loss of negative (anionic) charge leads to

      • Selective leakage of albumin

      • Albumin is most negatively charged of major plasma proteins

      • Foot process effacement

  • Circulating permeability factor or cytokine abnormality postulated

    • Various substances have been suggested, ranging in molecular weight from 12-160 kDa

    • IL-13, an anti-inflammatory Th2 cytokine for B cells and monocytes, is implicated

    • T-cell IL-13 content increases during relapse

    • Increased serum IgE, IgG4 in some patients

Secondary Forms of MCD

  • Infection

    • Human immunodeficiency virus (HIV)

    • Upper respiratory tract infection

  • Hodgkin disease and other lymphoproliferative disorders (lymphoma)

    • Possibly related to abnormal T-cell function

  • Allergy

    • Drugs, especially nonsteroidal anti-inflammatory drugs

    • Bee venom

    • Immunization

    • Mononucleosis

  • Systemic lupus erythematosus

  • Graft vs. host disease

  • Acute renal allograft rejection (rare manifestation)

Experimental Studies

  • Key features of MCD (e.g., foot process effacement [FPE], proteinuria) reproduced in rats or mice by

    • Overexpression of IL-13

    • Administration of puromycin aminonucleoside or Adriamycin

    • Supernatants from hybridomas made from T cells from patients with MCD

    • Administration of neuraminidase or protamine sulfate (removes sialic acid or neutralizes anionic charge, respectively)



  • Age

    • Most common in children (65-75% of cases)

      • Median age of onset is 2.5 years

      • Peak incidence is at 2-3 years

      • Causes ˜ 90% of nephrotic syndrome in preadolescents and ˜ 50% in adolescents

    • Adults have late peak incidence, > 80 years old

      • 26% of adults with nephrotic syndrome are < 65 years

      • 20% are 65-79 years

      • 46% are 80-91 years

  • Gender

    • In children, 2:1 ratio of males to females

    • In adults: Equal gender distribution

  • Ethnicity

    • More common in whites and Asians than in blacks


  • Sudden (days) onset of nephrotic syndrome

  • Nephrotic syndrome

    • Proteinuria defined as ≥ 3.5 g/d in adults and ≥ 40 mg/m2 body surface area (BSA)/hr in timed overnight collection in children

      • Selective proteinuria (chiefly albumin)

    • Edema

    • Hypoalbuminemia defined as serum albumin < 3.5 g/dL in adults and < 2.5 g/dL in children

    • Hypercholesterolemia

    • Lipiduria

      • Lipid-laden enucleated tubular cells may be seen as “oval fat bodies” in urinary sediment, with polarizable lipid

      • Gave rise to the term “lipoid nephrosis,” original term for MCD

  • Hematuria

    • Microscopic hematuria (10-30% of cases)

  • Renal dysfunction

    • Acute renal insufficiency may occur in adults with MCD from acute ischemic tubular injury due to poor perfusion

      • Associated with extreme hypoalbuminemia

      • May be accompanied by anasarca

      • Most recover with steroids and diuretics

    • Renal insufficiency (plasma creatinine > 98th percentile) in < 1/3 of children with MCD, typically mild

      • Due to reduced glomerular hydraulic conductivity secondary to loss of filtration slit pores, which are responsible for allowing flux of small molecules


  • Drugs

    • Corticosteroids

      • 90-95% respond over 4-6 weeks

      • 8-week course of steroids often used as 1st treatment of nephrotic syndrome in children

      • If no response to steroids, renal biopsy typically performed to rule out other diseases

      • Up to 50% of children and 30% of adults relapse after steroid treatment within 1st year; usually treated with another course of steroids

    • 2nd line of treatment for steroid failures

      • Alkylating agents (e.g., chlorambucil or cyclophosphamide)

      • Levamisole

      • Cyclosporine


  • Primary (idiopathic)

    • Rarely, if ever, leads to renal failure

    • Before steroids and antibiotics, fatalities from infection

    • Adults with MCD and acute renal failure also usually fully recover

  • Secondary

    • Remits if underlying condition can be cured

  • MCD may be initial manifestation of focal segmental glomerulosclerosis (FSGS) (˜ 5%), in which case prognosis is that of FSGS


General Features

  • Enlarged, waxy, yellow cortex because of lipid accumulation in proximal tubules

  • Gross examination is rare since advent of treatment with corticosteroids and comorbid conditions with antibiotics


Histologic Features

  • Glomeruli

    • Normal appearance by light microscopy

      • Slight increases in mesangial cellularity and matrix in minority

      • Glomerular basement membranes are normal

    • Podocytes may be swollen and prominent with basophilic cytoplasm, resembling plasma cells

      • Resorption droplets in visceral epithelial cells

    • Loss of normal negative charge revealed by decreased colloidal iron stain of podocytes

    • Globally sclerotic glomeruli may be seen in MCD in adults

      • 10% of glomeruli may be sclerotic by age 40 and 30% by age 80

    • In children, involuted glomeruli are sometimes present

      • Lack of atrophic tubules indicates developmental rather than acquired glomerular sclerosis

  • Tubules

    • Protein resorption droplets (“hyaline droplets”)

      • PAS(+) and red on trichrome stain

    • Lipid droplets

      • Origin of term “lipoid nephrosis”

      • Clear vacuoles on H&E, PAS, and trichrome

      • Red droplets on oil red O stained frozen sections

    • Usually little to no tubular atrophy

      • Older patients with concurrent arteriosclerosis may have underlying glomerular obsolescence and tubular atrophy

    • Tubular regenerative changes and injury in adults with acute renal failure

  • Interstitial inflammation and fibrosis are usually absent

    • Interstitial foam cells may be seen but are rare



  • Typically no deposits of immunoglobulin or complement

  • Minority have faint (≤ 1+) staining in glomeruli for IgM ± C3

    • < 5% of MCD cases have mesangial staining for IgG, IgM, IgA, C1q, &/or C3, particularly in children

      • Prognosis may be worse in these cases, with higher rate of steroid resistance

      • Paramesangial pattern suggests nonspecific entrapment

  • Renal tubular resorption droplets stain for albumin

    • Usually, there is little immunoglobulin or C3 droplets in tubules (variable)

Electron Microscopy

  • Transmission

    • Podocyte foot process effacement (FPE) is widespread and the only major change by EM

      • Usually, FPE is diffuse and severe, involving > 75% of capillary surface

      • “Effacement” preferred to “fusion” since foot processes retract rather than fuse and cell body spreads on GBM

      • Extent of FPE (% of surface) correlates with severity of proteinuria

      • Filtration slit diaphragms are lost

      • After remission, foot processes return to normal

      • Although FPE is primary feature of MCD, it occurs in any renal disease with severe glomerular proteinuria

    • Podocytes may be “swollen”

      • Vacuolization and microvillous transformation

      • Contain resorption droplets and increased cellular organelles

    • Mild mesangial expansion in minority of cases

      • Vague mesangial and paramesangial electron densities may be seen, representing nonspecific protein insudation rather than true immune complex deposition

    • Tubules

      • Proximal tubules contain electron-dense resorption droplets (secondary lysosomes) and electron-lucent lipid droplets


  • Decreased nephrin along GBM, corresponding with loss of slit diaphragms

    • Nephrin loss is seen in other diseases with FPE, and this stain is not routinely performed


Focal Segmental Glomerulosclerosis (FSGS)

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Minimal Change Disease

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