Nephrotic syndrome in children

Dr. Siva

Schema of presentation

• Normal histology

• Normal electron microscopy (ultrastructure)

• Immune complex deposition – patterns

• Immunofluorescence – patterns

• Nephrotic versus Nephritis – Tetrad

• Classification of nephrotic syndrome in children

• Minimal change disease

• Take-home message

Gross anatomy of kidney

Males: 343+/-39 nm Females: 300+/-12 nm GBM thickness increases throughout childhood from 194 +/- 6.5 nm (mean +/- SE) at one year to 297 +/- 6.0 nm at 11 years

Reduced rate of increase after age 11 years

Thickness of GBM

Localization of immune complexes in the glomerulus: (1) Subepithelial humps, as in acute glomerulonephritis (2) Epimembranous deposits, as in membranous nephropathy and Heymann nephritis (3) Subendothelial deposits, as in lupus nephritis membranoproliferative glomerulonephritis (4) Mesangial deposits, as in IgA nephropathy

Nephrotic Syndrome Vs Nephritic Syndrome

Nephrotic syndrome • Massive proteinuria

• Hypoalbuminemia

• Edema

• Hyperlipidemia

Nephritic syndrome • Hematuria

• Oliguria

• Azotemia

• Hypertension

Nephrotic Syndrome (NS) in Children

• Primary (95%): Idiopathic and most common • Pure minimal change disease (MCD) – 76.4%

• MCD with mesangial proliferation – 2.3%

• Focal segmental glomerulosclerosis (FSGS) – 6.9%

• Membranoproliferative glomerulonephritis 7.5%

• Membranous nephropathy – 1.5%

• Others – 5.4%

• Secondary (3-5%) • Infections

• Drugs

• Systemic disease

Minimal Change Disease (MCD)

MCD

• Most frequent cause of NS in children

• Peak incidence: 2 – 6 years of age

• May follow respiratory infection or routine prophylactic immunization

• Relatively benign disorder

• Diffuse effacement of foot processes of visceral epithelial cells (podocytes)

• Detectable only by electron microscopy

• Glomeruli appear normal by light microscopy

MCD: Aetiology and Pathogenesis

• Absence of immune deposits in the glomerulus probably excludes classic immune complex mechanisms

• Several features of the disease point to an immunologic basis: • Clinical association with respiratory infections and prophylactic immunization

• Response to corticosteroids and/or other immunosuppressive therapy

• Association with other atopic disorders (e.g., eczema, rhinitis)

• Increased prevalence of certain HLA haplotypes in patients with MCD

• Increased incidence of MCD in patients with Hodgkin lymphoma (defects in T-cell mediated immunity)

MCD: Aetiology and Pathogenesis

• Current hypothesis: • MCD involves some immune dysfunction

• Results in the elaboration of factors (angiopoietin-like-4)

• These factors damage visceral epithelial cells

• Ultrastructural changes point to a primary visceral epithelial cell injury (podocytopathy)

• Causes defects in the charge barrier

• May contribute to the proteinuria

• Normal glomerular basement membrane:

with healthy podocyte foot processes,

serum proteins, mainly albumin, remain

within the glomerular capillary lumen.

• Disregulated immune system modifies

this integrity.

• Therefore, the actin cytoskeleton of the

podocyte and the glomerular basement

membrane are disrupted.

• Albumin and other serum proteins filter

out of the bloodstream and into the

urinary space.

• This leads to the intense proteinuria seen in nephrotic syndrome.

MCD: Aetiology and Pathogenesis

• What is the actual route by which protein traverses the epithelial cell portion of the capillary wall? Ans: Remains an enigma

• Possibilities include • Transcellular passage through the epithelial cells

• Passage through residual spaces between remaining but damaged foot processes

• Passage through abnormal spaces developing underneath the portion of the foot process that directly abuts the basement membrane

• Leakage through foci in which the epithelial cells have become detached from the basement

MCD: Morphology

• Light microscopy: Normal glomeruli

• Electron microscopy: GBM normal and no electron-dense material is deposited

• Principal lesion: In the visceral epithelial cells - uniform and diffuse effacement of foot processes

• Corticosteroid therapy: completely reverses visceral epithelial changes – remission of the proteinuria

MCD: Morphology

• Foot process effacement : other proteinuric states (e.g., membranous glomerulopathy, diabetic nephropathy)

• Effacement + normal glomeruli by light microscopy = MCD

• The cells of the proximal tubules: often laden with lipid and protein

• Reflects tubular reabsorption of lipoproteins passing through diseased glomeruli

• The historical name “lipoid nephrosis”

• Immunofluorescence microscopy: No Ig or complement deposits

MCD: Take-home Message

• Commonest cause of NS among children

• Normal glomerulus by light microscopy

• No immune complex deposition

• Primary lesion – visceral epithelial cells

• Despite massive proteinuria, renal function remains good

• Commonly no hypertension or hematuria

• Proteinuria: usually highly selective, most of the protein – albumin

• Characteristic feature: dramatic response to corticosteroid therapy

• Most children (>90%) respond rapidly to this treatment

• Long-term prognosis is excellent

• Steroid-dependent disease usually resolves by puberty