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Primary Glomerulonephritis

Dr. Malik Mohd. Azharuddin


Lecturer
Dept. of Medicine

Glomerulous
Glomerulus consists of a combination of
Cellular elements:
Endothelial cells
Mesangial cells
Visceral and parietal epithelial cells

Extracellular matrix:
Glomerular basement membrane (GBM)
Mesangial matrix

Glomerular filtration
Extraordinarily high

permeability to water
and small solutes
Impermeability to
proteins, such as
molecules of the size of
albumin (3.6-nm
radius; 70 kDa) or larger.
Discrimination depends
on
size (the larger, the less

permeable)
charge (the more
cationic, the more
permeable).

Glomerulonephritis
Glomeulonephritis is an immune-mediated renal

disease induced by three mechanisms.

Antibody-mediated
Antibody react with fixed glomeular antigen (i.e.,

IgA)
Circulating antigen-antibody complex that trapped
by glomerulous (i.e., acute (diffuse) proliferative GN).
Cell-mediated: caused by sensitized T-cells
Activation of alternative complement pathway

Terminology
All glomeruli are involved: Diffuse (generalized)
< 50% glomeruli are involved: Focal
In one glomerulus:
if the whole glomerulus is involved : Global
portion of the tuft is involved: Segmental
Other terminologies in common use:
Proliferative: increase in cell number cells
Sclerosing: Hardining of the tissue

Histologic Lesions
Hypercellularity.
Cellular proliferation of mesangial or endothelial cells.
Leukocytic infiltration
Formation of crescents. These are accumulations of

cells composed of proliferating parietal epithelial cells


and infiltrating leukocytes.

Basement Membrane Thickening.


Deposition of amorphous electron-dense material, on

the endothelial or epithelial side of the basement


membrane or within the GBM itself. Most often immune
complexes but fibrin, amyloid, cryoglobulins, and
abnormal fibrillary proteins may also be deposited.
Increased synthesis of its protein components, as
occurs in diabetic glomerulosclerosis

Epimembranous deposits

Subepithelial humps

Mesangial deposits

Subendothelial

deposits

Histologic Lesions
Hyalinosis denotes the accumulation of homogeneous and

eosinophilic material by light microscopy that is extracellular


and amorphous on EM. It is made up of plasma proteins that
have insudated from the circulation into glomerular
structures. When extensive, this change contributes to
obliteration of the capillary lumens of the glomerular tuft.
Hyalinosis is usually a consequence of endothelial or
capillary wall injury and typically the end result of various
forms of glomerular damage. It is a common feature of focal
segmental glomerulosclerosis.

Sclerosis is characterized by accumulations of extracellular

collagenous matrix, either confined to mesangial areas as is


often the case in diabetic glomerulosclerosis, or involving the
capillary loops, or both. The sclerosing process may also
result in obliteration of some or all of the capillary lumens in
affected glomeruli, which in turn can result in formation of
fibrous adhesions between the sclerotic portions of glomeruli
and the nearby parietal epithelium and Bowman capsules.

The Glomerular Syndromes


Nephritic syndrome: Hematuria, azotemia,

variable proteinuria, oliguria, edema, and


hypertension

Rapidly progressive glomerulonephritis: Acute

nephritis, proteinuria, and acute renal failure

Nephrotic syndrome: >3.5 gm/day proteinuria,

hypoalbuminemia, hyperlipidemia, lipiduria

Chronic renal failure: Azotemia uremia

progressing for months to years

Isolated urinary abnormalities: Glomerular

hematuria and/or subnephrotic proteinuria

Glomerular diseases
PRIMARY GLOMERULOPATHIES
Diffuse proliferative

glomerulonephritis
Post-infectious
Other

Rapidly progressive

(crescentic)
glomerulonephritis
Membranous glomerulopathy
Minimal-change disease
Focal segmental
glomerulosclerosis
Membranoproliferative
glomerulonephritis
IgA nephropathy
Chronic glomerulonephritis

SYSTEMIC DISEASES WITH

GLOMERULAR
INVOLVEMENT
Systemic lupus
erythematosus
Diabetes mellitus
Amyloidosis
Goodpasture syndrome
Microscopic
polyarteritis/polyangiitis
Wegener granulomatosis
Henoch-Schnlein purpura
Bacterial endocarditis
HEREDITARY DISORDERS
Alport syndrome
Thin basement membrane
disease
Fabry disease

Glomerulonephritis
Primary glomeulonephritis (GN):
Acute (diffuse) proliferative GN
Rapidly progressive (crescentic) GN
IgA nephropathy
Nephritic syndrome
Anti-GBM Disease
Membranoproliferative GN
Minimal change disease
Nephrotic syndrome
Focal segmental glomeulosclerosis

Membraneous GN

Primary glomerulonephritis
(GN)
Nephritic syndrome:

Acute (diffuse) proliferative GN


Rapidly progressive (crescentic) GN
IgA nephropathy

Nephrotic syndrome:
Minimal change disease (lipoid nephrosis or nil)
Focal segmental glomeulosclerosis
Membranous GN
Membranoproliferative GN

Acute (diffuse) proliferative GN


(Poststreptococcal GN)
It is an immune complex-mediated disease.
It is caused by an exogenous antigen (endostreptosin)

following infection of the pharynx or skin with strain of


group A -hemolytic streptococcus .

Typically affects children between the ages of 2 and 14

years, but 10% of cases are patients older than 40.

It is more common in males, and the familial or cohabitant

incidence is as high as 40%.

Skin and throat infections with particular M types of

streptococci (nephritogenic strains) antedate glomerular


disease; M types 47, 49, 55, 2, 60, and 57 are seen
following impetigo and M types 1, 2, 4, 3, 25, 49, and 12
with pharyngitis.

Poststreptococcal glomerulonephritis due to impetigo

develops 26 weeks after skin infection and 13 weeks after


streptococcal pharyngitis.

Poststreptococcal GN
Classic presentation - acute nephritic picture with hematuria, pyuria,

red blood cell casts, edema, hypertension, and oliguric renal failure,
which may be severe enough to appear as RPGN.

Systemic symptoms of headache, malaise, anorexia, and flank pain

(due to swelling of the renal capsule) are reported in as many as 50%


of cases.

Five percent of children and 20% of adults have proteinuria in the

nephrotic range.

In the first week of symptoms, 90% of patients will have a decreased

levels of C3 with normal levels of C4. Positive rheumatoid factor (30


40%), cryoglobulins and circulating immune complexes (6070%),
and ANCA against myeloperoxidase (10%) are also reported.

Positive cultures for streptococcal infection are inconsistently present

(1070%), but increased titers of ASO (30%), anti-DNAase (70%) or


antihyaluronidase antibodies (40%) can help confirm the diagnosis.

The diagnosis of poststreptococcal glomerulonephritis rarely requires

a renal biopsy.

Poststreptococcal GN

Poststreptococcal GN
Treatment is supportive, with control of hypertension,

edema, and dialysis as needed. Antibiotic treatment


for streptococcal infection should be given to all
patients and their cohabitants.
There is no role for immunosuppressive therapy, even
in the setting of crescents.
Recurrent poststreptococcal glomerulonephritis is rare
despite repeated streptococcal infections.
Overall, the prognosis is good, with chronic renal
failure being very uncommon (13%), and even less
so in children. Early death is rare in children but does
occur in the elderly.
Complete resolution of the hematuria and proteinuria
in children occurs within 36 weeks of the onset of
nephritis.

Rapidly progressive (crescentic)


glomeulonephritis (RPGN)
Rapidly progressive glomerulonephritis

(RPGN) is a syndrome associated with severe


glomerular injury and does not denote a
specific etiologic form of glomerulonephritis
A PATHOLOGICAL DIAGNOSIS
It is immune-related disease characterized by:
Extensive extracapillary profileration (crescent

formation) in a large number of glomeruli.


The proliferation cells are composed of parietal
epithelial cells and inflammatory cells
(monocytes and macrophages)

Cresentric GN

Classification and
Pathogenesis.
Type 1; Anti-GBM disease:
Renal limited
Goodpasture syndrome

Type II; Immune-complex deposition


Idiopathic
SLE
Poststreptococcus GN
IgA nephropath

Type III; Pauci-immune: most patients have

antineutrophil cytoplasmic antibody (ANCA) in their


blood.
Wegener granulomatosis
Microscopic polyangiitis
ANCA-associated
Idiopathic

RPGN- Clinical course


Acute nephritic syndrome with rapidly progressive renal failure
In Goodpasture syndrome the course may be dominated by recurrent

hemoptysis or even lifethreatening pulmonary hemorrhage.

Serum analyses for anti-GBM antibodies, antinuclear antibodies, and

ANCAs are helpful in the diagnosis of specific subtypes.

lthough milder forms of glomerular injury may subside,


the renal involvement is usually progressive over a matter of weeks

and culminates in severe oliguria.

Recovery of renal function may follow early intensive plasmapheresis

(plasma exchange) combined with steroids and cytotoxic agents in


Goodpasture syndrome. This therapy can reverse both pulmonary
hemorrhage and renal failure.

Other forms of RPGN also respond well to steroids and cytotoxic

agents.

However, despite therapy, some patients may eventually require

chronic dialysis or transplantation, particularly if the disease is


discovered at a late stage.

IgA nephropathy
The most common type of primary GN worldwide (15-40%).
It is classically characterized by episodic hematuria associated with

the deposition of IgA in the mesangium.

Male preponderance
Peak incidence in the second and third decades of life with worse

prognosis in older age.

Two most common presentations


Recurrent episodes of macroscopic hematuria during or immediately

following an upper respiratory infection in children


Asymptomatic microscopic hematuria most often seen in adults.
Between episodes, the urinalysis is normal.
Proteinuria can occur late in the course of the disease
Rarely, patients can present with ARF and a rapidly progressive

clinical picture.

Clinical and laboratory evidence suggests close similarities

between Henoch-Schnlein purpura and IgA nephropathy. HenochSchnlein purpura is distinguished clinically from IgA nephropathy
by prominent systemic symptoms, a younger age (<20 years old),
preceding infection, and abdominal complaints. .

IgA nephropathy
Immune complex-mediated glomerulonephritis defined by the

presence of diffuse mesangial IgA deposits often associated with


mesangial hypercellularity.

IgM, IgG, C3, or immunoglobulin light chains may be codistributed

with IgA.

IgA deposited in the mesangium is typically polymeric and of the

IgA1 subclass.

Renal biopsy is necessary to make the diagnosis.


Immunofluorescent pattern of IgA on renal biopsy defines IgA

nephropathy in the proper clinical context

Histologic lesions may be seen on light microscopy:


DPGN
segmental sclerosis
segmental necrosis with cellular crescent formation, which typically

presents as RPGN.

By electron microscopy, electon-dense deposits are found in

mesangial and paramesangial areas.

IgA nephropathy
IgA nephropathy is a benign disease for the majority of

patients, with progression to renal failure seen in only


2530% over 2025 years; & 530% of patients go into
complete remission.

Risk factors for the loss of renal function include


Presence of hypertension or proteinuria
Absence of episodes of macroscopic hematuria
Male sex
Older age of onset
More severe changes on renal biopsy.

There is no agreement on optimal treatment.


Angiotensin-converting enzyme (ACE) inhibitors tried in

patients with proteinuria or declining renal function.

When presenting as RPGN, patients typically receive

steroids, cytotoxic agents, and plasmapheresis.

Anti-GBM Disease
Goodpasture's syndrome = GN + Pulm. Haemorrhage
Target Epitope 3 NC1 domain of collagen IV
Bimodal Presentation
young men in their late 20s
men and women in their 6070s.

Younger onset disease is usually explosive, with

hemoptysis, a sudden fall in hemoglobin, fever,


dyspnea, and hematuria.

Hemoptysis is largely confined to smokers.


Presentation with lung hemorrhage has a better

prognosis than older populations who have prolonged,


asymptomatic renal injury.

Urgent kidney biopsy is important to confirm the

diagnosis and assess prognosis.

Anti-GBM Disease
Renal biopsy
H&E

Focal or segmental

necrosis
Crescent formation
Interstitial nephritis
Fibrosis and tubular
atrophy.
IF - linear staining for

IgG (rarely IgA).

Treatment:

Plasmapheresis
Steroids
Cyclophosphamide

Membranoproliferative
Glomerulonephritis
Also Known as Mesangiocapillary

glomerulonephritis or lobar
glomerulonephritis.
It is an immune-mediated GN characterized by

thickening of the GBM with mesangioproliferative


changes
70% of patients have hypocomplementemia.
Idiopathic disease usually presents in childhood

or young adulthood.
MPGN is subdivided pathologically into Type I,

Type II, and Type III disease.

Membranoproliferative
Glomerulonephritis
Type I MPGN - most proliferative of the three types.
Mesangial proliferation with lobular segmentation on renal biopsy.
Tram-tracking- mesangial interposition between the capillary basement

membrane and endothelial cells producing a double contour.


Subendothelial deposits with low serum levels of C 3 are typical,
although 50% of patients have normal levels of C 3 and occasional intramesangial deposits
By immunofluorescence, C3 is deposited in a granular pattern.
Type II MPGN (dense deposit disease)
Irregular, ribbon-like lamina densa due to the deposition of extremely

electron-dense structure dense material.


Classically, the glomerular tuft has a lobular appearance; intramesangial
deposits are rarely present and subendothelial deposits are generally
absent.
Type III MPGN - Proliferation is less common than the other two types

and is often focal; mesangial interposition is rare, and subepithelial


deposits can occur along widened segments of the GBM that appear
laminated and disrupted.

Membranoproliferative
Glomerulonephritis
Type I Disease (Most Common)
Idiopathic
Subacute bacterial endocarditis
Systemic lupus erythematosus
Hepatitis C cryoglobulinemia
Mixed cryoglobulinemia
Hepatitis B
Cancer: Lung, breast, and ovary (germinal)
Type II Disease (Dense Deposit Disease)
Idiopathic
Partial lipodystrophy
Type III Disease
Idiopathic

Membranoproliferative
Glomerulonephritis
Patients present with Proteinuria, hematuria, and pyuria

(30%)

Systemic symptoms of fatigue and malaise are most

common in children with Type I disease

Acute nephritic picture with RPGN and a speedy

deterioration in renal function in up to 25% of patients.

Nephrotic syndrome, hypertension, and renal

insufficiency all predict poor outcome.

Fifty percent of patients with MPGN develop end-stage

disease 10 years after diagnosis, and 90% have renal


insufficiency after 20 years.

Treatment

Proteinuria - ACE inhibitors


Steroids , particularly in children with primary disease
Secondary MPGN, treating the etiology
renal diseases can recur over time in transplanted renal

allografts

Minimal change disease


Lipoid nephrosis or nil lesion.
7090% of nephrotic syndrome in childhood but only

1015% of nephrotic syndrome in adults.


MCD usually presents as a primary renal disease but
can be associated with several other conditions,
including Hodgkin's disease, allergies, or use of
NSIADs.
Renal biopsy:
Light microscopy - no obvious glomerular lesion
Immunofluorescent microscopy - negative for deposits

or occasionally shows small amounts of IgM in the


mesangium
Electron microscopy - consistently demonstrates an
effacement of the foot process supporting the epithelial
podocytes with weakening of slit-pore membranes.

Minimal change disease


Presents clinically with the abrupt onset of edema and

nephrotic syndrome accompanied by acellular urinary


sediment.

Less common clinical features include

Hypertension (30% in children, 50% in adults)


Microscopic hematuria (20% in children, 33% in adults)
Atopy or allergic symptoms (40% in children, 30% in adults)
Decreased renal function (<5% in children, 30% in adults).

Acute renal failure in adults is usually caused by intrarenal

edema (nephrosarca) that is responsive to intravenous albumin


and diuretics. This presentation must be distinguished from
acute renal failure secondary to hypovolemia.

In children, the abnormal urine principally contains albumin

with minimal amounts of higher molecular weight proteins, and


is sometimes called selective proteinuria.

Although up to 30% of children have a spontaneous remission

all children today are treated with steroids.

MCD -Treatment
Steroids- Prednisone is first-line therapy
other immunosuppressive drugs, such as cyclophosphamide,

chlorambucil, and mycophenolate mofetil, Cyclosporine are saved


for frequent relapsers, steroid-dependent, or steroid-resistant
patients.

Primary responders are patients who have a complete remission

(<0.2 mg/24 h of proteinuria) after a single course of prednisone;

Steroid-dependent patients relapse as their steroid dose is

tapered.

Frequent relapsers have 2 relapses in the 6 months following

taper.

Steroid-resistant patients fail to respond to steroid therapy.


Ninety to 95% of children will develop a complete remission after 8

weeks of steroid therapy, and 8085% of adults will achieve


complete remission, but only after a longer course of 2024 weeks.

Patients with steroid resistance can develop FSGS on repeat biopsy

Focal segmental
glomeulosclerosis

it is focal AND it is segmental.


Frequently manifest clinically by the nephrotic

syndrome or heavy proteinuria.


Can present with any level of proteinuria,
hematuria, hypertension, or renal insufficiency.
Nephrotic range proteinuria, African-American
race, and renal insufficiency are associated with
a poor outcome, with 50% of patients reaching
renal failure in 68 years.
Treatment
ACE inhibitors for proteinria
Steroids
Other agents like cyclosporine

Focal Segmental
Glomerulosclerosis

Focal segmental
glomeulosclerosis

Focal segmental
glomeulosclerosis

Most prominent in glomeruli located at the

corticomedullary junction
Focal and segmental scarring
Other variants
Endocapillary hypercellularity and heavy

proteinuria.
Collapsing glomerulopathy with
segmental/global glomerular collapse & rapid
decline in renal function.
Glomerular tip lesion, which seems to have a
better prognosis.

Membranous
glomerulonephritis

MGN, or membranous nephropathy


MC cause of nephrotic syndrome in adults (30%)
Peak incidence between the ages of 3050 years and

a male to female ratio of 2:1. It is rare in childhood.


80% present with nephrotic syndrome and

nonselective proteinuria.
Microscopic hematuria is seen in up to 50% of

patients.
MGN has the highest reported incidences of renal

vein thrombosis, pulmonary embolism, and deep vein


thrombosis.

Membranous
glomerulonephritis

1/3rd patients undergo spontaneous remissions, 1/3 rd

continue to have relapsing nephrotic syndrome with


normal renal function, and another 1/3rd develop renal
failure or die from the complications of nephrotic
syndrome.

Male gender, older age, hypertension, and the

persistence of proteinuria are associated with worse


prognosis.

Treatment
Treatment of edema, dyslipidemia, and hypertension,

inhibition of the renin-angiotensin system is recommended


Steroids
Other Agents: Cyclophosphamide, chlorambucil,
cyclosporine, mycophenolate mofetil or anti-CD20 antibody.