Nephrotic and Nephritic Syndromes and the Glomerulonephritidies

8/18/2019 Nephrotic and Nephritic Syndromes and the Glomerulonephritidies

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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 Bowman’s

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.


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• 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 ofthe 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), andnephrotic 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).


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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 releasemore 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


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- 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 antigens…etc).

- 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 (whichitself 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; hencethe 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


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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 Hodgkin’s

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;

that’s 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 don’t respond

well, second line drugs can be used such

as ciclosporin and CNI. Left untreated, patients with FSGS will progress


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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-α, 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


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

MGN.

Treatment depends on the level of proteinuria:

-

If mild (


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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 ofimmune complexes that deposit in the kidneys, and activate thecomplement system resulting in proliferation and inflammation. Most of

the cases are due to Group A β hemolytic streptococci strains 12 and 49.With strain 12, the GN occurs 1-3 weeks after the pharyngitis, while withstrain 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).


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- Blood tests: the titer of Anti-

Streptolysin O (ASO) antibodies, which

are usually raised. Its absence however

doesn’t 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 2months) 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 Bowman’s

capsule, along with macrophages

and monocytes. This can affect

some or all of the glomeruli. The

figure on the right shows two

cresentic glomeruli.


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RPGN is classified according to immunological findings in the kidneys

into:

1.

Anti-GBM disease (5–6 mg/dL, if oliguria

is present, or if there is a need for acute dialysis. In Goodpasture’s 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 Wegener’s 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


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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 x-

ray 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 PR3-

ANCA (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 malesand 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 Sjögren's syndrome.


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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-Schönlein 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 ofsystemic 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.


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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-α.

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:


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This table summarizes the important GNs:

Done by: Mohammed Bashabsheh & Osama Thiabat

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Nephrotic and Nephritic Syndromes and the Glomerulonephritidies