Lec : Nephritic diseases

Done by : Saef B Alabbadi

Date: 1/4/2018

before we start

*slides are included in bold

*robbins is very useful and Displays the information in interesting way so what i

do , i included the information from the book in notes regarding every topic

in slides

*if u did not understand any thing from sheet ,,read them from notes of book

lets go ...

Nephrotic syndrom

we will talk about 3 pattern of nephritic syndrom

1-poststreptococcal glomerulonephritis

2-IgA nephropathy

3-Hereditary nephritis

A clinical syndrome, composed mainly of

Hematuria--

…with dysmorphic red cells and red cell casts in the urine

some degree of oliguria and azotemia--

hypertension--

clinical syndrom of nephritic syndrom composed of:

-dysmorphic red cells and red cell casts in the urine , and that dysmorphic RBCs are

characteristic of glomerular pathology

-picture of acute renal failure like oliguria and azotemia

-and hypertenstion

-Proteinuria & edema may also be present but less severe than nephrotic syndrome (in

nephritic syndrom we talk only about minimal protein in urine less than 3.5 gram per day

-and usually acute onset

Acute postinfectious/poststreptococcal glomerulonephritis

*Deposition of immune complexes *Proliferation of different types of cells including WBCs & especially neutrophils *Typically: poststreptococcal, but may be: pneumococci, staphylococci…etc. …as well as several common viral diseases such as mumps, measles, chickenpox, and hepatitis B and C

*Lupus nephritis (endogenous antigen) may present with proliferative pattern…but more commonly to present with secondary membranous nephropathy Deposition of antigen-antibodies complex in glomeruli (maybe planted but mainly circulating

proliferative pattern very important here ,we see glomerulus large ,,and filled with cells like WBC ( neutrophils mainly ) ,,mesangial and endothelial cells

Lupus nephritis (endogenous antigen) Maybe come with picture similar stopoststreptococcal glomerulonephritis from side of similarity of the image like proliverative pattern ( we will see more cells in glomeruli like PSGN) but more commonly to present with secondary membranous nephropathy

Typically: a child 1-4 weeks after recovery from group A streptococcal infection …only certain “nephritogenic” strains …mostly pharyngeal or cutaneousthy Streptococcal exotoxin B (Spe B) and streptococcal GAPDH are the main streptococcal antigens

-circulating immune complexes…and may also be planted -complement classical & alternative pathway activation -hypocomplementemia -granular deposits of IgG & complement…mainly capillary (but mesangially also present to a lesser degree)

Alternative more than classical pathway…so mainly C3 is decreased in serum and it is the main complement that is deposited (C4 & C2 to a lesser extent)

--start to appear 1-4 weeks after infection of group A streptococcal (pharyngeal or

dermatome infection

--not all strains of group A streptococcus will lead to PSGN ,, only some types and we call

them nephritogenic” strains

--antigens that have possible to form immune complexes are Streptococcal exotoxin B (Spe

B) and streptococcal enzyme GAPDH

--hypocomplementemia because consuming of complement components

--complement classical & alternative pathway activation,, mainly alternative more than

classical

--in alternative more c3 deposition and consumption

--in classical more c4 and c2

--so clinically if u take blood test from pateint of PSGN You will notice less c3 in serum than

c2 or c4(consumption of c3 is more) ,,,cause more alternative activation than classical

Alternative activation lead to less c3 in blood

immunofluorescence of PSGN will show granular ,capillary pattern

--by the way in Lupus nephritis drop in c3 equivalent to c2 and c4 we call it ""full house""

all complement component droped

morphology

LM: -the most characteristic: increased glomerular cellularity…diffusely…

(caused by proliferation and swelling of endothelial and mesangial cells and by infiltrating

neutrophils and monocytes ,, as we said before : hypercellular but that hypercellular not

specific we can see it in many types of GN)

sometimes: necrosis in glomerulus

in a few cases: crescents…due to severe inflammatory injury ( rapidly progressive

GN but that’s not specific , we can see That’s rapidly progressive form in many types of GN)

EM: the deposits are seen

Subendothelially-

Intramembranous-

most prominent: subepithelial humps-

occasionally mesangial-

immunofluorescence : we said before that immunofluorescense will show granular and

capillary pattern

IgG & complement

…granular

…capillary (mainly) & some mesangial areas

These deposits usually are cleared over a period of about 2 months

Clinical course

Abrupt onset, starting by malaise, nausea, and slight fever--

Nephritic syndrome…in general here: mild to moderate--

May occasionally present as nephrotic syndrome (but mainly nephritic) --

--Recovery in most children in epidemic cases(we mean by epidemic >>child get

infection from another child ,,so if he developed PSGN it will be easy to recover from it)

--Some: rapidly progressive GN or progression to scarring and chronic kidney

disease

Sporadic (nonepidemic) cases:--

in adults: 15% to 50% of affected persons develop end-stage renal disease

over the ensuing few years or 1 to 2 decades (in adult PSGN worse than children)

--much lower incidence of developing chronic kidney disease in children

sporadic cases

--Serum complement levels are low during the active phase of the disease(as

we said before >>hypocomplementemia) , and serum anti–streptolysin O antibody

titers are elevated in poststreptococcal cases. ;)

IgA nephropathy

One of the most common causes of recurrent microscopic or gross hematuria--

and is the most common glomerular disease revealed by renal biopsy

worldwide

Usually children and young adults--

Begins as an episode of gross hematuria that occurs within 1 or 2 days of a--

nonspecific upper respiratory tract infection

Typically, the hematuria lasts several days and then subsides, only to recur--

every few month

This condition usually affects children and young adults and begins as an episode of gross

hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection.

Typically, the hematuria lasts several days and then subsides, only to recur every few

months. It may be associated with local pain. IgA nephropathy is one of the most common

the most common glomerular and is nt microscopic or gross hematuriacauses of recurre

. we can detect it by renal biopsy)( disease revealed by renal biopsy worldwide

The hallmark of the disease is: the deposition of IgA & IgA-containing--

complexes in the mesangium (IgA deposition in glomeruli mainly in mesangial cells

cells or IgA containing immune complexes )

Henoch-Schonlein purpura is a systemic syndrome involving the skin--

(purpuric rash), gastrointestinal tract (abdominal pain), joints (arthritis,)

and kidneys (in the form of mesangial IgA deposition) ""If Henoch-Schonlein

purpura involved in kidney ,, it will be very similar to IgA nephropathy ""

actually Henoch-Schonlein purpura = vasculitis ,, to be more specific it is leukocytoclastic

vasculitis but that’s leukocytoclastic vasculitis present mainly in form of Henoch-

Schonlein purpura in skin or GI or JOINTS not KIDNEY

for u to know about leukocytoclastic vasculitis : vessels fibrosis ,, necrosis of the wall ,,,

neutrophilis affect the wall of vessels nucleus of neutrophilis will be like dust

(due to abnormal Increased IgA 1 production and decreased IgA 1 clearance--

glycosylation)…suggested pathogenesis

also antibodies against abnormal IgA 1, so: also: IgA-containing immune...

complexes are also deposited

--C1q & C4 are not deposited…the alternative pathway is activated here

alternative pathway activation so that’s mean we will find deposition of C3 with IgA ))

In genetically susceptible individuals, respiratory or gastrointestinal-

exposure to microbial or other antigens (e.g., viruses, bacteria, food

proteins) will induce the increase in IgA

--Secondary IgA nephropathy is seen in celiac and liver disease(( Celiac and liver

disease can lead to IgA nephropathy Or by abnormal clearance of IgA ))

morphology

LM: variable

…normal

…or mesangial widening and segmental inflammation confined to

some glomeruli (focal proliferative GN)

…or diffuse mesangial proliferation (mesangioproliferative GN)

…or (rarely) crescentic GN

mesangial proliferation Possible occur due to mesangial deposition that lead to

hypercellular

on light microscope maybe normal or focal proliferative GN or mesangioproliferative GN or

rarely crescentic GN

IF:

The characteristic immunofluorescence picture is of mesangial deposition of IgA, often

note that C3 because it and properdin and smaller amounts of IgG or IgM ,, with C3

alternative activation

Electron microscopy: confirms the presence of electron-dense deposits in the mesangium

in a minority of cases: also subendothelial…especially in focal proliferative GN

**in focal proliferative GN : Endocapillary proliferation Accompanied by segmental

inflammation ,,,Endocapillary proliferation was result due to subendothelial deposition so

lobules become closed ,, prescence of that Indicates worse prognosis

clinical course

--More than half of those with IgA nephropathy present with gross

hematuria after an infection of the respiratory or, less commonly,

gastrointestinal or urinary tract

--30% to 40% have only microscopic hematuria, with or without proteinuria

--5% to 10% develop typical acute nephritic syndrome

--The hematuria typically lasts for several days and then subsides, only to

return every few months

Many patients maintain normal renal function for decades--

Slow progression to chronic renal failure occurs in 25% to 50% of cases over--

a period of 20 years

--Prognosis can be predicted by biopsy :

worse if: diffuse mesangial proliferation, segmental sclerosis, endocapillary

proliferation, or tubulointerstitial fibrosis

Hereditary nephritis

**Mutations in genes encoding GBM proteins

Alport syndrome…the best studied among these entities--

..nephritis is accompanied by:

-nerve deafness

-various eye disorders

..most common:

-x-linked (Mainly X linked )

-alpha 5 type IV collagen (also mainly attack alpha 5 but not always)

**The GBM is composed largely of type IV collagen, which is made up of

heterotrimers of α3, α4, and α5 type IV collagen. This form of type IV collagen

is crucial for normal function of the lens, cochlea, and glomerulus. Mutation of

any one of the α chains results in defective heterotrimer assembly and,

consequently, the disease manifestations of Alport syndrome

--Hereditary nephritis refers to a group of hereditary glomerular diseases caused by

mutations in genes encoding GBM proteins. The best-studied entity is Alport syndrome, in

which nephritis is accompanied by nerve deafness and various eye disorders, including lens

dislocation, posterior cataracts, and corneal dystrophy

Collagen 4 important in lens and cochlea ,,lens and glomeruli so damage to it ,lead to

problem in eye and ear also

**morphology

LM: unremarkable until late in the course…due to secondary sclerosis

…In some kidneys, interstitial cells take on a foamy appearance as a

result of accumulation of neutral fats and mucopolysaccharides

(foam cells) as a reaction to marked proteinuria…is this specific? NO

…With progression :

--increasing glomerulosclerosis

--vascular sclerosis

--tubular atrophy

--interstitial fibrosis

**EM: the basement membrane of glomeruli is thin and attenuated early in

the course

late: the GBM develops irregular foci of thickening or attenuation with

pronounced splitting and lamination of the lamina densa, yielding a

“basketweave” appearance

--maybe u are not able to see anything in light microscope till secondary sclerosis

developed ,, but in electron microscope we able to see thinning of basement membrane

foamy macrophage in interstitium but that not specific

**clinical course

:present at age 5 to 20 years

gross or microscopic hematuria and proteinuria

overt renal failure occurs between 20 and 50 years of age

**Female carriers of X-linked Alport syndrome or carriers of either gender of

the autosomal forms usually present with persistent hematuria, which most

often is asymptomatic and is associated with a benign clinical course. In these

patients, biopsy specimens show only thinning of the GBM

Males therefore tend to be affected more frequently and more severely than females and

are more likely to develop renal failure

Rapidly progressive glomerulonephritis (RPGN)

Not specific, just a clinical syndrome--

--Laboratory findings typical of the nephritic syndrome, and often severe

oliguria

--If untreated, it leads to death from renal failure within a period of weeks to

months

--The characteristic histologic finding associated with RPGN is the presence of

crescents

(crescentic GN)

…….produced predominantly by the proliferation of the parietal epithelial

cells lining

--Bowman capsule and by the infiltration of monocytes and macrophages

Idiopathic or due to a known cause—

--severe nephritic syndrom

--Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome and not a specific

etiologic form of GN. It is characterized by progressive loss of renal function,laboratory

findings typical of the nephritic syndrome, and often severe oliguria. If untreated, it leads to

death from renal failure within a period of weeks to months. The characteristic histologic

finding associated with RPGN is the presence of crescents (crescentic GN)""rapidly

progressive""

RPGN, classification & pathogenesis

3 **types

**type 1 : Anti-Glomerular Basement Membrane Antibody–Mediated

--renal limited or involving of lung ( goodpasture syndrome)pulmonary

hemorrhage here ,, remember 3 features in pulmonary hemorrage

hemoptysis ,,, anemia... infiltration in chest X-RAY

-- linear deposits of IgG and, in many cases, C3 on the GBM

…Anti-GBM antibodies are present in the serum …diagnosis is important to do

plasmapheresis which is effective here

the only one to do linear capillary pattern on IF--

--Plasmapheresis is the removal, treatment, blood plasma or components there It is thus

an extracorporeal therapy

--type 1 is the least common between the 3 types

type 2: immune complexes

we talk about immune complexes we see it in

postinfection glomerulonephritis ,, lupus nephritis ,,IgA nephropathy and

henoch schonlein purpura

or maybe idopathic not regarding to any of the previous causes

type 3 (paucal-immune) the most common

defined by the lack of anti-GBM antibodies or of significant immune complex deposition

detectable by immunofluorescence and electron microscopy

ANCA typically are found in the serum (P-ANKA,,C-ANKA)

C-ANKA positive in wegener granulomatosis and –

--P-ANKA positive in chrug-strauss syndrome and microscopic polyangitis

--P-ANKA antibody against MPO ,,,C-ANKA antibody against pr3 ((MPO and PR3 component

inside neutrophils))

granulomatous with polyangitis its another name of the wegener polyangitis

cuz wegener was nazi

( الشريف وليد العاق مثل)

note from our colleague abdullah ayyoub**

Just a simple explanation for the ANCA Test:

Basically this is a diagnostic test in which we put a neutrophile on a slide, and then we put

the patient's serum on it, now what happens is that the antibodies of the patient's serum

can either bind adjacent to the nucleus of the neutrophile or in the cytoplasm away from

the nucleus, now if they bind adjacent to the nucleus this is called the p-ANAC and the (p)

refers to "Perinuclear" that means around or near the nucleus.

Now if they bind in the cytoplasm this is called C- ANCA and (c) refers to "cytoplasm "

This is very high-yield to differntiate between type 3 RPGN diseases : ( a small recap for

this)

.C-Anca : comes with wegner

.P-anca comes with either microscopic polyangitis or chrug-strauss disease and we can

differentiate between these 2 diseases clinically after we rule out wegner by the ANCA test

12% of the patients have anti-GBM antibody–mediated crescentic GN with or

without lung involvement

44% have immune complex GN with crescents

•The remaining 44% have pauciimmune crescentic GN

BEST OF LUCKS