GLOMERULAR DISEASE

There are many forms of glomerular disease with pathogenesis. Variably linked
to the presence of genetic mutations, infection, toxin exposure, autoimmunity,
atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus.
 Genetic mutations

1. congenital nephrotic syndrome from mutations in NPHS1 (nephrin) and

NPHS2 (podocin) affects the slit-pore membrane at birth, TRPC6 cation
channel mutations produce focal segmental glomerulosclerosis (FSGS) in
adulthood.
2. monogenetic causes of FSGS are increasingly linked to early age of onset
and to genes encoding type IV collagen in older adults.
3. mutations in control of the complement pathway increasingly associate
with various forms of membranoproliferative glomerulonephritis (MPGN)
4. C3 glomerulopathies include dense deposit disease, or atypical hemolytic-
uremic syndrome (aHUS)
5. Alport’s syndrome, from mutations in the genes encoding for the a3, a4, or
a5 chains of type IV collagen. Produces split basement membranes with
glomerulosclerosis.
6. lysosomal storage diseases, such as a- galactosidase A deficiency causing
Fabry’s disease and N acetylneuraminic acid hydrolase deficiency causing
nephrosialidosis, produce FSGS.

 Systemic hypertension and atherosclerosis can produce pressure stress,

ischemia, or lipid oxidants that lead to chronic glomerulosclerosis,
Diabetic nephropathy is an acquired sclerotic injury associated with
thickening of the GBM secondary to the long-standing effects of
hyperglycemia, advanced glycosylation end products, and reactive oxygen
species.

 Inflammation of the glomerular capillaries is called glomerulonephritis.

1. Glomerular epithelial or mesangial cells may shed or express epitopes that

mimic other immunogenic proteins made elsewhere in the body. Bacteria,
fungi, and viruses can directly infect the kidney producing their own
antigens.
2. Autoimmune diseases such as idiopathic membranous glomerulonephritis
(MGN) or MPGN are confined to the kidney whereas systemic inflammatory
diseases such as lupus nephritis or granulomatosis with polyangiitis
spread to the kidney, causing secondary glomerular injury.
3. Antiglomerular basement membrane disease producing Goodpasture’s
syndrome primarily injures both the lung and kidney because of the narrow
distribution of the a3 NC1 domain of type IV collagen that is the target
antigen.
Mechanism: Local activation of Toll-like receptors on glomerular cells,
deposition of immune complexes, or complement injury to glomerular
structures induces mononuclear cell infiltration which subsequently
leads to an adaptive immune response attracted to the kidney by local
release of chemokines. Neutrophils, macrophages, and T cells are drawn
by chemokines into the glomerular tuft, where they react with antigens and
epitopes on or near somatic cells or their structures, producing more
cytokines and proteases that damage the mesangium, capillaries, and/or
the GBM. Immune deposits stimulate the release of local proteases and
activate the complement cascade, producing C5–9 attack complexes. In
addition, local oxidants damage glomerular structures, producing
proteinuria and effacement of the podocytes.