Glomerular disease postgraduate magdi sasi 2019

GLOMERULAR DISEASE
Glomerulonephritis is a renal disease characterized by inflammation & damage of the
glomeruli. This allows the leak of protein +/- blood in the urine.
It may present with…
A. Isolated haematuria and/or proteinuria
B. Nephrotic syndrome
C. Nephritic syndrome
D. Acute renal failure
E. Chronic renal failure
 Glomerulonephritis (GN) is generally categorized into either proliferative or non-
proliferative .
 Diagnosing the pattern of GN is important because outcome & treatment depend
on the type. Chronic glomerular disease is one of the most common causes of
chronic renal failure .
 Glomerular disease can be primary kidney lesions or secondary to some systemic
disease like diabetes mellitus ,SLE , Vasculitis.
 Rarely it can be hereditary like Alport syndrome and fabry disease.
CLININAL MAINFESTATION:
GLOMERULAR DISEASE CLINICAL MAINFESTATION
Acute nephritic syndrome Hematuria
Hypertension
Azotemia
Mild proteinuria
Oliguria
Odema
Rapidly progressive glomerulonephritis Features of acute nephritis
Proteinuria
Acute renal failure
Nephrotic syndrome Heavy proteinuria >3 gm
Hypoalbuminemia
Oedema
Lipiduria
Chronic renal failure Azotemia
Uremia
HISTOLOGIC ALTERATIONS:
 HYPERCELLULARITY
 BASEMENT MEMBRANE THICKENING
 HYALINIZATION AND SCLEROSIS

HISTOLOGIC CHANGES IN GLOMERULI CAN BE :
1. DIFFUSE:--involving all glomeruli
2. FOCAL:-- involving a few glomeruli
3. GLOBAL:--involving the entire glomerulus
4. SEGMENTAL:-- involving a apart of the glomerulus
5. MESENGIAL :--affecting predominantly the mesengial region.
Non-Proliferative Glomerulonephritis:
 Characterised by the lack of proliferation of cells in the glomeruli
 Generally cause Nephrotic Syndrome
Proliferative Glomerulonephritis
 Characterised by ↑ numbers of cells in glomeruli
 Usually presents with Nephritic Syndrome
 Dangerous! – can progress to end-stage-renal-failure over weeks to years

PATHOGENSIS OF GLOMERULAR INJURY:
Immune mechanisms are responsible for most of the primary & secondary glomerular disorders.
IMMUNE MECHANISMS OF GLOMERULAR INJURY
1. Antibody mediated injury:
a. INSITU IMMUNE COMPLEX DEPOSITION
Fixed tissue antigens present in kidney----
1.Type IV collagen of the basement membrane
2. Heymann antigen ( basal surface of visceral epithelial cells )
3. Mesangial antigens
4. Others
b. PLANTED ANTIGENS:
i. 1.Exogenous ( bacteria , drugs )
ii. Endogenous ( DNA , nuclear proteins ,immune complexes
immunoglobulin
2. Circulating immune complex deposition
A. Endogenous antigens ---DNA ,tumor antigens
B. Exogenous antigens ----infectious products
3. Cytotoxic antibodies
4. Cell mediated immune injury
5. Activation of alternate complement pathway

RENAL SYNDROMES:
1) NEPHROTIC SYNDROME
2) NEPHRITIC SYNDROME
3) ACUTE RENAL FAILURE
4) CHRONIC RENAL FAILURE
NEPHROTIC SYNDTOME
N.S. is defined as the excretion of more than 3.5gm protein/24hours associated
with hypoalbuminemia ,hypercholesterolmia and odema.
MAINFESTATION OF N.S.:
1. MASSIVE PROTEINURIA
2. HYPOALBUMINEMIA
3. GENERALIZED OEDEMA
4. HYPERLIPEDEMIA AND LIPIDURIA
Causes of nephritic syndrome:
1. PRIMARY GLOMERULAR DISEASE:
DISEASE CHILDREN (( %)) ADULTS (( % ))
MEMBRANOUS GLOMERULOPATHY 5 30
MINIMAL CHANGE DISEASE 65 10
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 10 35
MEMBRANOGLOMERULONEPHRITIS 10 10
IGA NEPHROPATHY 10 15
2. SYSTEMIC DISEASES:
A. Diabetes mellitus
B. SLE
C. Amyloidosis
D. Drugs ----NSAIDS ,Heroin ,Penicillamine
E. Infection ----malaria ,syphilis ,hepatitis B
F. Malignancy ---carcinomas ,lymphoma
G. Miscellaneous ---allergy , hereditary
MINIMAL CHANGE DISEASE(( LIPOID NEPHROSIS ))
Clinical :
 Most common cause of NS in children , 20—15%
cases of NS in adults
 Selective proteinuria
 Sudden onset of sever NS , with
hypoalbuminemia ,hypercholesterolemia
,normal BP/ GFR

 Urinalysis ---4+ protein ,oval fat bodies ,hematuria in 20% cases
 Initial treatment ---steroids
 Does not cause progressive renal failure with good prognosis.
 Diagnosis is by renal biopsy.
BIOPSY:
Notice the four black arrows in the normal specimen. They are
pointing out a normal feature of kidney cells called “foot
processes”. These foot processes are an important part of the
kidney filters themselves, and are essential for determining what
gets filtered out of and what stays in the circulation.
The individual foot processes can no longer be made out- it is
like they have all just “melted” together into a single thin
layer. This important barrier in the filtration process can no
longer keep protein from being filtered out of the blood and
into the urine.
L.M. finding : no glomerular abnormality
I.F .finding : no glomerular Ig deposits (( occasionally Ig M))
E.M. finding : diffuse foot process effacement

How did the patient get it?
Minimal Change Disease is one of the most common causes of the Nephrotic Syndrome ,
especially in children. In fact, almost 90% of children 10year and under with the Nephrotic
Syndrome end up having MCD when biopsied (as opposed to 20% of adults).
It is of two categories, primary and secondary. Secondary means that the MCD was
caused by, or is at least associated with, another medical condition. MCD has been
associated with all of the following, usually in adults:
1. Drugs NSAIDs, lithium, some antibiotics, bisphophonates
2. Malignancy Leukemia, Lymphoma
3. Infection Syphillis, HIV, Hepatitis
4. Allergy Associated with multiple environmental allergies
Secondary MCD is very uncommon, and a diagnosis of MCD does not need any a
“workup” for any of the above conditions.
What are the symptoms?
The clinical presentation is Nephrotic Syndrome. This syndrome always includes-
1. >3 g proteinuria per day
2. Hypoalbuminemia
3. Generalized edema (swelling)`
4. Hyperlipidemia (high cholesterol)
Hypercoagulability (increased tendency to form blood clots)
The most noticeable symptom of MCD is often edema, or swelling, which can be profound. This
typically starts in the feet and legs, but can move into the hips and abdomen as well. In contrast
to many of the other diseases that can cause the Nephrotic Syndrome, the proteinura and edema
of MCD can develop very rapidly- almost overnight. Unlike the majority of other kidney diseases,
especially those that cause the Nephrotic Syndrome, the ability of the kidney to clean the blood is
often unaffected in MCD. This is especially true in children and young adults.
None of the above symptoms, or even all of them together, is specific for MCD. If your doctor are
concerned about MCD, the only way to know for sure is to have a kidney biopsy. However,
because of how common this disease is in children, when a child is diagnosed with the Nephrotic
Syndrome he is typically treated for Minimal Change Disease before undergoing a biopsy. If this
therapy does not immediately improve symptoms and decrease the amount of protein in his
urine, then a biopsy to look for another cause is considered.
What is the treatment?
Minimal Change Disease is one of the more treatable kidney diseases, especially in children.
Therapy almost always consists of a course of oral steroids (prednisone), which is generally
effective within weeks. A complete remission is not uncommon, though the disease can come
back later in life. Patients with recurrent MCD, or with MCD that does not completely resolve with
steroids, may require other forms of chemotherapy.

It is also important for someone with MCD to be on medication that reduces the amount of
protein in the urine. These are ACE-inhibitors (angiotensin converting enzyme inhibitors) and
ARBs (angiotensin II receptor blockers). If urine protein levels are high, the complications of the
Nephrotic Syndrome should also be considered; patients should receive routine cholesterol
screening/treatment, and remember their tendency to form clots(( anticoagulant)) .
FOLLOW UP:
Every patient with MCD must have their kidney function monitored regularly. If kidney function
declines, certain other interventions may become necessary.
What is the prognosis?
Even in adults, Minimal Change Disease typically has a favorable prognosis. Over 90% of
patients will respond to oral steroids, with most of these having a complete remission.
However, more than 50% of the adults who go into remission will relapse at some point
in their lives, and for these patients either another course of steroids or another form of
chemotherapy entirely may be necessary.
Although it is rare for Minimal Change Disease itself to lead to End Stage Kidney Disease,
some patients with MCD eventually develop another disease called Focal Segmental
Glomerulosclerosis (FSGS). FSGS is generally seen as a more aggressive disease, with less
treatment options and more of a tendency towards eventual kidney failure.
SUMMARY:
MCD ---present with nephrotic syndrome
Common in children
Can be 1ry or 2ry to drugs ,infections , CTD
Generalized edema within 24 hours is characteristic
Respond to steroids
High risk of DVT ,renal artery thrombosis
Need heparin while the patient is under treatment in hospital
Diagnosed by 24 hour urine collection for proteinuria , decreased serum albumin with
Hypercholestremia in blood with edema as the only clinical sign

MEMBRANOUS GLOMERULOPATHY:
Clinical :
Non selective type of proteinuria
Most common cause of nephrotic syndrome in adults ,after FSGS.
Most frequently is idiopathic . It can be associated with chronic antigenic
stimulation : infections (( HBV , HCV ,Syphilis ,Malaria )) , cancer , mediaction ((
gold ,penicillamine )) systemic diseases(( thyroditis ,SLE )).
50% of cases have hematuria
Prognosis is variable . Although mild cases have spontaneous remission ,some
patients evolve to ESRD.
Diagnosis is confirmed by renal biopsy.
What is Membranous Nephropathy?
Membranous Nephropathy (MN) is a kidney disease that can occur by itself (primary) or in
conjunction with several other diseases (secondary). MN is one of the most common causes of the
nephrotic syndrome in adults. Over time this can lead to kidney failure as well.
MN is caused by the buildup of immune complexes within the kidney itself. Immune complexes
are made when a person’s antibodies attack something they consider foreign to the body (an
antigen). This is often an infection of some sort. An antibody +an antigen = an immune complex.
These immune complexes are normally eliminated while still in the circulation.
BIOPSY:
L.M. finding: normal glomeruli or thick glomerular capillary basement membrane ,normal
cellularity , spikes on silver stains.
I.F.findings: Granular IgG and complement are present along glomerular capillary loops.
E.M. findings: subepithelial electron –dense deposits and foot process effacement.
PATHOGENSIS:
An insitu I.C. formation and complement activation .
Ag in experimental models is Gp 330 (( Heyman Ag )) in coated pits of epithelial cells .Ag
can also be entrapped or planted.

The antibodies floating in the blood pass through the vessel wall and encounter the antigen. The
resulting immune complexes become stuck in that space. Over time they begin to further activate
the immune system. This activation causes inflammation and damages the kidney itself.
This damage can be seen under the microscope as a “thickening” of the vessel walls within the
kidney filters.
How did I get it?
MN usually occurs in adults older than forty, and is fairly rare in children.
Men are affected more often than women.
Whites are affected more commonly than blacks.
Though we know how the kidney damage occurs in MN, we don’t know exactly why the
immune complexes occur in all people.
In these cases the disease is called Primary MN.

In Secondary MN, the same type of kidney injury occurs but is associated :
a) Systemic Lupus Erythematosis (Lupus)
b) Hepatitis B and C
c) Cancers (especially of the lung or colon)
d) Drugs, such as penicillamine, gold, and non-steroidal anti-inflammatory drugs.
Anyone who is found to have MN, especially those over 50 years old, should be tested for
Hepatitis and undergo routine age-appropriate cancer screening.
SYMPTOMS:
MN often causes the Nephrotic Syndrome .
The most noticeable symptom of MN is often edema, or swelling, which can be serious.
This typically starts in the feet and legs. But it can move into the hips and abdomen as well.
Other symptoms include high blood pressure, high cholesterol, and a tendency to form
blood clots.
Protein levels can be measured in a urine sample. Kidney function can be calculated from a
blood test alone or measured more directly using a 24-hour urine collection. MN can cause
protein in the urine alone. It can also cause protein in the urine and kidney failure
together.
None of the above symptoms or even all of them together, is specific for MCD. If the
doctor are concerned about MN, the only way to know for sure is to have a kidney biopsy.
MN is not an easy disease to treat.
1. Should be seen regularly by a kidney specialist.
2. It is important to be on a medication that reduces the amount of protein in the
urine. ACE-inhibitors and ARBs
3. If urine protein levels are high, the complications of the Nephrotic Syndrome should
also be considered—anticoagulant to avoid DVT ,PE.
4. Patients should receive routine cholesterol screening/treatment.
5. Finally, patients with MN must have their kidney function monitored regularly. If
kidney function declines, certain other interventions may become necessary.
6. Immunosuppressants are also being used to treat MN. The most common of these
are steroids. For MN this is often combined with another type of chemotherapy, such as
cyclophosphamide or chlorambucil. Unfortunately, all of these drugs have significant
side effects. Their use must be considered on a patient-by-patient basis.
In secondary MN , it is most important to treat the underlying disease (infection, cancer, or
autoimmune) or to stop the causative drug. Often this is enough to get rid of, or at least significantly
improve, the kidney disease.
What are the chances of getting better?
Up to 40% of patients with MN undergo a spontaneous remission within 5 years, even
without therapy. These patients do not necessarily stay in remission, however.
On average, 20 years after diagnosis, 1/3 complete remission, and 1/3 progressed to end-
stage renal disease and need dialysis. Another 1/3 will be somewhere in the middle. Those
people that initially have more than a gram of protein in their urine per day for more than
six months tend to do worse. Their renal function often declines regardless of therapy.
Kidney Transplant in Membranous Nephropathy:
Unfortunately, many patients diagnosed with MN will eventually progress to kidney
failure. Fortunately, kidney transplant is a treatment option for these patients.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS
It is a relatively common form of kidney disease, especially in the US. Although there are several
known risk factors, we don’t yet know why most people develop FSGS.
FSGS is named for the scarring, or “sclerosis,” ((found in the kidney of people)). When glomeruli are
damaged they become scarred. They are no longer able to filter blood appropriately. This is called
“glomerulosclerosis”.
The word “focal” is added because in FSGS, only some of the filters are damaged. “Segmental” is
included because often only parts of the filters are scarred.
Clinical :
 Most common cause of idiopathic NS in adults ,especially African-Americans.
 The disease is twice as common in blacks than in whites.
 Occurs in all age groups ,very heterogenous disease .
 HTN and reduction in GRF common.
 Non selective proteinuria.
 When nephritoc syndrome does not respond to treatment ,the prognosis is poor .
 It may evolve to ESRD .
 Most common cause of nephritic syndrome and renal failure associated with HIV
infection.
How is at risk?
No one is sure. There are two big categories, primary and secondary. These are some of
the secondary causes/associations.
a) Kidney defects from birth
b) Urine backing up into kidneys--
Reflux nephropathy
c) Viruses –HIV 1 ,parvovirusB19
,CMV ,EBV, simian virus 40
d) Heroin ,Interferon α β Ɣ ,lithium ,
lithium ,pamidronate ,sirolimus
anabolic steroids ,calcineurine
inhibit nephrotoxicity
e) Adaptive –mediated by adaptive
structural and functional response
to glomerular HTN caused by
elevated glomerular capillary
pressure and flow:
Conditions with reduced renal mass---oligomeganephronosis ,very low birth
weight , renal dysplasia ,cortical necrosis causes ,reflux nephropathy ,renal
allograft ,aging kidney ,surgical renal ablation
f) Conditions with normal renal amss—HTN ,acute or chronic veno-occlusive
processes (( atheroembolization ,thrombotic microangiopathy ,renal artery

stenosis)) ,increased body mass index (( obesity ,body building –increased lean
body mass )) ,cyanotic congenital heart disease, Sickle Cell Anemia
g) Obstructive Sleep Apnea
Secondary focal segmental glomerulosclerosis from exposure may be due to virus-induced
or drug-induced disease. Viruses can act on the podocyte either by direct infection or by
the release of inflammatory cytokines that interact with podocyte receptors. The best
studied of such viruses is human immunodeficiency virus type 1 (HIV-1), which directly
infects podocytes and tubular epithelial cells. The form of focal segmental
glomerulosclerosis associated with untreated HIV-1, called HIV-associated nephropathy
(HIVAN), typically progresses rapidly and is associated with glomerular collapse.
Parvovirus B19 is another virus that can infect podocytes and tubular cells, leading to
collapsing focal segmental glomerulosclerosis.
Other viruses associated with this disease, such as simian virus 40, cytomegalovirus, and
Epstein-Barr virus, are less well characterized. Heroin use is associated with focal
segmental glomerulosclerosis, though the incidence of this drug-induced disease has fallen
sharply in parallel with the increasing purity of modern street heroin.
The bisphosphonate pamidronate, an osteoclast inhibitor, has been linked to the
development of focal segmental glomerulosclerosis.
All forms of interferon therapy, including interferon-alfa (widely used to treat hepatitis C),
interferon-beta (indicated for multiple sclerosis), and interferon-gamma have been
reported to induce focal segmental glomerulosclerosis.
In the transplanted kidney, toxic effects from calcineurin inhibitors as well as sirolimus are
associated with development of focal segmental glomerulosclerosis
Most people with the above conditions do not have FSGS. Having FSGS does NOT put
patient at risk for any of these conditions if he do not already have. However, having
family members with FSGS does increase the patient chances of developing it yourself.
Also, the disease is twice as common in blacks than in whites.
Proteinuria is a defining feature of Fssg .GS can cause nephrotic syndrome.
Many people with FSGS have no symptoms at all. The most common complaint is edema,
or swelling, especially in the legs. Often patients find that their shoes no longer fit, or that
they have suddenly put on weight. High blood pressure, or hypertension, is also a very
common finding. The hypertension in people with FSGS can often be very difficult to treat.
A blood test, urine tests, and a kidney biopsy will determine glomerulosclerosis.
FSGS can also cause abnormal results in two different routine laboratory tests .
The first is renal function test kidney (( urea and “creatinine")) .A higher level of
creatinine is expected finding .

The second test is for protein in your urine. Some people with a large amount of protein in
their urine say that their urine looks “foamy,” like bubbles built up in dishwater.
Biopsy: Having a low GFR and protein in the urine is not proof of glomerulosclerosis,
though. Since these are associated with other kidney conditions, a kidney biopsy is needed
to diagnose glomerulosclerosis. The diagnosis is made from the signs of scarring seen on
the kidney tissue sample.
Treatment :----- usually steroids and ACE-I
Diagnosis is confirmed by renal biopsy.
BIOPSY:
L.M.findings---- focal segmental glomerular sclerosis
I.F. findings --- IgM deposition in the mesangium in some cases.
E.M. findings ---- severe foot process effacement ; in patients with AIDS ,
INTRACYTOPLASMIC TUBULORETICULAR structures and test tubes are observed by EM.
PATHOGENSIS:
Probably glomerular hyperfiltration .
Exact mechanism unknown.
Which clinical and pathologic features predict outcome FSSG?
A: Black race, increased degrees of proteinuria and renal insufficiency, and severity of
interstitial fibrosis and tubular atrophy in biopsy specimens are associated with a worse
outcome. Patients with a partial or complete remission of proteinuria have better
outcomes than those who do not. The prognosis in the hemodynamic adaptive form of the
disease is typically much better than in the primary, possibly as a consequence of an
increased likelihood of complete or partial remission with RAS inhibition in this

population
In the tip variant, the glomerular scarring and damage occurs at the “tip” of the filter. This “tip” is the
beginning of the tube that carries away the urine, and it is usually on the opposite side of the filter from where
the blood vessels enter and exit. In the picture on the left, the tip is at the top- you can see that the green tube
exiting the top of the filter is blocked with a scar. The symptoms of FSGS in the tip variant often appear
suddenly. There is a large amount of protein in the urine and a tendency to develop the full Nephrotic
Syndrome .This variant also seems to be the most responsive to treatment, with most of the patients who
receive steroids undergoing a full or partial remission.
The perihilar variant has scar that forms at the hilum of the filter. This is where the blood vessels enter and
exit. The hilum is at the bottom of the filter. In this variant, the cause of the FSGS is often something that has
previously caused a reduction in the number of filters someone has. Being born with only one kidney or having
significant kidney damage early in life from reflux nephropathy can cause this type of damage.

The collapsing variant is considered the most rapidly progressive form of FSGS. It does not typically respond to
therapy. The scarring quickly affects the entire filter, causing it to collapse. Most patients that are diagnosed
with the Collapsing variant will require dialysis or a kidney transplant within one to two years despite
treatment. This variant was previously thought only to effect people with HIV. It is now found in increasing
numbers of HIV-negative patients. Collapsing FSGShas also been associated certain drugs, such as
pamidronate.
The cellular variant implies a slightly different type of scarring. The problem is an overabundance of cells that
make up the filter itself. As these cells build up, the blood vessels that make up the filter narrow and
eventually close off completely. This variant can only be diagnosed if none of the above variants are seen on
the biopsy.
Classic FSGS
If none of the above specific variations are seen on biopsy, the disease is called Classic FSGS, or FSGS NOS. This
stands for “not otherwise specified”. This form is generally less severe than the collapsing form. But having a
diagnosis of Classic FSGS does not indicate how severe the disease will be, or how it will respond to treatment.

FSGS is not an easy disease to treat.
Once a diagnosis is established on biopsy, potential secondary causes that require
specific therapies should be ruled out before a patient is presumed to have
primary focal segmental glomerulosclerosis. For example ;
The form of the disease that is caused by HIV-1 ----- antiretroviral therapy
Drug-induced forms are managed by discontinuation of the inciting agent.
1. Dietary sodium restriction as initial therapy.
2. It is also important for someone with either primary OR secondary FSGS to be
on medication that reduces the amount of protein in the urine((ACE-inhibitors
and ARBs)).
3. Many immunosuppressant are used to treat FSGS. The most common of these
are steroids . Glucocorticoid and calcineurin inhibitor therapies are successful
in approximately 50% of patients... Unfortunately, all of these drugs have
significant side effects. Their use must be considered on a patient-by-patient basis.
4. Other therapies have been tried, including alkylating agents, plasmapheresis,
and even the anti-B-cell monoclonal antibody rituximab, which also stabilizes
the podocyte actin cytoskeleton, but none of these therapies have been shown
to be effective
5. If urine protein levels are high, the complications of the Nephrotic Syndrome
should also be considered. Patients should receive routine cholesterol
screening/treatment.
Every patient with FSGS should have their RFT monitored regularly with both blood and urine studies.
COURSE?
If not treated, most patients with FSGS will eventually develop complete renal failure
and require dialysis or a kidney transplant to survive. Even with treatment, many
patients will still eventually require dialysis. How long this will take varies widely (2-20
years), and is difficult to predict. Specific forms of FSGS have been associated with
different rates of progression and responsiveness to therapy.
Kidney Transplant in FSGS:
Unfortunately, many patients diagnosed with FSGS will eventually progress to kidney
failure. Kidney transplant is a treatment option for these patients.
The risk of FSGS returning in the transplanted kidney varies from 20-50%. The risk factors that put
patients at higher risk of recurrence of FSGS are:
1. Young age (< 15 years old)
2. If it took less than 3 years from the time the FSGS was found in original kidneys to reach
kidney failure
3. The appearance of certain cells on original kidney biopsy.
4. Caucasian (White) race
5. If the patient lost a previous kidney transplant to a return of FSGS
Usually a return of FSGS in the transplant occurs very soon after the surgery. The FSGS can return
within hours to days. Most episodes will be within the first year after transplant.

Over half of the patients with recurrent FSGS in their transplant will lose their kidney within 5 years. Of all the
patients with FSGS who get a kidney transplant, about 15% will lose the kidney due to recurrent FSGS.

FSSG
Primary FSSG with FSSG with nephritic Adaptive 2ry drug ,virus
Subnephrotic proteinuria
RAS inhibition and Na restriction RAS inhibition and Na restriction TR cause
Glucocorticoid daily or alternative + RAS inhibition
No response/worsening disease
OR C.I. IF STEROID INTOLERANCE
Adult 16 weeks ,children 4-6 weeks treatment
GLUCOCORTICOID RESISTANT
CALCINEURINE INHIBITION

NEPHRITIC SYNDROME((POSTSTREPTOCOCCAL GN))
Clinical
 Nephritic syndrome usually follows a 6 –14 day latent period after a group A
beta –hemolytic streptococcal infection or a longer latent period after skin
infection. Treatment of infections has decreased incidence of postinfectious GN.
 Usually presents as –gross hematuria ,edema and hypertension.
 Reduce C3 and C4 during first 6 – 8 weeks.
 Identical clinical picture can be with complete recovery of renal function
particularly in children.
 Biopsy is performed only in cases with atypical presentation.
 This condition can occur at any age. However, it is mostly common in children ages
six to ten. This condition is also known to affect twice as many males than females.
Biopsy
L.M. findings ---hypercellular glomeruli are observed
I.F. findings ---deposition of IgG and of complement ,with a granular pattern ,along
glomerular capillary loops.
E.M. findings----confirms the presence of subepithelial electron dense deposits.
In some cases, it is possible to see well-defined rounded deposits outside of the capillary
walls which look like humps. The presence of these humps may be a sign of Post-Infectious
GN. But it can also be seen in other types of glomerulonephritis.

How did the patient get it?
The immune system protects us against diseases by finding and killing bacteria. Bacteria
and its toxins, which are called antigens, activate the immune system. The immune
system then builds antibodies which bind to the toxin. This binding activates another part
of the immune system which is called the complement system. This system is responsible
for destroying these bacteria. In other words, antibodies find the target and complement
destroys it.
In the case of Post-Infectious GN, these immune complexes (formed from antigen,
antibodies, and complement) get trapped in the kidney filters. The filters become
inflamed, which leads to ineffective kidney function. Not everybody who has a sore throat
or skin infection develops this type of glomerulonephritis. For this reason it is thought that
there are some genetic factors that put people at risk for this.
Pathogenesis :
In situ I.C.formation and complement activation. The Ag is possibly a planted cationic
bacterial protein.
The symptoms of this condition are fluid retention with generalized swelling; swelling of
the abdomen; swelling of the face or eyes; swelling of the feet, ankles, and arms and legs.
Symptoms also include high blood pressure, Coca-Cola colored urine, blood in the urine,
decreased amount of urine, joint stiffness and joint pain
How is Post-Infectious Glomerulonephritis diagnosed?
Blood pressure is often high
Physical examination shows swelling, especially of the face
Blood testing shows indicators of a specific type of recent infection.

Serum complement levels are usually decreased
Urinalysis shows protein and blood in the urine
Kidney biopsy confirms Post-Infectious GN, although biopsy is not usually necessary
 There is no specific treatment for Post-Infectious GN.
 Treatment is focused on relieving symptoms.
 Antibiotics, such as penicillin, should be used to treat any bacterial infection.
 Blood pressure medications and diuretic medications may be needed to control swelling
and high blood pressure.
 Dietary salt restriction may be necessary to control swelling and high blood pressure
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (( CRESENTRIC GN ))
1. TYPE I RPGN ( ANTI-GBM ANTIBODY )
Idiopathic
Good pasture syndrome
2. TYPE II RPGN ( IMMUNE COMPLEX )
Idiopathic
Post infectious
SLE
Henoch –Schonlein purpura
Others
3. TYPE III RPGN ( PAUCI IMMUNE )
ANCA associated
Idiopathic
Wegener granulomatosis
Polyarteritis nodosa /Microscopic polyangitis
MEMBRANOPROLIFERATIVE GN
Membranoproliferative glomerulonephritis (MPGN) is a disease that affects the glomeruli, or filters,
of the kidneys. Most instances of MPGN are caused by other diseases or disorders, including
autoimmune diseases (such as systemic lupus erythematosis), chronic infections (like hepatitis B or
more commonly hepatitis C), monoclonal immunoglobulin deposition diseases, and hereditary
diseases. However, a few cases are idiopathic, or of unknown cause. The idiopathic type of MPGN is
seen more commonly in persons aged 8-30.
Who is at risk?
As stated above, MPGN is usually found in patients who have other diseases. The diseases associated
most often are:
1. Autoimmune diseases (most often systemic lupus erythematosus)
2. Hepatitis B infection
3. Hepatitis C infection
4. Cryoglobulinemia
5. Monoclonal immunoglobulin deposition diseases (such as AL amyloidosis and light and
heavy chain deposition diseases)
6. Subacute bacterial endocarditis
7. Infection of a ventriculoatrial shunt
8. Chronic lymphocytic leukemia (CLL)

So, if a patient is diagnosed with MPGN, the above associated diseases should be tested for and ruled
out before the MPGN is considered idiopathic (of unknown cause). Also, as noted above, the
idiopathic type of MPGN is seen more commonly in persons aged 8-30.
The symptoms of MPGN are very similar to those of a focal glomerulonephritis. Specifically, patients
have hematuria (blood in the urine), either macroscopic, which can be seen by the naked eye, or
microscopic. Many of the red blood cells are dysmorphic (malformed or misshapen). In addition,
mild or severe proteinuria can be found (including the nephrotic syndrome).
MPGN TYPE I---MESANGIOCAPILLARY GN
Type I – Discrete immune complexes are found in the mesangium and subendothelial
space. This activates the immune system, which causes inflammation and damage to the
kidney itself.
Clinical
Can present as an acute nephritic syndrome with nephrotic syndrome.
Frequently associated with hepatitis C virus
More common in adolescents and children
Complement activation occurs in only 50% of cases in adults
Not a frequent disease
Diagnosis by renal biopsy
Biopsy
L.M. finding--- hypercellular lobulated glomeruli with double capillary basement
membrane on special stains.
I.F.findings ---demostrates IgG ,IgM and complement at the periphery of the glomerular
lobules
E.M. findings--- subendothelial electron dense deposits and new basement membrane
deposition are observed .
Pathogenesis:
Deposition of circulating IC complement activation

Type II – This is also called dense deposit disease. When viewed under the microscope, continuous,
dense ribbon-like deposits are found along the basement membranes of the glomeruli, tubules, and
Bowman’s capsule.

Type III – This is also an immune complex disease, similar to Type I. However, the immune complexes
are found in the subepithelial space, and there is disruption of the glomerular basement membrane
with large open areas.
When MPGN is associated with another condition or disease, it is usually resolved by successfully
treating the associated condition or disease. However, the optimal treatment of idiopathic MPGN is
not entirely known.
The type of treatment will depend on the type of proteinuria that the patient has. If a patient has
proteinuria that is “non-nephrotic”, then specific immunosuppressive therapy may not be necessary, as
the long-term outcome is not life-threatening. However, patients with nephrotic-range proteinuria will
typically be treated with steroids (Prednisone).
There are some treatments that patients try if the disease does not respond to steroids, including a
trial of aspirin and dipyridamole, or a combination of cyclosporine and prednisone. However, the
clinical trials that have been done on these types of alternative treatments have given us very limited
data. Decisions regarding treatment should be made after significant discussion between a patient and
his or her nephrologist
Patients with the following signs when they are first diagnosed have a worse prognosis:
Nephrotic syndrome
Kidney insufficiency
Hypertension
Crescents on kidney biopsy
What is the prognosis?
When MPGN is associated with another condition or disease, it is usually resolved by successfully
treating the associated condition or disease. For example, if MPGN is associated with Hepatitis B or C
viral infection, then MPGN tends to resolve either spontaneously or following treatment of the virus.
Specific immunosuppressive therapy for MPGN is not necessary in this case.
Alternatively, if the MGPN is considered idiopathic, then the outcome is not as good. Up to 50-60% of
untreated patients will progress to end-stage kidney disease within 10-15 years, while 25-40% of
untreated patients will continue to have normal renal function. Spontaneous remission or
improvement occurs in less than 10% of cases
IgA NEPHROPATHY OR BERGERS DISEASE –1RY NEPHRITIC SYNDROME WITH NORMAL S.COMPLEMENT
What is IgA Nephropathy?
IgA Nephropathy is a relatively common kidney disease. It affects millions of people worldwide. It is a
disease that affects the filters, or glomeruli, of the kidneys. IgA is characterized by the hematuria .This
blood may be visible to the naked eye or only seen under a microscope. Most people with this disease
lose kidney function very slowly, or not at all.
IgA Nephropathy is named for the deposits of IgA that can be seen stuck in the kidney filters when
viewed under a microscope. These components normally attach themselves to infection in the body
and trigger the immune response. This works to eliminate the infection. In this disease, a defective

form of IgA gets bound to another IgA molecule instead of an infection. This forms an immune
complex. This immune complex can become stuck in the kidney. Here it activates the immune system
just like it would if it were fighting off infection. The immune system activation causes swelling and
damage to the kidney itself. However, a diagnosis of IgA Nephropathy requires a kidney biopsy. The
sample of kidney can then be viewed under a microscope and the diagnosis confirmed .
Clinically:
Hematuria ,either recurrent gross hematuria immediately following a viral illness or as persistent
microscopic hematuria .Serum creatinine is normal . Occasionally presents with acute renal failure.
Prognosis good when patients have only hematuria
Patients with significant proteinuria more likely to have progressive renal insufficiency
Frequent world wide .In north America ,frequent among Native Americans.
Diagnosis made by renal biopsy.
Some patients ,more frequently children ,can have a systemic disease with disseminated vasculitis –Henoch
Schoenlein purpura
Biopsy—
L.M.findings—glomeruli
show increased mesengial
matrix cellularity
I.F.findings----intense
granular IgA deposition ,with
a mesengial pattern is
observed.
E.M.findings—confirms
electron dense deposits in
the mesengium
Pathogenesis
Deposition of circulating IC ((
unknown antigen))
IC are found in the glomeruli
and in many vessels
The IgA deposits have activated the immune system and damaged the vessel wall. Therefore, red blood
cells (and protein, the tiny yellow dots) are spilling out the bottom of the vessel and into the urine.
Shown is a single filter in
which the actual IgA
deposits have been
stained florescent green.

WHO IS AT RISK?
IgA is an autoimmune disease . It likely has both genetic and environmental components.
A person is born with a predisposition for the disease, and then some sort of “trigger,” for
example an infection or food exposure, turns the disease “on ”.
IgA commonly occurs in Caucasians and Asians. It is relatively uncommon in those of
African descent. It is twice as common in males as females. Though it potentially affects
any age group, IgA is most commonly diagnosed in early and middle adulthood.
Blood in the urine, either constant or occasional, is the most common finding in people
with IgA. Sometimes this blood can become visible as well. Though when it does, the
urine typically appears browner or “cola” colored, rather than bright red. Bouts of visible
blood in the urine from this disease often occur during or immediately after other short-
term illnesses, such as an upper respiratory infection.
In addition to blood in the urine, people with IgA can have protein in the urine as well. The
amount of protein in the urine is generally less than 3.5g. It can sometimes result in
significant leg swelling and fluid retention.
IgA can be suspected from blood or protein in the urine and other symptoms. But it can
only be diagnosed by a kidney biopsy.
 This disease is common, but there is no single treatment about which all doctors
agree. This is in part because of the disease tends to progress very slowly, if at all.
 Many of the drugs that could be used in treatment can be very harmful.
 It is generally accepted that blood pressure control and limiting the amount of
protein in the urine are of primary importance. Both of these goals can often be
accomplished with the use of two types of blood pressure medications. ACE-
inhibitors and ARBs both help to reduce blood pressure.
 Another commonly used agent is Fish Oil. Studies do not agree on its true benefit.
However, its lack of serious side-effects leads many doctors to recommend it.
 This disease is essentially an over-activation of the immune system. Therefore,
many immunosuppressive drugs have been tried with varying success. The most
widely used are steroids, given either through a needle, by mouth, or both for at
least 6 months.
IgA often progresses slowly. Doctors may simply follow some patients with normal renal
function and minimal protein in the urine without starting any therapy at all. It is the
disease’s generally slow progression that has made it difficult for doctors to decide on the
one “best” treatment
PROGNOSIS:

Some patients spontaneously undergo a complete remission of symptoms and never
experience a loss of kidney function. More often, the symptoms will stabilize, or the
disease will progress slowly. On average, at 20 years (from diagnosis), 20% of patients will
have moved to end stage kidney disease. This requires either dialysis or a kidney
transplant.
Rarely, a more rapidly progressive type of IgA is seen on biopsy. In these patients,
immediate and aggressive immunosuppression is generally needed.
Kidney Transplant in IgA Nephropathy:
A portion of the patients diagnosed with IgA nephropathy will eventually progress to renal
failure. Fortunately, kidney transplant is a treatment option for these patients.
gA Vasculitis (Formerly Henoch-Schönlein Purpura or HSP)
IgA vasculitis (formerly known as Henoch Schönlein purpura) is a form of blood vessel
swelling ((inflammation)) , also known as vasculitis. It affects the small vessels called
capillaries in the skin and the kidneys. The swelling is due to an abnormal response of
the immune system. This is due to the immune system product called IgA
immunoglobulin.
What does it look like (under the microscope)?
Skin samples under a microscope show proteins IgA and C3 deposited in the blood vessel walls.
In the kidney, IgA vasculitis (Henoch Schönlein purpura) is characterized by IgA deposits in a
part of the glomerulus . These deposits can be seen under a microscope. The pathologist uses a
special staining called immunofluorescence. The deposits will give a fluorescent glow under the
microscope.

The pathologist can also white blood cells, and abnormal cell growth in some parts of
the filter. Sometimes the pathologist will see the development of cell growths called
crescents, named for their moon-like shape use Light microscopy which magnifies the
kidney by 10 to 100 times its original size. This can show a wide range of changes in
the kidney filter. These may range from increased cells in the filtering area, increase in.
WHO IS AT RISK?
IgA vasculitis has no known cause. It occurs most often in the spring. It frequently follows an
infection of the throat or the respiratory tract. It seems to represent an unusual reaction of the
body's immune system. This is in response to this bacterial or viral infection. Aside from
infection, certain medications can also trigger the condition. IgA vasculitis occurs most
commonly in children. People of all age groups can be affected.
What does it affect?
It affects the skin, joints, bowels and the kidneys. Infrequently, problems in other areas
of the body, such as the nerves, brain and lungs may occur.
 Kidney -----------33% child, 665 adults ,Red or tea colored urine, weight gain,
swelling on legs ,proteinuria ,azotemia.
 Joints -----------arthralgias and periarticular edema ((2/3)) --Joint pain and
swelling of ankles , knees , wrists and elbows
 Skin -----------Rash in buttocks and legs, appearing as red or purple
spots,nonblanching ,urticarial ,purpuric papules may become confluent ---
leukocytoclastic vasculitis
 Gastrointestinal Tract------------Abdominal pain (2/3 of the cases) may precede
the rash , nausea, vomiting, constipation or diarrhea, periumbilical pain
 Major complication --bowel obstruction ,intussuption , blood in the stools
 Lungs -------------Cough, coughing up blood
IgA vasculitis usually causes a skin rash most prominent over the buttocks and behind
the lower legs.
Purpura
It could also result in joint pain and swelling (arthritis). There is sometimes fever and
cramping pain in the abdomen. The joints that are usually affected are the ankles and
the knees. Swelling of the blood vessels in the kidneys can cause blood and/or protein
leakage into the urine. Serious kidney complications are uncommon but can lead to
advanced kidney disease. Symptoms usually last about a month.
How is it diagnosed?

No single laboratory test can confirm IgA vasculitis. Certain tests can help detect the
illness. Urine and blood tests for casts and kidney function can detect the presence of
IgA vasculitis. Samples of the skin or kidneys can be used to diagnose vasculitis.
Special stainings can be used to find the abnormal immune system product (IgA) in the
blood vessels of the areas involved.
There is no specific treatment for IgA vasculitis. IgA vasculitis is generally a mild
illness that resolves spontaneously. However, when it is severe it can cause serious
problems in the kidneys and bowels.
The treatment of IgA vasculitis will depend on what is most significantly affected.
1. Joint pain can be relieved by NSAIDS as aspirin or ibuprofen
2. Some patients require corticosteroid medications, prednisone or prednisolone.
This is especially true for those with significant abdominal pain or kidney
disease.
3. With more severe kidney disease,glomerulonephritis or nephritis.
Cyclophosphamide (Cytoxan), azathioprine (Imuran), or mycophenolate mofetil
(Cellcept) have been used to suppress the immune system.
4. Infection, if present, can require antibiotics.
PROGNOSIS:
The outlook for IgA vasculitis is generally excellent. Nearly all patients have no long-
term problems. The kidney is the most serious organ involved. Some patients might
have serious long-term kidney damage. Rarely, patients will experience a bowel
obstruction. Surgery may be necessary to correct this.
The chance of the disease coming back is low but can occur. It is usually in the form of
skin rash, that comes back a few months to a year after symptoms of IgA vasculitis
begin.
IgA vasculitis in adults is generally more severe than in children. Adults have
more severe kidney involvement. They may need more aggressive treatment.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (( CRESENTRIC GN ))
1. TYPE I RPGN ( ANTI-GBM ANTIBODY )
Idiopathic
Good pasture syndrome
2. TYPE II RPGN ( IMMUNE COMPLEX )
Idiopathic
Post infectious
SLE
Henoch –Schonlein purpura
Others
3. TYPE III RPGN ( PAUCI IMMUNE )
ANCA associated
Idiopathic
Wegener granulomatosis
Polyarteritis nodosa /Microscopic polyangitis

Thin Basement Membrane (TBM)
What is Thin Basement Membrane Disease?
TBM disease (also known as benign familial hematuria and thin basement membrane
nephropathy) is, along with IgA nephropathy, the most common cause of blood in the
urine without any other symptoms. The only abnormal finding in this disease is a
thinning of the basement membrane of the glomeruli (filters) in the kidneys.
Thin basement membrane disease is a type of nephritic syndrome. It is hereditary and
usually transmitted in autosomal dominant fashion. Not all genetic mutations have
been characterized, but in some families with thin basement membrane disease there
is a mutation in the type IV collagen α4 gene. Prevalence is estimated to be 5 to 9%.
What does it look like (under the
microscope)?
Thin basement membrane disease
is diffuse thinning of the
glomerular basement membrane
from a width of 300 to 400 nm in
normal subjects to 150 to 225 nm.
The glomerular basement wall in
patients with TBM disease appears
thinner.
The image below is taken with an
electron microscope. On the left
shows a healthy kidney filter
basement wall, and on the right
shows a basement wall in a person
with TBM disease
CLINICALLY
Most patients are asymptomatic and are incidentally noted to have microscopic
hematuria on routine urinalysis, although mild proteinuria and gross hematuria are
occasionally present. Patients with TBM usually have normal blood pressure and
normal kidney function. Mild protein in the urine (less than 1.5g/day) and high blood
pressure are seen in a small group of patients. Renal function is typically normal, but a
few patients develop progressive renal failure for unknown reasons.Recurrent flank
pain, similar to that in IgA nephropathy, is a rare manifestation.
Diagnosis is based on family history and findings of hematuria without other
symptoms or pathology. Renal biopsy is unnecessary but is often done as part of a
hematuria evaluation. Early on, thin basement membrane disease may be difficult to
differentiate from hereditary nephritis because of histologic similarities.

Long-term prognosis is excellent, and no treatment is necessary in most cases.
Patients with frequent gross hematuria, flank pain, or proteinuria (eg, urine
protein/creatinine ratio of > 0.2) may benefit from ACE inhibitors or angiotensin
receptor II blockers, which may lower intraglomerular pressure.
LUPUS GN
What is lupus nephritis?
Lupus nephritis is kidney inflammation caused by systemic lupus erythematosus (SLE
or lupus). SLE is an autoimmune disease—a disorder in which the body’s immune
system attacks the body’s own cells and organs. Up to 60 percent of people with SLE
are diagnosed with lupus nephritis, which can lead to significant illness and even
death.
What are the symptoms of lupus nephritis?
The symptoms of lupus nephritis may include high blood pressure, foamy urine, and edema—
swelling, usually in the legs, feet, or ankles and less often in the hands or face.
Kidney problems often develop at the same time or shortly after lupus symptoms appear and
can include:
 Joint pain or swelling
 Muscle pain
 Fever with no known cause
 Red rashes, often on the face, which are also called butterfly rashes .
How is lupus diagnosed?
Lupus nephritis is diagnosed through urine and blood tests and a kidney biopsy
A. Urine R/E When blood or protein is found in the urine.
B. RFT---- the serum creatinine level is abnormally high.
This can result in a decreased Glomerular Filtration Rate (GFR).
C. A biopsy is the only test which can diagnose lupus nephritis.
The test can confirm a diagnosis of lupus nephritis, determine how far the disease has
progressed, and guide treatment. The American College of Rheumatology recommends
biopsies for all people with evidence of active lupus nephritis that has not been
previously treated.
Once you have a biopsy, the sample is then identified based upon the degree and
pattern of swelling and damage. There are six classes of the disease.
Table 1: The 2003 International Society of Nephrology and International
Pathology Society Classification of lupus nephritis
Class I: Minimal mesangial lupus glomerulonephritis (LGN)
Class II: Mesangial proliferative LGN
Class III: Focal LGN (< 50% glomeruli)
Class IV: Diffuse LGN (> 50% glomeruli)
Class IV-S: Predominantly segmental
Class IV-G: Predominantly global
Class V: Membranous LGN
Class VI: Advanced sclerotic LGN (> 90% sclerotic glomeruli)
Why are these classes important?
There are several treatment choices for people with lupus nephritis. Some of these
treatment options are considered “aggressive.” They also have side effects which may
not be appropriate for individuals with certain forms of lupus nephritis. The classes
were based on several factors that help doctors discuss the best treatment options
and outlook for people with lupus nephritis.
i. Class I: Mild disease with small amount of swelling
ii. Class II: Still fairly mild disease but more swelling than Class I

iii. Class III : Moderate degree of swelling < 50% of the (glomeruli) affected
iv. Class IV : Severe degree of swelling with > 50% glomeruli affected
v. Class IV-S: Of the affected filtering unit, < ½ of it is affected by swelling
vi. Class IV-G: Of the affected filtering unit, most of it is affected by inflammation
vii. Class V: Most of the swelling is confined to the outer layer surrounding the
filter unit
viii. Class VI : Most of the filter units show scarring
What does lupus look like in a biopsy?
The kidney filter of a patient with lupus will show deposits in the kidney tissue. The
deposits are made up of proteins turned on to help the kidney protect itself. In this
image, these deposits are pointed out with arrows and are dark gray here. There are
many of them in this image collecting along the walls of the inner layer of the filter

How is lupus treated?
The treatment of lupus can be complex, and should always.
Doctors use a combination of approaches to try to reduce the symptoms of the disease
without causing negative side effects from the treatment.
Lupus nephritis is treated with medications that suppress the immune system, so it
stops attacking and damaging the kidneys. Standard treatment includes a
corticosteroid, usually prednisone, to reduce inflammation in the kidneys. An
immunosuppressive medication, such as cyclophosphamide or mycophenolate
mofetil, is typically used with prednisone.
The goal of the treatment is to reduce the swelling to protect organs from damage
without harming the immune system and allowing other infections to spread.
Exact treatment depends on:
i. The type of blood vessel swelling
ii. The severity of the disease
iii. How many organ systems are affected
Treatment options may include a combination of some of the following:
Corticosteroids---(prednisone, methyl prednisone, or Medrol®)
Hydroxychloroquine (Plaquenil®)
Immunosuppressive Drugs: (cyclophosphamide, cyclosporine, tacrolimus,
azathioprine, mycophenolate mofetil, or Rituximab)
Controlling blood pressure to reduce increased damage to the kidneys-ACE
inhibitors
SUMMARY:

 Lupus nephritis is kidney inflammation caused by systemic lupus
erythematosus (SLE or lupus).
 The symptoms of lupus nephritis may include high blood pressure, foamy
urine, and edema.
 Lupus nephritis is diagnosed through urine and blood tests and a kidney
biopsy.
 Lupus nephritis is treated with medications that suppress the immune system,
so it stops attacking and damaging the kidneys. Standard treatment includes a
corticosteroid, usually prednisone, to reduce inflammation in the kidneys. An
immunosuppressive medication, such as cyclophosphamide or mycophenolate
mofetil, is typically used with prednisone.
 People with lupus nephritis that is causing high blood pressure may need to
take medications that lower their blood pressure, which can also significantly
slow the progression of kidney disease.
 In many cases, treatment is effective in completely or partially controlling lupus
nephritis, resulting in few, if any, further complications. However, even with
treatment, 10 to 30 percent of people with lupus nephritis develop kidney
failure
ANCA Vasculitis
What is ANCA Vasculitis?
ANCA vasculitis is an autoimmune disease. ANCAs are autoantibodies that attack the
(cytoplasm) of neutrophils. ANCA =Anti-Neutrophil Cytoplasmic Autoantibody. When ANCAs
attack these neutrophils, they cause the white blood cells to attack the walls of small vessels
in different tissues and organs of the body. This causes vasculitis. For example, vasculitis in
the skin causes red spots. In the lungs or nose it causes bleeding. In the nerves it causes
tingling or weakness. In the eyes it causes redness and itching. In the kidneys vasculitis
causes leaking of blood and protein into the urine and kidney failure.
Autoantibodies:
Most patients with
ANCA vasculitis
have autoantibodies
specific for
perinuclear (P-
ANCA) or
cytoplasmic (C-
ANCA) antibodies. C-
ANCA is usually
directed against
proteinase 3 (PR3)
and P-ANCA is
usually directed

again myeloperoxidase (MPO).
What are the different types of ANCA Vasculitis?
In different people, ANCA vasculitis attacks different organs. It may have different disease signs.
These are used to make the diagnosis of a specific form of ANCA vasculitis.
Renal limited vasculitis or ANCA glomerulonephritis: The blood vessel swelling is causing capillary
swelling. No other organs are affected.
Microscopic polyangiitis: The swelling is causing injury to blood vessels in multiple tissues at the
same time. It can be seen in the kidneys, skin, nerves, and lungs.
Granulomatosis with polyangiitis -GPA- (Formerly Wegener's granulomatosis): The swelling
happens with another kind of swelling called granulomatous inflammation. This often affects the
lung, sinuses, nose, eyes or ears.
Eosinophilic granulomatosis with polyangiitis -EGPA- (Formerly Churg-Strauss Syndrome): There is
swelling, granulomatous inflammation, as well as asthmawith eosinophilia.

What is ANCA Glomerulonephritis?
ANCA can cause (neutrophils) to attack the capillaries in the (glomeruli) of the kidney
leading to glomerulonephritis. The destruction of the glomerular capillaries causes blood
and proteins to spill into the urine. This causes the kidney to stop functioning.
Glomerulonephritis often occurs in patients with ANCA disease.

What does it affect, and what are the symptoms?
Vasculitis can affect any part of the body.
The symptoms of vasculitis include flu-like symptoms such as fever, body aches, joint and
muscle pain. There can also be reduced appetite, and weight loss. Symptoms can appear in
the particular body part that is affected by the disease. The chart below explains some
common symptoms that are specific to the affected body part.
Kidney Brown, tea-colored urine from blood leaking into the urine
Joints Joint pain or swelling
Lungs Heavy cough, often mistaken for pneumonia, coughing up blood
Skin Red or purple spots , itching, hives, rash
Sinus/Nose Runny nose that get worse and worse, nose pain, trouble breathing
through nose
Trachea Shortness of breath
Gastrointestinal Tract Stomach pain, or blood in stool
Eyes Red, painful eyes, blurry vision, headaches
Ears Hearing problems or hearing loss

DIAGNOSIS:
A combination of lab tests and physical exams to diagnose vasculitis. These tests
usually focus on the area of the body that is affected. Many times patients need
specialists to look at a specific area.
 A blood test to check for ANCA
 Blood and urine tests to check to see if vasculitis is affecting the kidneys
 Chest x-rays or CT scan to check for lung problems
 Endoscopic exam by an ENT to check the ears, nose, and throat
 A biopsy, may be taken from an affected area for a lab to look at more closely
How is it treated?
The treatment of vasculitis can be complicated. It should always involve specialists for
each affected body system. Doctors can use different approaches to try to reduce the signs
of the disease. At the same time, dangerous or uncomfortable side effects from the
treatment should be minimized. The goal of the treatment is to reduce the inflammation
to protect organs from damage without hurting the immune system.
Exact treatment depends on:
The type of vasculitis
How serious the disease is
How many organ systems are affected
Treatment options include:
A. Corticosteroids: (prednisone, methyl prednisone, or Medrol)
B. Immunosuppressive Drugs: (cyclophosphamide, cyclosporine, azathioprine,
mycophenolate mofetil, or Rituximab)
C. Antibiotics: (trimethoprim/sulfamethoxazole) Drugs that kill foreign infections
that can live in the nose or in patients with a weak immune system
D. Plasmapheresis: A treatment that removes the ANCA from the blood. This
treatment is usually only for patients with bleeding in the lungs or kidney failure.
In some patients, even with treatment, involvement of the kidney with ANCA
vasculitis will lead to kidney failure. Fortunately, kidney transplant is a treatment
option for these patients.
Will the ANCA disease come back in my kidney transplant?
About 10-15% of patients will have symptoms of ANCA disease after a kidney
transplant. This is called recurrent disease. Not all return symptoms affect the
kidney, but some will. It is important that ANCA disease be inactive prior to getting
a kidney transplant. This reduces the chance that the ANCA disease will come back
after the transplant.

Generally, ANCA disease recurrence will occur between 2.5 and 4 years after
transplant. But it can occur any time.
Is there any treatment for ANCA disease that comes back in a transplant?
Treatments are similar to those for patients with ANCA disease in their original
kidneys. They include corticosteroids and immunosuppressive drugs. These are
different from the ones taken to prevent kidney transplant rejection.
If the ANCA disease comes back, will it cause patient to lose the kidney transplant?
Recurrent ANCA disease can rarely cause loss of a transplanted kidney. If you look
at all patients with ANCA disease 10 years after their transplant, about 8% of them
will have lost their kidney due to recurrent ANCA disease.
A patient with ANCA disease who gets a kidney transplant can expect a similar life
span and kidney transplant survival as a transplant patient who has kidney failure
from another disease.
Anti-GBM Disease
What is Anti-Glomerular Basement Membrane Disease ( Goodpasture's Syndrome)?
Anti-GBM disease is the result of injury to the (capillaries) in the kidney or lung.
This can be caused by autoantibodies that attack the walls of these blood vessels.
In the kidneys, the capillaries that are attacked are in the glomeruli, which filter
blood and make urine. These glomerular capillaries have thin membranes in their
walls that are the targets of the autoantibodies. These are called anti-glomerular
basement membrane (anti-GBM) antibodies. The antibodies are found moving in
the serum. The antibodies are connected to a very specific basement membrane
protein. Injury to glomerular capillaries causes bleeding into the urine. It can also
cause spillage of blood proteins into the urine, and reduced kidney function.
In the lungs, the capillaries that are attacked are in the thin walls of air sacs where
oxygen enters the blood and carbon dioxide exits. Injury to these pulmonary
capillaries causes lung bleeding and impaired breathing.

Anti-GBM disease that only affects the kidneys is called anti-GBM
glomerulonephritis. This is a form of inflammation, which is injury to tissue caused
by white blood cells (leukocytes).
Anti-GBM disease that causes both kidney disease and lung disease is called
Goodpasture’s syndrome. The lung disease is anti-GBM alveolar capillaritis.
This is inflammation of capillaries in the air sacs of the lungs. The kidney
disease is anti-GBM glomerulonephritis.
Under normal
conditions, a
layer of cells
called
endothelium
protects the
lower membrane
from moving
antibodies.
However, at
times there is
increased
leakiness of the
cell layer. This
happens in
certain types of
lung injury can be
caused by
exposures to
organic solvents
or hydrocarbons,
smoking,
infection, cocaine
inhalation, and
metal dusts. The
lower membrane
becomes more
accessible to anti-
GBM antibodies.
This allows them
to connect to the
vessel wall and cause the swelling and bleeding that signals this anti-GBM disease.

AGE and SEX:
Glomerulonephritis due to Anti-GBM antibody disease is rare. It occurs in less than
1 case per million persons. It affects mostly young, white men aged 15-35. It also
can affect those beginning in the late 50’s. At this age, women are more likely to be
affected. It affects both sexes equally and very rarely in children.
Some evidence suggests that genetics may play an important role in this disease.
CLINICAL FEATURES:
 60-70% of patients have both lung and kidney involvement. This is called
Goodpasture’s Syndrome.((HEMATURIA & HEMOPTYSIS))
 20-40% have only kidney involvement, which is called "renal limited" anti-
GBM disease
 Coughing up blood is the most frequent symptom when the lungs are
involved.
Other symptoms may include:
Chills and fever
Nausea and vomiting
Weight loss
Chest pain
Bleeding may cause anemia, respiratory failure
Kidney failure
How is Anti-GBM diagnosed?
A Chest X-ray may be done to look for bleeding or infection.

Blood and urine tests can be done to check for kidney involvement.
A CBC often shows anemia
A blood test that shows that Anti-Glomerular Basement Membrane Antibodies are
in the blood is essential to making the diagnosis.
One third of patients with Anti-GBM disease will have (ANCA) also present at
some time during their disease.
Bronchoscopy with cultures may be required to fully investigate the cause of the
lung bleeding.
A lung sample and/or kidney sample may be taken to get a definitive diagnosis.
How is Anti-GBM treated?
Once the diagnosis is confirmed, there are primarily three parts to treatment.
1. The antiGBM antibody is removed from the blood stream by plasmapheresis.
The number of plasmapharesis treatments can vary by patient response., Most
patients receive between 5-14 treatments. These can be daily or at some approved
spacing over 14 to 21 days.
2.) Further antibody production is prevented by immunosuppression.
Most patients are given “pulse” large dose methylprednisolone through a needle
inserted into a vein for 3 days to change the immune system function. This will
reduce the production of new antibody. This is then followed by daily oral steroid
therapy. The oral steroid may be given for as long as 3 months. The length of time
is based on disease response to therapy.

Cyclophosphamide (Cytoxan®) is the It is generally delivered through a vein in a
single monthly dose.
3.) Future exposures are avoided or prevented.
Avoiding potential chemical exposures that may have caused the disease is
important. Shots to prevent lung infections may also be useful.
Kidney Transplant in Anti-GBM Disease:
When Anti-Glomerular Basement Membrane (GBM) disease involves the kidneys,
it can lead to kidney failure. Fortunately, kidney transplant is a treatment option
for these patients.
Will the Anti-GBM Disease come back in my kidney transplant?
Treatment of anti-GBM disease is focused on removing the anti-GBM antibody
from the blood. Before having a kidney transplant, it is recommended that
patients wait at least 6 months after finishing treatment for anti-GBM disease.
Once it is sure that the disease is no longer active, transplant is very safe. The
chance that the anti-GBM disease will come back in the kidney is very low. This
occurs in less than 5% of patients
DM NEPHROPATHY
Diabetic nephropathy is glomerular sclerosis and fibrosis caused by the metabolic and
hemodynamic changes of diabetes mellitus. It manifests as slowly progressive albuminuria
with worsening hypertension and renal insufficiency. Diagnosis is based on history,
physical examination, urinalysis, and urine albumin/creatinine ratio. Treatment is strict
glucose control, angiotensin inhibition (using ACE inhibitors or angiotensin II receptor
blockers), and control of BP and lipids.
WHO AT RISK?
Diabetic nephropathy (DN) is the most common cause of nephrotic syndrome in adults and
of end-stage renal disease in the US, accounting for up to 80% of cases of the latter. The
prevalence of renal failure is probably about 40% among patients with type 1 diabetes
mellitus. The prevalence of renal failure among patients with type 2 diabetes mellitus is
usually stated as 20 to 30%, but this figure is probably low. Renal failure is particularly
common in certain ethnic groups, such as blacks, Mexican-Americans, Polynesians, and
Pima Indians. Other risk factors include the following:
1) Duration and degree of hyperglycemia
2) Hypertension
3) Dyslipidemia
4) Cigarette smoking

5) Certain polymorphisms affecting the renin-angiotensin-aldosterone axis
6) Family history of diabetic nephropathy
7) Genetic variables (decreased number of glomeruli)
Renal failure usually takes ≥ 10 yr after the onset of nephropathy to develop; however,
because type 2 diabetes is often present for several years before being recognized,
nephropathy often develops < 10 yr after diabetes is diagnosed.
PATHOPHYSIOLOGY:
3 Types of lesions:
1. Glomerular disease
2. Vascular lesions---nephrosclerosis
3. pyelonephritis
Pathogenesis begins with small vessel disease. Pathophysiology is complex, involving
glycosylation of proteins, hormonally influenced cytokine release (eg, transforming
growth factor-β), deposition of mesangial matrix, and alteration of glomerular
hemodynamics. Hyperfiltration, an early functional abnormality, is only a relative
predictor for the development of renal failure.
Hyperglycemia causes glycosylation of glomerular proteins, which may be responsible
for mesangial cell proliferation and matrix expansion and vascular endothelial damage.
The glomerular basement membrane classically becomes thickened.
Each nephron has 3 parts: 1) a small blood vessel that brings in unfiltered blood, 2) a
glomerulus that filters the blood and 3) a small blood vessel that returns filtered blood to
the body. The earliest detectable change in glomeruli is thickening of the thin basement

membrane. Damage to this membrane causes proteins to leak from the blood into the
urine which is identified in a kidney using an electron microscope .
Lesions of diffuse or nodular intercapillary glomerulosclerosis are distinctive; areas of
nodular glomerulosclerosis may be referred to as Kimmelstiel-Wilson lesions . There is
marked hyalinosis of afferent and efferent arterioles as well as arteriosclerosis;
interstitial fibrosis and tubular atrophy may be present. Only mesangial matrix
expansion appears to correlate with progression to end-stage renal disease.
Diabetic Nephropathy Nodules (DN)
(Mesangial Cell Proliferation and Matrix Expansion)
DN begins as glomerular hyperfiltration (increased GFR); GFR normalizes with early
renal injury and mild hypertension, which worsens over time. Microalbuminuria,
urinary excretion of albumin in a range of 30 to 300 mg albumin/day, then occurs.
Urinary albumin in these concentrations is called microalbuminuria because detection
of proteinuria by dipstick on routine urinalysis usually requires > 300 mg albumin/day.

Microalbuminuria progresses to macroalbuminuria (proteinuria > 300 mg/day at a
variable course, usually over years. Nephrotic syndrome (proteinuria ≥ 3 g/day)
precedes end-stage renal disease, on average, by about 3 to 5 yr, but this timing is also
highly variable. Other urinary tract abnormalities commonly occurring with DN that
may accelerate the decline of renal function include papillary necrosis, type IV renal
tubular acidosis, and UTIs. In DN,
the kidneys are usually of normal
size or larger.
HYALINOSIS
Symptoms and Signs
DN is asymptomatic in early stages.
Sustained MICROALBUMINURIA is
the earliest warning sign((30mg/day
but < 300mg/day)). Within 10—15
years patients with diabetes
develop overt nephropathy with
MACROALBUMINURIA .This is
associated with HTN. Hypertension
and some measure of dependent
edema eventually develop in most
untreated patients. In later stages,
patients may develop symptoms
and signs of uremia (eg, nausea,
vomiting, anorexia) earlier (ie, with higher GFR) than do patients without DN, possibly
because the combination of end-organ damage due to diabetes (eg, neuropathy) and
renal failure worsens symptoms.
 Capillary basement membrane thickening
 Diffuse mesangial sclerosis
 Nodular glomerulosclerosis
 Renal arteriolosclerosis and atherosclerosis
 Hyaline arteriolosclerosis affects both afferent &efferent arterioles.
Patient develop nephritic syndrome after long standing glomerulosclerosis
Nodular glomerulosclerosis is characterized by distinctive ball like deposits of a
laminated matrix situated in the periphery of the glomerulus . These are PAS
positive and contain trapped mesangial cells. ((KIMMELSTIEL-WILSON KIDNEY))
Diagnosis :
Yearly screening of all patients with diabetes with random urine albumin/creatinine ratio.
Urinalysis for signs of other renal disorders (eg, hematuria, RBC casts)
The diagnosis is suspected in patients with diabetes who have proteinuria, particularly
if they have diabetic retinopathy (indicating small vessel disease) or risk factors for
DN. Other renal disorders should be considered if there are any of the following:
1) Heavy proteinuria with only a brief history of diabetes

2) Absence of diabetic retinopathy
3) Rapid onset of heavy proteinuria
4) Gross hematuria
5) RBC casts
6) Rapid decline in GFR
7) Small kidney size
HOW TO DETECT PROTEINURIA?
Patients are tested for proteinuria by routine urinalysis; if proteinuria is present,
testing for microalbuminuria is unnecessary because the patient already has
macroalbuminuria suggestive of diabetic renal disease. In patients without proteinuria
on urinalysis, an albumin/creatinine ratio should be calculated from a mid-morning
urine specimen. A ratio ≥ 0.03 mg/mg (≥ 30 mg/g) indicates microalbuminuria if it is
present on at least 2 of 3 specimens within 3 to 6 mo and if it cannot be explained by
infection or exercise. Some experts recommend that microalbuminuria be measured
from a 24-h urine collection, but this approach is less convenient, and many patients
have difficulty accurately collecting a specimen. The random urine albumin/creatinine
ratio overestimates 24-h collection of microalbuminuria in up to 30% of patients > 65
due to reduced creatinine production from reduced muscle mass. Inaccurate results
can also occur in very muscular patients or if vigorous exercise precedes urine
collection.For most patients with diabetes who have proteinuria, the diagnosis is
clinical. Renal biopsy can confirm the diagnosis but is rarely necessary
Screening:
Patients with type 1 diabetes without known renal disease should be screened for
proteinuria and, if proteinuria is absent on routine urinalysis, for microalbuminuria,
beginning 5 yr after diagnosis and at least annually thereafter.
Patients with type 2 diabetes should be screened at the time of diagnosis and annually
thereafter
Prognosis :
Prognosis is good for patients who are meticulously treated and monitored. Such care
is often difficult in practice, however, and most patients slowly lose renal function;
even prehypertension (BP 120 to 139/80 to 89 mm Hg) or stage 1 hypertension (BP 140
to 159/90 to 99 mm Hg) may accelerate injury. Systemic atherosclerotic disease
(stroke, MI, peripheral arterial disease) predicts an increase in mortality.
TREATMENT:
Prevention and awareness are very important to everyone with diabetes.
1. Urinalysis : All diabetics should have a urine test at least once every year. This
test looks for the presence of the protein albumin.
2. Blood Sugar Control: Maintenance of glycosylated Hb (HbA 1c ) ≤ 7.0
Keeping blood sugar levels well controlled helps maintain kidney health. In a
recent study, diabetic patients that kept their blood sugar below 150 mg/dl
greatly reduced the risk of kidney disease.The American Diabetes Association
recommends that blood sugars be kept between 90-130 mg/dl on an empty
stomach. Blood sugar should be less than 180 mg/dl one hour after eating.
3. Blood Pressure: High blood pressure is extremely common in diabetics. It is a
major cause of kidney disease. Additionally, kidney disease can make high
blood pressure even higher. This creates a vicious cycle. Often, it takes
multiple medications to control high blood pressure. This is especially true for

diabetics, obese patients, and the elderly. The American Diabetes Association
recommends checking blood pressure twice every year. Keeping blood
pressure below 130/80 is also recommended. Patients who cannot control their
blood pressure with diet and exercise alone are usually prescribed blood
pressure reducing medicine. This is known as an "ACE inhibitor" or an "ARB".
Some experts suggest BP should be 110 to 120/65 to 80 mm Hg, particularly in
patients with protein excretion of > 1 g/day; however, others claim that BP
values < 120/85 mm Hg are associated with increased cardiovascular mortality
and heart failure.
Angiotensin inhibition is first-line therapy. Thus, ACE inhibitors or angiotensin
II receptor blockers are the antihypertensives of choice; they reduce BP and
proteinuria and slow the progression of DN. ACE inhibitors are usually less
expensive, but angiotensin II receptor blockers can be used instead if ACE
inhibitors cause persistent cough. Treatment should be started when
microalbuminuria is detected regardless of whether hypertension is present;
some experts recommend drugs be used even before signs of renal disease
appear.
Diuretics are required by most patients in addition to angiotensin inhibition to
reach target BP levels. Dose should be decreased if symptoms of orthostatic
hypotension develop or serum creatinine increases by more than 30%.
Nondihydropyridine Ca channel blockers (diltiazem and verapamil) are also
antiproteinuric and renoprotective and can be used if proteinuria does not
meaningfully decrease when target BP is reached or as alternatives for patients
with hyperkalemia or other contraindications to ACE inhibitors or angiotensin II
receptor blockers. In contrast, dihydropyridine Ca channel blockers (eg,
nifedipine, felodipine, amlodipine) do not reduce proteinuria, although they are
useful adjuncts for BP control and may be cardioprotective in combination with
ACE inhibitors. ACE inhibitors and nondihydropyridine Ca channel blockers
have greater antiproteinuric and renoprotective effects when used together,
and their antiproteinuric effect is enhanced by Na restriction.
Nondihydropyridine Ca channel blockers should be used with caution in
patients taking β-blockers because of the potential to worsen bradycardia.
4. Statins should be used as first-line therapy for hyperlipidemia treatment in
patients with DN because they reduce cardiovascular mortality and urinary
protein. Cholesterol: High cholesterol is common in diabetics. Therefore, the
risk of developing kidney disease from high cholesterol is a concern. This
concern makes controlling cholesterol very important. Sometimes a healthy,
balanced diet is enough to control cholesterol. Sometimes medication is
needed. The American Diabetes Association recommends that the LDL (bad
cholesterol) be less than 100. HDL (good cholesterol) should be higher than 40.
Triglycerides should be less than 150.
5. Dietary protein restriction yields mixed results. Significant protein restriction
is not recommended. Evidence shows that too much or too little protein can be
harmful. The American Diabetes Association recommends following USDA
guidelines. Patients should consume 5-6 ounces of meat and 2-3 servings of
dairy every day. The American Diabetic Association recommends that people
with diabetes and overt nephropathy be restricted to 0.8 to 1.2 g protein/kg/day.
6. Smoking: Smoking worsens the progression of kidney disease. Quitting
smoking is extremely difficult. There are several treatments which have been
proven to help people quit.

7. Weight loss and Exercise: Being overweight contributes to kidney disease by
making diabetes harder to control. It raises blood pressure and causes scarring
in the kidneys. Weight loss often improves blood sugars. It also decreases the
number of medications necessary to control blood pressure.
8. Body Mass Index (BMI) is a scale that uses weight and height to determine
whether someone is overweight. A BMI 25-30 indicated that someone is
overweight. An obese person has a BMI over 30. Planning a diet and exercise
program to reach a BMI of less than 25 will greatly reduce diabetic risk factors
9. Kidney transplantation with or without simultaneous or subsequent pancreas
transplantation is an option for patients with end-stage renal disease. The 5-yr
survival rate for patients with type 2 diabetes receiving a kidney transplant is
almost 60%, compared with 2% for dialysis-dependent patients who do not
undergo transplantation . Renal allograft survival rate is > 85% at 2 yr
 Diabetic nephropathy is very common, asymptomatic until late, and should be
considered in all patients with diabetes.
 Periodically screen all patients with diabetes with urinalysis and, if proteinuria
is absent, albumin/creatinine ratio calculated from a mid-morning urine
specimen.
 Treat BP aggressively, usually beginning with angiotensin inhibition.
 Control glucose to maintain HbA 1c at ≤ 7.0.
Myeloma Kidney
What is Multiple Myeloma?
Multiple Myeloma is a blood cancer of the plasma cells.(( Plasma cells are immune
cells that normally make special proteins, called antibodies, to fight off disease. These
antibodies are part of the body’s defense system to neutralize infections that invade
the blood stream)). Patients who have multiple myeloma make plasma cells that are
abnormal. These plasma cells do not make normal antibodies anymore, but instead
make too much of one kind of protein-paraprotein. When this happens, the levels of
these proteins in the blood become higher than normal.
The abnormal plasma cells and the abnormal proteins cause the major symptoms of
multiple myeloma: bone disease, anemia, renal failure, increased risk of infection, and
high levels of calcium.
What is Myeloma Kidney?
Kidney failure is a common complication of multiple myeloma. When first diagnosed,
as many as 20-40% of patients with multiple myeloma will have some amount of kidney
failure. Multiple myeloma can affect the kidney in several ways. It can affect
1. The filter (glomerulus)
2. The tubules (pipes)-- myeloma kidney ((cast nephropathy ))
3. The tissue of the kidney itself (interstitium).
The effect of multiple myeloma on the glomerulus (filter) due to light chain, heavy
chain deposition, and amyloidosis.

How does Multiple Myeloma affect the kidneys?
The tubules are the pipes through which filtered blood ultimately becomes urine and
exits the body as waste. The blood passes through the glomeruli and then enters the
tubules (pipes). The abnormal proteins that are made by the plasma cells in patients
with multiple myeloma float around in the blood stream. The blood passes through the
filters in the kidneys and these abnormal proteins enter the tubules. These abnormal
proteins then travel through the tubules and can join up with another type of protein
normally present in the urine, Tamm Horsfall protein. If these two proteins join together
they become too big to pass on through the tubules and therefore cannot exit the
kidney in the form of
urine. This combination
of proteins results in
large casts that block the
tubules inside the kidney.
These tubules are just
like pipes that carry
water, when they get
blocked fluid cannot flow
through. These blockages
lead to kidney damage.
In addition to blockages,
these casts cause an
inflammatory reaction in
the tissue of
the kidney
around them.
When kidney
failure
occurs due
to these
blockages,
we call this
cast
nephropathy
or myeloma
kidney.
The tubules
of the kidney
can also be
damaged
simply due to
the toxic
effects of
these filtered
proteins.
This can lead
to abnormal kidney function even in the absence of cast formation. However, myeloma
kidney is by far the most common manifestation of kidney disease in patients with
multiple myeloma.

Three distinct syndromes account for most cases of Ig-mediated kidney disease but
virtually all nephropathologic syndromes have been observed.
Panel A shows amyloid.
(i) Amyloid fibrils consisting of monoclonal Ig and serum proteins appear here as pink
material disrupting glomeruli architecture.
(ii) (ii) Amyloid is visible on electron microscopy as 7- to 12-nm fibrils.
Panel B shows MIDD. Monoclonal light chains kappa (1) or without evidence of
lambda (ii) and/or heavy chains (IgG), deposit along glomerular (iii) and tubular
basement membranes (iv), altering the glomerular structure and causing dose-
dependent proximal tubular toxicity.
Panel C shows cast nephropathy. Filtered monoclonal Ig, Tamm-Horsfall, and
other proteins form casts, which obstruct tubules and collecting ducts. Casts can
rupture and result in interstitial inflammation.
Panel D shows interstitial inflammation. Inflammation also results from the
processing of filtered monoclonal light chains, which induces NF-κB and other
signaling pathways leading to cytokine-mediated inflammatory infiltrate (shown
here with a Trichrome stain) and subsequent matrix deposition and fibrosis. Panel
E shows glomerular crescent. Shown here is a glomerular crescent in a patient
with Waldenström macroglobulinemia productive of IgMλ and amyloidosis
What does it look like (under the microscope)?
By biopsy ,in cast myeloma kidney, the tubules full of proteins that blocks the inside
of the tubule.
The glomeruli (filters) of the kidney are typically not affected in cast nephropathy and
usually appear normal.
How is at risk?
UKNOWN. It is a rare disease and affects only about 1 in 4,000 people. Each year about
13,000-20,000 people will be diagnosed with this disease.
There are some studies that show people who have been exposed to certain toxins like
radiation, benzene, herbicides, insecticides, and organic solvents are more at risk than
the general population. However, many people develop multiple myeloma without any
exposure to these agents.
The age --- 50s and 60s.
It is unknown why people develop this disease and it is not possible to predict who will
develop it.
Not all patients with multiple myeloma will develop myeloma kidney, generally about
30-50% of patients develop this problem. There are things that will make a patient with
multiple myeloma more at risk to develop myeloma kidney. Dehydration, therapy with

furosemide (a fluid pill), high blood levels of calcium, and high levels of sodium in the
urine all can lead to increased formation of these casts.
The symptoms of multiple myeloma are typically fatigue, bone pain, and infections.
This is because multiple myeloma causes anemia, destruction of the bones, and
decreased production of normal antibodies (proteins) that fight infection. The
destruction of the bones due to multiple myeloma can often lead to fractures of the
bone that occur with little or sometimes no trauma. Often, though, the signs of kidney
dysfunction will be first discovered on lab work done for another medical reason.
Lab results could show increased level of creatinine, or increased amount of protein in
the urine. People who develop advanced kidney disease will have symptoms related to
kidney failure including nausea, itching, confusion, and fatigue.
How is it diagnosed?
In order to diagnose myeloma kidney, a biopsy needs to be done.
In cast nephropathy---- tubular casts in the distal nephron, often with accompanying
interstitial nephritis.
In MIDD, tubular and glomerular basement membranes are thickened by refractile
precipitates that are granular and dense on electron microscopy.
Glomerular nodules resembling the Kimmelstiel-Wilson lesion of diabetic nephropathy
may be present and cause the nephrotic syndrome.
In AL amyloidosis, the tubular basement membranes are typically of normal thickness
but the Congo red stain is positive, with characteristic green birefringence under
polarizing microscopy. Electron microscopy demonstrates organized deposits of
nonbranching amyloid fibrils, 7 to 10 nm in diameter
These include blood tests, urine tests, x-rays of the bones, and a bone marrow biopsy.
The blood tests and urine tests can detect the abnormal proteins that are made by the
plasma cells. The x-rays of the bones look for lesions in the bones caused by the
multiple myeloma. The bone marrow biopsy will find the abnormal plasma cells inside
the bones.
The treatment for the kidney disease associated with multiple myeloma depends upon
treating the myeloma itself. Patients with multiple myeloma are treated with
chemotherapy and/or bone marrow transplant. Bone marrow transplant is only for
patients who have good mobility and function and do not have severe kidney, liver, or
heart disease. For chemotherapy, the most common regimen involves a combination
of prednisone, thalidomide, and melphalan. Chemotherapy can help reduce the
production of the abnormal proteins by the plasma cells, which is very important for
patients with myeloma kidney. By reducing the abnormal protein in the blood, the
kidney will have a chance to recover. The role of stem cell transplantation, plasma
exchange, and kidney transplantation in the management of patients with paraprotein-
related kidney disease continues to evolve.
In addition to chemotherapy to treat the multiple myeloma, there are a few other things
that can help patients with myeloma kidney.

A. Keeping hydrated is very important, because being dehydrated can lead to
more cast formation. Therefore, drinking 2-3L of water a day is recommended.
B. Avoiding NSAIDs (like ibuprofen) and diuretics (like furosemide) are important
because these medications cause more cast formation.
C. Treating high blood levels of calcium is important so that the high calcium
levels do not filter through the kidney and make cast formation worse. High
calcium levels are usually treated with medications such as pamidronate and
zolendronic acid.
D. Finally, patients with multiple myeloma and especially those with myeloma
kidney should not get IV contrast.
What are the chances that I will get better?
The prognosis for multiple myeloma depends in large part on if the kidney is affected
and how badly. Patients who have kidney dysfunction will have an average survival of
20 months (slightly less than 2 years). Those patients without kidney dysfunction will
have an average survival of 40 months (between 3 and 4 years). Among all patients,
response to chemotherapy is very important as well. Patients whose kidney function
improves with chemotherapy have an average survival of 3 years. Those patients
whose kidney function does not improve with chemotherapy will only live an average
of 10 months.
OTHER ENTITY OF MM IN KIDNEY:
A. Glomerulonephritis may occur, of either a membranoproliferative, diffuse
proliferative, crescentic, or cryoglobulinemic variety.
B. Nephrotic syndrome may result from an Ig-induced minimal change or
membranous lesion.
C. Renal limited thrombotic microangiopathy can result directly from monoclonal
Ig-induced endothelial injury or after chemotherapy .
D. IgA myeloma can rarely result in Henoch-Schonlein purpura and IgA
nephropathy.
E. Patients with circulating monoclonal IgM can develop kidney injury from
hyperviscosity or when deposits composed of monoclonal IgM occlude
glomerular capillaries.
F. Crystalline inclusions in the proximal tubule consisting of monoclonal Ig can
.0result in a mild tubulointerstitial nephritis or the Fanconi syndrome, which is
often indolent and may not require systemic therapy
The reversible, first in class proteasome inhibitor bortezomib is a U.S. Food and Drug
Administration–approved small molecule boronic acid–derived peptide that targets
protein handling mediated by the ubiquitin proteasome pathway. Bortezomib has
emerged along with high-dose dexamethasone as among the most effective
approaches for treating myeloma when associated kidney injury is present. It is also
now well established as therapy for relapsed myeloma and has recently received
approval for initial therapy.Rapidly acting, it is characterized by a median time to best
response of approximately 30 days in previously treated patients. As malignant plasma
cells synthesize and assemble large quantities of Ig, they are particularly susceptible
to proteasome inhibitors, which induce myeloma cell apoptosis in part by interfering
with protein handling. Bortezomib also inhibits the NF-κB and MAPK pathways, which

leads directly to myeloma cell apoptosis while also disrupting myeloma-stromal cell
interactions and tumoral angiogenesis. The proinflammatory cascade is mediated by
mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways.
Importantly, by inhibiting the NF-κB and MAPK pathways, bortezomib mitigates the
inflammatory state induced in proximal tubule cells by excessive light chain handling
and so may protect these cells from apoptosis by up-regulating heat shock and other
survival-associated proteins. In contrast to traditional agents whose toxicity increases
in renal impairment, the antimyeloma effects and safety profile of bortezomib appear
unchanged in this setting, and renal dose adjustment is therefore not required.
When combined in various regimens with dexamethasone, melphalan, doxorubicin, or
thalidomide, 40% to 50% of patients who respond to therapy will experience significant
recovery of renal function within 2 to 3 weeks. Improvement in renal function appears
to precede the expected antiplasma cell effects of bortezomib, possibly reflecting anti-
inflammatory properties of the agent.
To improve efficacy of dexamethasone, it is often combined with thalidomide or its
potent, newer derivative, lenalidomide, which interferes with myeloma cell growth,
disrupts myeloma and bone marrow stromal cell interactions, down-regulates
promyeloma cytokines, and up-regulates antimyeloma T-cell activity. Although the
pharmacokinetics of thalidomide appear unaffected by renal function, hyperkalemia
has been reported in the setting of renal dysfunction. Dose reduction is required with
lenalidomide, as the drug's clearance falls significantly in advanced CKD.
Importantly, patients with creatinine in excess of 2.5 mg/dL have been excluded from
lenalidomide trials, and patients with lesser degrees of renal dysfunction experience
more adverse events, particularly myelosuppression.
Fibrillary and Immunotactoid Glomerulopathies
fbrillary and immunotactoid glomerulopathies are rare conditions defined
pathologically by organized deposition of nonamyloid microfibrillar or microtubular
structures within the renal mesangium and basement membrane.
Fibrillary and immunotactoid glomerulopathies are thought by some experts to be
related disorders. They are found in about 0.6% of renal biopsy specimens, occur
equally in men and women, and have been described in patients ≥ 10 yr. Average age
at diagnosis is about 45. Mechanism is unknown, although deposition of
immunoglobulin, particularly IgG κ and λ light chains and complement (C3), suggests
immune system dysfunction. Patients may have accompanying paraproteinemia,
cryoglobulinemia, plasma cell dyscrasia, hepatitis C infection, or SLE, or they may
have a primary renal disease without evidence of systemic disease.
CLINICAL:
All patients have proteinuria, > 60% nephrotic range. Microscopic hematuria ((60%));
hypertension, in about 70%. Slightly > 50% have renal insufficiency at presentation.
Diagnosis : Renal biopsy
Diagnosis is suggested by laboratory data and confirmed by renal biopsy. If nephrotic
syndrome is present, testing is done as for other cases of nephrotic syndrome.
Urinalysis usually shows features of nephritic and nephrotic syndromes. Serum C3
and C4 are usually measured and are occasionally decreased. Light microscopy of a

biopsy specimen shows mesangial expansion by amorphous eosinophilic deposits
and mild mesangial hypercellularity. Various other changes may be present on light
microscopy (eg, crescent formation, membranoproliferative patterns). Congo red
staining is negative for amyloid. Immunostaining reveals IgG and C3 and sometimes κ
and λ light chains in the area of the deposits. Electron microscopy shows glomerular
deposits consisting of extracellular, elongated, nonbranching microfibrils or
microtubules. The diameter of the microfibrils and microtubules varies from 20 to 30
nm for fibrillary glomerulonephritis and from 30 to 50 nm for immunotactoid
glomerulonephritis, in contrast to the 8 to 12 nm fibrils that occur in amyloidosis.
Some experts distinguish immunotactoid from fibrillary glomerulopathy by the
presence of microtubular (as opposed to smaller microfibrillar) structures in the
deposits; others distinguish them by the presence of a related systemic illness such as
a paraproteinemia, cryoglobulinemia, or SLE in immunotactoid glomerulonephritis.
Fibrillary Glomerulopathy (Mesangial Proliferation) Fibrillary Glomerulopathy (IgG Deposition)
Fibrillary
Glomerul
opathy
(Fibrils)
Immunotactoid Glomerulopathy
Prognosis :

The condition is usually slowly progressive with renal insufficiency, progressing to
end-stage renal disease in 50% of patients within 2 to 4 yr. A more rapid decline is
predicted by the presence of hypertension, nephrotic-range proteinuria, and renal
insufficiency at presentation.
Treatment
Evidence is lacking, but consider ACE inhibitors or angiotensin II receptor blockers,
immunosuppressants, and/or corticosteroids
Evidence to support specific treatments is lacking although ACE inhibitors and
angiotensin II receptor blockers may be used to reduce proteinuria.
Immunosuppressants have been used based on anecdotal evidence but are not a
mainstay of therapy; success may be greater with corticosteroids when serum
complement is decreased. The disorder may recur after transplantation.
AL Amyloidosis
AL Amyloidosis (also called “primary” amyloidosis) is a blood illness in which a
special protein builds up in various parts of the body. This protein, called “M-protein,”
is actually made up of pieces from immunoglobulins (also called antibodies) which are
naturally in the body and fight off infection. In the case of people with amyloidosis, too
many of these disease fighting pieces are present in blood flow. They can get stuck in
almost any organ in the body, such as the brain, the lungs, the liver, the heart, the skin,
or the kidneys. As these proteins build up, they begin to get in the way of the job of
whichever organ they are in. Although AL amyloidosis can be assumed from many of
its different symptoms , the only way to know for sure that it is there is to analyze the
cells with a biopsy.
Kidney, amyloidosis happens when the irregular proteins began to get stuck in the
kidneys. As the amyloid builds up, the kidneys are no longer able to work properly
leading to kidney failure. Eventually kidney failure can also cause problems with low
red blood cell count, high blood pressure, and fluid buildup.
What does it look like?

Glomerulus affected by AL Amyloidosis
In the affected filter on the right, almost all of these loops have flattened because of all
the built up M-protein. Shown above are two glomeruli, or kidney filters, as they look
under a microscope. The normal filter is on the left, and the filter damaged by this
disease is on the right. See that in the normal filter, there are many open “loops”
scattered throughout- these are all small blood vessels seen in a small piece cut from
the kidney.
This time a “stain” has been added that turns the
damaged cells bright green.
This is another
stain that is used
in finding
disease, called
“Congo Red”.
This stain turns
“bright apple
green” when it
touches the sick
cells.
WHO AT RISK?
We don’t yet know why some people get AL amyloidosis, even though 1,000-3,000 new
cases are found each year in the US. About 2/3 of these patients are male, and almost
all of them are over the age of 40. Although this type of amyloidosis can occur by itself,
it often happens with other blood disorders, such as multiple myeloma and

Glomerular disease postgraduate magdi sasi 2019

Glomerular disease postgraduate magdi sasi 2019

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Glomerular disease postgraduate magdi sasi 2019