Nephrotic and Nephritic Syndromes and the

Glomerulonephritidies
The basic functional unit of the kidney is the nephron, which consists of the
glomerulus and the tubular system. Glomeruli are the basic units of the
nephrons; there are about 1 million glomeruli in each kidney (constituting
about 5% of the kidney weight).
The glomerulus is a net of
anastomosis of afferent
capillaries which are held
together by the mesangium
(composed of mesangial
cells and matrix) which
keeps the capillaries patent.
The figure on the right
demonstrates the structure of
the glomerulus; it is
composed of capillaries
lined by endothelial cells.
Podocytes (the epithelial
cells that make up the
visceral layer of Bowmans
capsule) extend foot
processes that cover the
capillaries.
Fusion of the basement
membranes of the epithelial
cells (podocytes) and endothelial cells make up the glomerular basement
membrane (GBM), the charge and size dependent filtration barrier (it
prevents large and negatively charged molecules such as albumin from being
filtrated).
Important terminology in kidney disease:
- Diffuse: all the glomeruli in the kidney are involved.
- Focal: patchy involvement of glomeruli.
- Global: the whole glomerulus is affected by the pathologic process.
- Segmental: part of the mesangium is involved in the pathologic
process.

 Mechanisms of kidney inflammation: there is involvement of antibodies,

immune complexes and T cells.
- Humoral mediated: through antibodies that bind structures in the
kidneys (as anti-GBM disease), or antibodies that bind structures
outside the kidneys, resulting in the formation of immune complexes
that later deposit in the kidneys (as lupus nephritis with anti-DNA
antibodies). Normally, when immune complexes form, the cells of
the reticuloendothelial system get rid of them and they are cleared. In
susceptible patients, the immune complexes will not be cleared and
will accumulate and deposit in the kidneys causing complement
activation and inflammation.
- Cell mediated: T cell activation and the release of cytokines and
chemokines results in inflammation (in the kidneys and other organs
as well).
Classification of glomerulonephritis (GN):
- Clinical classification: according to the history and physical
examination (which are the key to the diagnosis) GNs are
classified into either acute or chronic, primary (starting in the
kidney) or secondary (kidney involvement is secondary to a
systemic disease as SLE, multiple myeloma or infection), and
nephrotic and/or nephritic.
- Pathologic classification: according to the histopathology on kidney
biopsies GNs are classified into proliferative and non-proliferative.
The clinical picture, diagnosis, treatment and outcome differ between
them.
o Proliferative: proliferation of mesangial cells, endothelial cells
or epithelial cells. The proliferation can be global, crescentic or
segmental.
o Non-proliferative such as minimal change nephropathy, focal
segmental glomerulosclerosis (FSGS) and membranous
glomerulonephritis (MGN).

Nephrotic Syndrome
It is a syndrome characterized by the following features:
- Proteinuria > 3.5 g/day (3+ or 4+); due disturbance in the GBM.
- Hypoalbuminemia.
- Dyslipidemia; due to the hypoproteinemia and reduction in oncotic
pressure which stimulate the liver to synthesize LDL and release
more cholesterol.
Edema; especially of the face (puffy face).
Nephrotic syndrome has important complications; such as
atheroslcerosis due to the dyslipidemia, and increased risk of thrombosis
(such as renal vein thrombosis) due to urinary loss of anti-thrombin III;
the more the proteinuria, the more is the risk of thrombosis.
Also, patients are at an increased risk of infections due to urinary loss of
immunoglobulins, apart from the fact that the treatment is that of
immunosuppression.
Work up in nephrotic syndrome:
- Urinalysis (dipstick): chemical reaction with the urine; it gives
information about RBCs, WBCs, sugars, ketones, and proteins. It is
sensitive to only albumin.
- Urine sediment examination under the
microscope (oval fat bodies in nephrotic
syndrome, as seen in the adjacent figure).
- Measurement of urine protein, by 24 hour
urine collection (normally it is <150
mg/day); proteins measured by this method
include albumin and other proteins such as
paraprotein (seen in multiple myeloma).
There are two methods to quantify protein in
the urine:
1. Compare with dipstick result, if dipstick is negative for
protein, but 24 hour urine protein is high, this means that
albumin is not the protein involved, and this needs more
investigation (as it could be multiple myeloma with
paraproteinuria).
2. Spot test for urine albumin:creatinine ratio (ACR) which is
normally less than 2.5 in males and 3.5 in females.

- Serology; according to the clinical picture (we can look for ANA,
anti-DNA antibodies if lupus is suspected, C3 and C4 levels, HBV,
HCV, HIV antigensetc).
- Renal ultrasound: it gives information about the size of the kidney (if
small; biopsy is contraindicated, the patient may be in end stage renal
disease (ESRD)).
- Doppler ultrasound; which can detect renal vein thrombosis (which
itself can cause proteinuria, hematuria, and acute kidney injury).
- Renal biopsy for definitive diagnosis; most adult patients with GN
undergo a renal biopsy.

Diseases that cause nephrotic syndrome:

1. Minimal change disease (MCD): the most common cause in
children, and is responsible for 5-10% of cases in adults. There is a
defect in the charge or pore size of the GBM, and there will be
effacement of the foot processes of the podocytes which is seen on the
electron microscope. This disease is of sudden onset, and results in
fluid and salt retention, edema and weight gain. Symptoms are related to
fluid overload, and 30% develop hypertension and microscopic
hematuria (with no RBC casts, or dysmorphic RBCs). 20% of adult
patients (> 40 years of age) present with renal dysfunction due to either
intravascular volume depletion and 3rd spacing of fluid, or direct protein
toxicity on the tubules (acute tubular necrosis). Patients with MCD have
selective proteinuria (only to albumin), with normal complement levels
and serological tests.
Diagnosis (in adults) is by renal
biopsy; where electron microscopy
shows effacement of the podocyte foot
processes, as seen in the figure on the
right. Light microscopy and
immunofluorscence are normal; hence
the name.
Treatment is with steroids (2mg/kg for 46 weeks, followed by 1mg/kg
for 46 weeks in adults).
Relapses could be infrequent, frequent (2 or more within 6 months), or
steroid dependent (while the patient is on steroids or within 2 weeks of
therapy). After treatment, 30% remit with no relapses, 30% will have

infrequent relapses (in such patients, the course of steroids has to be

repeated), and a further 30% will have frequent relapses and need to be
treated with steroids and second line therapy (cyclophospohamide,
mycophenolate mofetil (MMF), or calcineurin inhibitor (CNI)); the choice
of a second line drug depends on the patient; for example,
cyclophosphoamide is not favorable in young female patients due to side
effects on reproduction. Second line drugs have also to be used in
steroid dependent relapses.
Minimal change disease could also be secondary (not idiopathic); to
drugs (NSAIDs for example), or to malignancies (as Hodgkins
lymphoma, and leukemias).
MCD does not progress to chronic kidney disease.
2. Focal segmental glomerulosclerosis (FSGS): this is a histological
description with involvement of parts of some glomeruli in the kidneys,
and thus its diagnosis requires a kidney biopsy.
20-25 % of cases are idiopathic (more common in African Americans).
Other forms are familial (autosomal dominant or recessive); and these
are usually resistant to treatment.
The cause is believed to be the presence of a permeability factor in the
serum of patients, which increases the GBM permeability to protein;
thats why plasma exchange is a modality of treatment. It is important to
know if the patient has primary (idiopathic) or secondary FSGS,
especially if the patient is going to have a renal transplantation (to know
the recurrence rate of the disease in the transplanted kidney).
Proteinuria (nonselective) can be asymptomatic or it can reach the
nephrotic range, with edema and swelling. 30-50% of patients will have
hypertension, 20-30% will have a reduced glomerular filtration rate
(GFR) at presentation and 50% will have microscopic hematuria.
Diagnosis is by kidney biopsy, which
shows sclerosis on light microscopy as
seen in the figure on the right, electron
microscopy shows foot process
effacement as that seen in MCD.
Treatment is with steroids for at least 6
months, and if patients dont respond
well, second line drugs can be used such
as ciclosporin and CNI. Left untreated, patients with FSGS will progress

to ESRD in about 5-20 years (the range depends on the type of FSGS,
and other therapies such as ACE inhibitors).
Secondary causes of FSGS could be:
a. Viral infections such as HIV (especially in African Americans),
Hepatitis B virus and Parvovirus B19.
b. Drugs such as INF-, lithium and bisphosphonates (pamidronate).
c. Hypertensive nephropathy.
d. Reduced renal mass and hyperfiltration (as in patients with a
single kidney).
e. Reflux nephropathy.
f. Obesity.
g. Sick cell disease.
3. Membranous glomerulonephritis (MGN): it is the commonest
cause of nephrotic syndrome in white people. Most cases in the west are
idiopathic, whereas in our part of the world, they are mostly secondary.
Manifestations are those of the nephrotic syndrome; patients can also
have hypertension and microscopic hematuria. Renal function is normal
at the time of diagnosis (normal GFR).
MGN is the worst disease, among the causes of nephrotic syndrome, in
terms of thrombosis, and the risk is increased if serum albumin is <
28g/L.10-30% present with renal vein thrombosis (with flank pain,
hematuria and deterioration of renal
functions). Thrombosis can occur in
other sites as well (deep vein
thrombosis (DVT) for example).
Renal biopsy shows thickened and rigid
capillary loops without cellular
proliferation as seen in the figure,
immunoflourscence and electron
microscopy show immune complex
deposition on the capillaries.
Renal survival is about 75% over 10 years, and this depends on the level
of proteinuria; the more it is, the less is the renal survival (and thus,
lowering the proteinuria improves renal survival). One third of patients
remit spontaneously. In older patients (above 50), age appropriate cancer

screening should be done, since malignancy is one secondary cause of

MGN.
Treatment depends on the level of proteinuria:
- If mild (<4 g/day with a normal GFR), maintain blood pressure at
< 130/80 mmHg with ACE inhibitors.
- If moderate (4-8 g/day with a normal GFR), monitor the patient
after 6 months, while maintaining blood pressure at < 130/80 mmHg
with ACE inhibitors; if proteinuria improves (<4 g/day), continue
with the same method; and if it doesnt, steroids and second line
drugs should be given.
- If severe (>8 g/day with or without an abnormal GFR), monitor the
patient after less than 6 months, and if there is no improvement, give
steroids and second line drugs (such as ciclosporin).
Secondary causes of MGN include:
a. Malignancies: solid organs such as: lung, breast, colon, or kidney.
Proteinuria can be the first presentation in such malignancies.
b. Infections; including Hepatitis B and C, malaria, syphilis,
schistosomiasis, leprosy, and filariasis.
c. Drugs: gold, mercury, penicillamine, NSAIDs, and
probenecid.
d. Autoimmune diseases: SLE, RA, primary biliary cirrhosis,
dermatitis herpetiformis, bullous pemphigoid, myasthenia gravis,
Sjgren's syndrome, and Hashimoto's thyroiditis.
Symptomatic therapy for nephrotic syndrome (whatever the cause)
includes low salt diet, ACE inhibitors, or ARBs, and diuretics; even if
the patient is not hypertensive.
Generally, in diseases causing the nephrotic syndrome, complement
levels are normal.
If there is proteinuria > 3.5 g/day without other features of the nephrotic
syndrome (dyslipidemia and hypoalbuminemia), patients are said to
have nephrotic range proteinuria.

Nephritic Syndrome
It is a syndrome characterized by the following features:
- Hematuira (with RBC casts or dysmorphic RBCs).
- Hypertension.
- Edema.
- Mild to moderate proteinuria (< 3g/day; not in the nephrotic range).
- Increased serum creatinine.
Oliguria (often)
There might also be generalized nonspecific symptoms such headache and
fatigue.
The mechanism is inflammation of the glomeruli, which causes hematuria,
reduction in the GFR, oliguria, as well as salt and water retention which
causes hypertension and edema (as opposed to nephrotic syndrome where
they are caused by hypoalbuminemia).
Most of the diseases that cause nephritic syndrome are proliferative,
whether they are primary or secondary.

Diseases that cause nephritic syndrome:

1. Post-infectious glomerulonephritis: this is due to formation of
immune complexes that deposit in the kidneys, and activate the
complement system resulting in proliferation and inflammation. Most of
the cases are due to Group A hemolytic streptococci strains 12 and 49.
With strain 12, the GN occurs 1-3 weeks after the pharyngitis, while with
strain 49, the GN occurs 2-6 weeks after the impetigo. It is very important to
know the time frame between the initial infection and the onset of the
nephritic syndrome to differentiate it from IgA nephropathy in which the
nephropathy occurs concurrently with, or immediately after the infection.
Other microorganisms can cause post-infectious glomerulonephritis,
including other bacteria, viruses and fungi.
The classic presentation is an acute nephritic picture with hematuria,
pyuria, RBC casts, edema, hypertension, and oliguric renal failure, which
may be severe enough to appear as rapidly progressive glomerulonephritis
(RPGN).
Diagnosis:
- History: infection in the recent previous months (pharyngitis or
impetigo).

- Blood tests: the titer of AntiStreptolysin O (ASO) antibodies, which

are usually raised. Its absence however
doesnt exclude the disease, but its
presence strongly suggests it. It may
remain positive in the serum for several
months.
- Urinalysis; which shows protein.
Microscopic examination of the urine
may show dysmorphic RBCs, RBC
casts (as shown on the right), or WBC
casts (active urine sediment).
- High serum creatinine.
- Hypocomplementemia (returning to the
normal values within 6 to 8 weeks).
- Renal biopsy confirms the diagnosis;
but it is invasive and not done to all
patients (especially if the other methods
are suggestive); biopsy shows mesangial hypercellularity,
endocapillary hypercellularity and leukocytes.
Treatment is nonspecific and supportive. More than 90% of patients fully
recover (especially children), hematuria might be prolonged (for 1 to 2
months) but renal failure is rare.
2.Rapidly progressive glomerulonephritis (RPGN): it is a syndrome, not
a single disease characterized by a rapid increase in serum creatinine and
deterioration of kidney function. It is uncommon, and comprises 10-15% of
all the glomerulonephritidies. It is due to damage of the glomeruli and the
formation of crescents; which
occur due to triggering of the
proliferation of the podocytes that
form layers of cells in Bowmans
capsule, along with macrophages
and monocytes. This can affect
some or all of the glomeruli. The
figure on the right shows two
cresentic glomeruli.

RPGN is classified according to immunological findings in the kidneys

into:
1. Anti-GBM disease (<10%): in which there is linear deposition of
immune complexes on the GBM; this can involve only the kidneys, or it
can involve the lungs as well; where it is called Goodpastures
syndrome.
2. Immune complex disease: in which there is a granular pattern of immune
complex deposition in the glomeruli; this includes IgA nephropathy,
lupus nephritis, post-infectious glomerulonephritis, and
membranoproliferative glomerulonephritis (MPGN).
3. Pauci-immune disease: in which there is no evidence of immune
complex or complement deposition in the glomeruli. It is the most
common type of RPGN. It includes the ANCA small vessel vasculitidies.
Anti-GBM disease: autoantibodies are directed against antigens in the
GBM ( alveolar-capillary membrane). It has a bimodal distribution; the first
peak occurs in young men (<20 years of age), and the second in older men
and women (60-70 years). Pulmonary involvement (Goodpastures
syndrome) occurs more frequently in smokers. Disease in the younger age
group is usually explosive, with hemoptysis, a sudden fall in hemoglobin,
fever, dyspnea, and hematuria. Prognosis is usually bad; especially if there is
multi- organ involvement, and the earlier the diagnosis and initiation of
therapy, the better the outcome. Thus, serum anti-GBM and an urgent kidney
biopsy are needed in those patients. Sometimes, if the clinical picture is
suggestive, initiation of treatment can be done even before the biopsy is
taken. Prognosis at presentation is worse if there are >50% crescents on renal
biopsy with advanced fibrosis, if serum creatinine is >56 mg/dL, if oliguria
is present, or if there is a need for acute dialysis. In Goodpastures syndrome,
the lung hemorrhage should also be treated. Patients are treated with high
dose steroids, cyclophosphoamide and plasma exchange. Isolated renal
involvement needs less aggressive treatment.
ANCA small vessel vasculitidies:
1. Granulomatosis with polyangiitis (GPA): formerly known as Wegeners
granulomatosis. Patients present with respiratory (usually upper, but also
lower) and renal symptoms. Usually in the 5th and 6th decades. Patients
classically present with fever, purulent rhinorrhea, nasal ulcers, sinus pain,
polyarthralgias or arthritis, cough, hemoptysis, shortness of breath,
microscopic hematuria, and non-nephrotic range proteinuria; occasionally

there may be cutaneous purpura and

mononeuritis multiplex. Proptosis may occur
due to retro-orbital inflammation as seen in the
figure on the right, leading to diplopia. Chest xray often reveals nodules and persistent
infiltrates, sometimes with cavities, as seen in
the figure. This disease can spare the kidneys;
where it is called limited GPA. When there is
renal involvement, the prognosis is bad, with
80% progression to GN. This disease is PR3ANCA (formerly known as c-ANCA) positive.
Treatment is by steroids and
immunosuppresion.
2. Microscopic polyangiitis: clinically, these
patients look somewhat similar to those with
GPA, except they rarely have significant lung
disease or destructive sinusitis. The distinction is made on biopsy, where
the vasculitis in microscopic polyangiitis is without granulomas. Patients
are usually MPO-ANCA (formerly known as p-ANCA) positive.
3. Eosinophilic granulomatosis with polyangiitis (EGPA): formerly known
as Churg-Strauss syndrome. Patients usually have peripheral eosinophilia,
cutaneous purpura, asymmetrical mononeuritis, asthma, and allergic
rhinitis. Lung inflammation, including fleeting cough and pulmonary
infiltrates, often precedes the systemic manifestations of disease by years.
The lung is rarely spared in this disease.
Immune complex disease:
1. IgA nephropathy: it is an immune complex disease, in which IgA
antibodies deposit in the mesangium of glomeruli. It is the most common
cause of GN; especially in Asia. It is usually diagnosed incidentally,
because it causes microscopic hematuria. It is slightly commoner in males
and has a peak incidence in the second and third decades of life, and rare
familial clustering. IgA deposition in the mesangium is either idiopathic, or
associated with other diseases including chronic liver disease, Crohn's
disease, gastrointestinal adenocarcinoma, celiac disease, dermatitis
herpetiformis, chronic bronchiectasis, idiopathic interstitial pneumonia,
mycosis fungoides, ankylosing spondylitis, and Sjgren's syndrome.

It is usually asymptomatic, but there are episodic attacks of macroscopic

hematuria during or immediately after an upper respiratory tract infection,
often accompanied by proteinuria or persistent asymptomatic microscopic
hematuria. Acute renal failure and a rapidly progressive clinical picture is
rare. Prognosis for the kidneys is good, unless there is renal impairment at
presentation, hypertension, or proteinuria > 1g/day. Treatment is
supportive and nonspecific, ACE inhibitors or ARBs can be used when
there is proteinuria. Fish oil might help as well. When presenting as
RPGN, patients typically receive steroids, and cytotoxic agents (but not
plasmapheresis). Henoch-Schnlein purpura is a similar disease with
systemic features; it is associated with purpra over the buttocks and lower
legs, abdominal pain or bleeding, and arthritis; usually following an upper
respiratory tract infection. Weeks later, it can be followed by nephritis.
Tissue biopsy shows IgA deposition in blood vessels.
2. Lupus nephritis: lupus nephritis is a common and serious complication of
systemic lupus erythematosus (SLE) and most severe in African-American
female adolescents. 60% of patients with SLE will have lupus nephritis.
Patients might present with lupus nephritis alone, or with other manifestations
of SLE. The most common clinical sign of renal disease is proteinuria, but

hematuria, hypertension, varying degrees of renal failure, and active urine

sediment with RBC casts can all be present. Proteinuria can be in the
nephrotic or non-nephrotic range. SLE can also have non-glomerular renal
manifestations such as tubulointerstitial nephritis and vasculitis.
Lupus nephritis has 6 classes; they differ in their presentation, treatment
and prognosis. Patients can have more than one class (for example; class
III and V, together). Most of the classes present as nephritic syndrome.
Class V can present as nephrotic syndrome. Class V usually occurs with
another class. Treatment depends on the class; but is usually with
steroids, cytotoxic drugs (MMF or cyclophosphoamide), and rituximab.
3. Membranoproliferative glomerulonephritis (MPGN): this disease
usually presents in young age. It has two types; 1 and 2.
- Type 1: patients have a history of recent upper respiratory tract
infection. It usually manifests as nephrotic syndrome.
- Type 2 (dense deposit disease): less common. It usually presents as
nephritic syndrome. It is associated with hypocomplementemia,
and it is C3 (nephritic factor) positive. Treatment is by cortisone,
and antiplatelet drugs such as aspirin. 50% will have ESRD in 10
years.

Other diseases that can cause GN:

1. Hereditary nephritis: Alport syndrome (nephritis, with deafness, and eye
disorders).
2. Subacute bacterial endocarditis: patients present with gross or
microscopic hematuria, pyuria, and mild proteinuria or, less commonly,
RPGN with rapid loss of renal function.
3. Cryoglobulonemic vasculitis: cryglobulins are antibodies which from
against immunoglobulins forming immune complexes that deposit in the
cold. They are classified into 3 types according to the immunoglobulin
involved. Type III is associated with polyclonal antibodies directed at IgG,
and it is the one that is usually associated with GN. It is caused by HBV,
HCV, or rheumatoid arthritis (RA). In type III cryglobulonemia, there will
be necrotizing skin lesions, arthralgia, fever, and hepatosplenomegaly. The
GN can lead to RPGN.
4. HIV nephropathy: it usually occurs in young black men, especially IV
drugs abusers. It usually presents as nephrotic syndrome with normal
complement levels.
5. Hepatitis C virus infection: this can cause either nephritic or nephrotic
syndrome. It can cause three patterns of GN: MPGN (type I), MGN, or
cryoglobulonemia associated GN. Treatment is with INF-.
6. Amyloidosis: renal amyloidosis is of two types: primary (AL) which is
idiopathic, or associated with multiple myeloma, and secondary (AA)
which is associated with RA, inflammatory bowel disease (IBD), familial
mediterranean fever (FMF) and tuberculosis. Treatment includes alkylating
agents, melphalan, and corticosteroids. Renal transplantation could be
indicated in secondary amyloidosis.
This table lists the causes of GN that cause hypocomplementemia:

This table summarizes the important GNs:

Done by: Mohammed Bashabsheh & Osama Thiabat