– Neutrophils and monocytes
– Macrophages, T lymphocytes, and NK,
– Resident glomerular cells, mesangial cells
• Generation of C5a and the recruitment of
neutrophils and monocytes.
• Release proteases- GBM degradation; ROS-cell
damage and AA metabolites- reduction in GFR.
Mediators of Immune Injury
The membrane attack complex, C5b-C9: causes cell lysis
Eicosanoids, NO, angiotensin, and endothelin : involve in
Cytokines, particularly IL-1 and TNF
Chemokines such as MCP-1 and RANTES promote monocyte and
Growth factors: PDGF, TGF-β etc seem to be critical in the ECM
deposition and hyalinization leading to glomerulosclerosis in chronic
The coagulation protein: fibrin stimulate crescent formation in
The Nephrotic Syndrome
• Non-immune complex
– FSGS, collapsing glomerulopathy
– C1q nephropathy, congenital NS(Finnish type)
• Immune complex
– Membranous glomerulopathy
– MPGN type 1
– Dense Deposit Disease
– Fibrillary GN
– Immunotactoid GN
The Nephrotic Syndrome
• Nephrotic syndrome refers to a clinical complex that
includes the following:
– Massive proteinuria, with the daily loss of 3.5 gm
or more of protein
– Hypoalbuminemia, with plasma albumin levels
less than 3 gm/dL
– Generalized edema
– Hyperlipidemia and lipiduria
• The initial event is a derangement in the capillary walls
of the glomeruli, resulting in increased permeability to
• The primary glomerular lesions:
– Minimal-change disease (MCD)
– Membranous glomerulopathy
– Focal segmental glomerulosclerosis (FSGS)
• Systemic causes: DM, amyloidosis, and SLE.
• The MCD- most common in children
• Membranous glomerulopathy- common in older
• FSGS- occurs at all ages.
• The MPGN, frequently present as a mixed
syndrome with nephrotic and nephritic features.
Minimal Change Disease (Lipoid Nephrosis)
• The most frequent cause of nephrotic syndrome in
It is characterized by diffuse effacement of foot
processes of visceral epithelial cells (podocytes) in
glomeruli that appear virtually normal by light
• The peak incidence is between 2 and 6 years of age.
The disease sometimes follows a respiratory infection or
routine prophylactic immunization.
Its most characteristic feature is its usually dramatic
response to corticosteroid therapy
Etiology and pathogenesis
• Associated with respiratory infections,
immunizations, lead or mercury ingestion, allergies,
• In elderly, associated with NSAIDs
• Increased prevalence of certain HLA haplotypes
• LM: glomeruli appear normal
• Cells of the proximal convoluted tubules - heavily laden with
protein droplets and lipids (lipoid nephrosis).
• IF: no immune deposits
• EM: uniform and diffuse effacement of the foot
processes of the podocytes
• Massive selective proteinuria, most of the protein
Most children (>90%) respond rapidly to
• MCD in adults can be associated with Hodgkin
• Prognosis - good
• < 5% develop CRF after 25 years
Focal segmental glomerulosclerosis
• Characterized by sclerosis of some (focal ) but
not all glomeruli and involving only segments of
each affected glomerulus
• FSGS can be:
– Primary (or idiopathic)
– Secondary to heroin abuse, HIV infection,
sickle cell disease, HTN, adaptive process to
loss of kidney or another primary glomerular
disease (IgA nephropathy) or mutation in
podocin, actin or nephrin
• Most common cause of nephrotic
syndrome in USA
• differs from minimal change disease
i) higher incidence of hematuria,
reduced GFR, and hypertension
ii) poor response to corticosteroids
iii) proteinuria is non selective
iv) progression to chronic
v) IgM and C3 trapping on sclerotic
• whether this is a specific disease or is an
evolution of minimal change disease is
• Damage of visceral epithelial cells-hallmark of
• Genetic basis
- NPHS1 gene → encodes nephrin
- several mutations of this gene give rise to
congenital nephrotic syndrome .
• Permeability-increasing factors produced by
lymphocytes have been proposed.
• Deposition of hyaline masses in the glomeruli
represents the entrapment of plasma proteins
and lipids in foci of injury where sclerosis
• Circulating mediator is the cause of the damage
• First affects only some of the glomeruli
• With progression, eventually all levels of the
cortex are affected.
• LM: Segmental glomerular sclerosis, more
pronounced at vascular pole near afferent
– Affected glomeruli exhibit increased
mesangial matrix, obliterated capillary
lumens, and deposition of hyaline masses
(hyalinosis) and lipid droplets.
IF: IgM and C3 staining
EM: effacement of foot processes.
With progression- global sclerosis of the glomeruli with pronounced
tubular atrophy and interstitial fibrosis.
Variant of FSGS: Collapsing glomerulopathy : collapse of the
entire glomerular tuft and podocyte hyperplasia.
– more severe manifestation of FSGS that may be idiopathic or
associated with HIV infection or drug-induced toxicities.
– EM: Tubuloreticular bodies +
• Little tendency for spontaneous remission
• Responses to corticosteroid therapy- poor.
• 50% of individuals: renal failure after 10
• The recurrence of proteinuria in some
persons with FSGS after transplantation
IgA Nephropathy (Berger
• Usually affects children and young adults
• One of the most common causes of recurrent
microscopic or gross hematuria
• The pathogenic hallmark is the deposition of IgA in the
• Localized variant of Henoch-Schönlein purpura
• is a systemic syndrome involving the skin (purpuric
rash), GIT (abdominal pain), joints and kidneys.
• Associated with an abnormality in IgA production and
• IgA is low in normal serum but increased in 50% of
patients with IgA nephropathy.
• Circulating IgA-containing immune complexes are
present in some individuals.
• An abnormality in glycosylation of the IgA - reduce
plasma clearance of IgA
• Entrapment of IgA immune complexes in the
mesangium, and activation of the alternative
• Glomeruli may be normal or may show
mesangial widening and segmental inflammation
confined to some glomeruli
• Diffuse mesangial proliferation
• IF: mesangial deposition of IgA, often with C3
and properdin and smaller amounts of IgG or
• EM: electron-dense deposits in the mesangium.
• Affects people of any age, but older children and young
adults are most commonly affected.
• Gross hematuria
• 30% to 40% have only microscopic hematuria, with or
without proteinuria; and 5% to 10% develop a typical
acute nephritic syndrome.
• Slow progression to chronic renal failure occurs in 15%
to 40% of cases over a period of 20 years.
• Recurrence of IgA deposits in transplanted kidneys is
• Diffuse intracapillary proliferative GN
– Post streptococcal
• Diffuse extracapillar proliferative GN (Crescentic
– Goodpasture’s syndrome
• Focal proliferative GN: Berger disease (IgA
Acute Post Streptococcal GN
• Associated with nephritogenic strains of Streptococcus
pyogenes (beta hemolytic Strep group A) infection of the
pharynx or skin
• Children age 6-10:
– Hematuria, oliguria, fever, malaise and nausea 14 weeks after strep infection of pharynx or skin
(impetigo); RBC casts, proteinuria, periorbital
• Adults: may have atypical presentation with sudden
hypertension, edema, elevated BUN; 60% recover,
others develop RPGN
Etiology and Pathogenesis
• Is an immunologically mediated disease.
• Only certain strains of group A β-hemolytic streptococci
• > 90% of cases- types 12, 4, and 1
• Identified by typing of M protein of the cell wall
• The latent period between infection and onset of
nephritis is compatible with the time required for the
production of antibodies and the formation of immune
• LM: The classic diagnostic picture is enlarged,
• The hypercellularity is caused by
– infiltration by leukocytes, both neutrophils
– proliferation of endothelial and mesangial
– and in severe cases by crescent formation
• The proliferation and leukocyte infiltration are
diffuse involving all lobules of all glomeruli.
• There is also swelling of endothelial cells, and
the combination of proliferation, swelling, and
leukocyte infiltration obliterates the capillary
• There may be interstitial edema and
inflammation, and the tubules often contain red
• IF: Granular deposits of IgG, IgM, and C3 in the
mesangium and along the GBM. Although immune
complex deposits are almost universally present, they
are often focal and sparse.
• EM: Discrete, amorphous, electron-dense deposits on
the epithelial side of the membrane, often having the
appearance of “humps”.
• Subendothelial and intramembranous deposits are also
• Mesangial deposits may be present
Post Strepto GN
Post Streptococcal GN
Enlarged hypercellular glomeruli.
Obstruction to blood flow.
• Young child
– Sudden malaise, fever, nausea, oliguria, and
hematuria 1 to 2 weeks after recovery from a sore
• O/E: RBC casts in the urine, mild proteinuria (usually < 1
gm/day), periorbital edema, and mild to moderate
• In adults: sudden appearance of HTN or edema,
elevation of BUN.
• Elevations of ASO titers and a decline in the serum C3
and other components of the complement cascade.
• More than 95% of affected children recover
totally with conservative therapy.
• In adults: about 60% of patients recover
• In the remainder the glomerular lesions fail to
resolve quickly, as manifested by persistent
proteinuria, hematuria, and hypertension.
• May develop chronic GN or a syndrome of
• (1% develop RPGN, 1-2% develop chronic GN;
2-5% die from pulmonary edema, hypertensive
Nonstreptococcal Acute GN
• A similar form of GN occurs sporadically in
association with other infections
– staphylococcal endocarditis, pneumococcal
pneumonia, and meningococcemia
– hepatitis B, hepatitis C, mumps, HIV infection,
varicella, and infectious mononucleosis
– malaria, toxoplasmosis
• IF: Granular deposits and subepithelial humps
• Syndrome associated with severe glomerular
• Characterized clinically by rapid and progresive
loss of renal function associated with severe
oliguria and renal failure within weeks to months
• Regardless of cause, classic histologic pattern is
presence of crescents in most of the glomeruli
Rapidly progressive GN (RPGN)
• Also called extracapillary proliferative GN, because
cell proliferation is primarily in Bowman’s space
• Crescents are end result of damage to glomerular
BM or Bowman's capsule; due to deposition of fibrin,
epithelial cells and inflammatory cells
• Crescents affect at least in 50% of glomeruli
• Rapid, usually irreversible loss of renal function
associated with severe oliguria and hematuria,
unresponsive to steroids
• Symptoms of nephritic syndrome, nephrotic
syndrome and renal failure
• Causes death within weeks if untreated.
• It represents the end stage of a variety of
entities, prominent among which are the
CrGNs, FSGS, MN, IgA nephropathy, and
• 20% of cases arise with no history of
symptomatic renal disease.
Kidneys are symmetrically contracted.
Microscopically, the feature common to all cases is advanced
scarring of the glomeruli, sometimes to in the point of complete
Obliteration of the glomeruli is the end point
Marked interstitial fibrosis- atrophy and dropout of many of the
tubules in the cortex, and diminution and loss of portions of the
peritubular capillary network.
The small and medium-sized arteries are frequently thick walled,
with narrowed lumina, secondary to hypertension.
Lymphocytic infiltrates are present in the fibrotic interstitial tissue.
• Often discovered only late in its course
• Proteinuria, HTN, or azotemia- routine
• In some individuals - nephritic or the
• Without treatment, the prognosis is poor
• Renal dialysis and kidney transplantation