pathophysiology of acute glomerulonephritis - PD2009fkub

pointdepressedMechanics

Feb 22, 2014 (3 years and 1 month ago)

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M
ODULE
:

ACUTE GLO
MERULONEPHRITIS

Contributor:

dr. Krisni
S ., Sp.
A(K)

LEARNING

OBJECTIVE

:

After completing this module, the students be able to:

1.

D
escribe
the
acute glomerulonephritis


2.

E
xplain
the
pathophysiology
of
acute glomerulonephritis

3.

D
escribe many causes of
acute glomerulonephritis

4.

D
e
scribe the complication of
acute glomerulonephritis

5.

P
lan assessement of
acute glomerulonephritis

6.

C
ommunicate
and taking history
with
acute glomerulonephritis

LEARNING

ACTIVITY

:


Knowledge

& Attitude

Skill
& attitude

1.

Overview lecture

2.

Self directed learning

3.

Small class discussion

4.

Instructure lecture

5.

Assessement


1.

Overview lecture of History taking in
acute glomerulonephritis

2.

History taking formative assessement
(checklist)

3.

OSCE summative assessement in
the
last semester



OVERVIEW

:


Acute glomerulonephritis (AGN) is a disease characterized by the sudden
appearance of edema, hematuria, proteinuria, and hypertension. It is a representative
disease of acute nephritic syndrome in which inflammation of the glom
erulus is manifested
by proliferation of cellular elements secondary to an immunological mechanism.

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PATHOPHYSIOLOGY

OF

ACUTE

GLOMERULONEPHRITIS

Pathophysiology

Acute GN has 2 components: structural changes and functional changes.

Structural changes



Cellular proliferation: This leads to an increase in the number of cells in the

glomerular

tuft because of the proliferatio
n of endothelial, mesangial
and epithelial cells. The
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proliferation could be endocapillary (ie, within the confines of the glomeru
lar

capillary

tufts) or extracapillary (ie, in the Bowman space involving the

epithelial cells).
In

extracapillary proliferation, proliferation of parietal epithelial cells leads to
the

formation of crescents, a feature characteristic of certain forms

of rapidly

progressive GN.



Leukocyte proliferation: This is indicated by the presence of neutrophils and

monocytes

within the glomerular capillary lumen and often accompanies cellular

proliferation.



Glomerular basement membrane thickening: This
development appears as

thickening

of capillary walls using light microscopy. Using electron microscopy, this may

appear as the result of thickening of basement membrane proper (eg, diabetes) or

deposition of electron
-
dense material, either on the endot
helial or epithelial side of

the

basement membrane.



Hyalinization or sclerosis: These conditions indicate irreversible injury.



Electron
-
dense deposits: Such de
posits could be subendothelial,
subepithelial,

intramembranous, or mesangial, and they correspond to an area of immune complex

deposition.



These structural changes could be focal, diffuse or segmental, and global.


Functional changes


Functional changes include proteinuria, hematuria, reduction in
GFR (ie, oligoanuria),
and active urine sediment with RBCs and RBC casts. The decreased GFR and avid distal
nephron salt and water retention result in expansion of intravascular volume, edema, and,
frequently, systemic hypertension.


Poststreptococcal glom
erulonephritis


M
-
protein of the organism was previously believed to be responsible for PSGN, but
these studies have been discounted. Nephritis
-
associated streptococcal cationic protease
and its zymogen precursor (NAPR) have been identified as a glyceralde
hyde
-
3
-
phosphate
dehydrogenase that functions as a plasmin(ogen) receptor.
2

This binds to plasmin and
activates complement via alternate pathway. Antibody levels to NAPR are elevated in
streptococcal infections (of group A, C, and G) associated with glomer
ulonephritis but are
not elevated in streptococcal infections without glomerulonephritis, whereas anti
-
streptolysin
-
O titers are elevated in both circumstances.
3

These antibodies to NAPR persist for years and
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perhaps are protective against further episodes

of PSGN. In a study in adults, the 2 most
frequently identified infectious agents were streptococcus (27.9%) and staphyl
ococcus
(24.4%).
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Clinical

History

Taking a proper history is important and helpful.



Determine onset of disease: Ask the patient about onset and duration of illness.



Identify a possible etiologic agent (eg, streptococcal throat infection [pharyngitis], skin

infection [pyoderma]): Recent fever, sore throat, joint pains, hepatitis, trave
l, valve

replacement, and/or intravenous drug use may be causative factors. Rheumatic fever

rarely coexists with acute PSGN.



Identify systemic disease (eg, arthralgia, diabetes).



Assess the consequences of the disease process (eg, uremic symptoms):

Inquire

about loss of appetite, generalized itching, tiredness, listlessness, nausea, easy

bruising, nose bleeds, facial swelling, leg edema, and shortness of breath.



Identify clinical features: Inquire about edema, decreased volume and frequency of

urination, systemic hypertension, uremic symptoms, costovertebral tenderness (ie,

enlarged kidneys [rare]), and gross hematuria. Gross hematuria is the most common

abnormality observed in patients with acute PSGN and often manifests as smoky
-
,

coffee
-
,

or cola
-
colored urine.

Physical



Signs of fluid overload

o

Periorbital and/or pedal edema

o

Edema and hypertension due to fluid overload (in 75% of patients)

o

Crackles (ie, if pulmonary edema)

o

Elevated jugular venous pressure

o

Ascites and
pleural effusion (possible)



Rash (ie, vasculitis, Henoch
-
Schönlein purpura)



Pallor



Renal angle (ie, costovertebral) fullness or tenderness, joint swelling, or tenderness


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Causes

The causal factors that underlie this syndrome can be broadly divided
into infectious and
noninfectious groups.


Infectious

o

Streptococcal: Poststreptococcal GN usually develops 1
-
3 weeks following


acute infection with specific nephritogenic strains of group A beta
-
hemolytic


streptococcus. The incidence of GN is appr
oximately 5
-
10% in persons with

pharyngitis and 25% in those with skin infections.
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o

Nonstreptococcal postinfectious glomerulonephritis


Bacterial
-

Infective endocarditis, shunt nephritis, sepsis, pneumococcal



pneumonia, typhoid, secondary syphili
s, meningococcemia, and infection with


methicillin
-
resistant Staphylococcus aureus (MRSA)


Viral
-

Hepatitis B, infectious mononucleosis, mumps, measles, varicella,



vaccinia, echovirus, parvovirus, and coxsackievirus


Parasitic
-

Malaria, toxoplas
mosis


Noninfectious

o

Multisystem systemic diseases
-

Systemic lupus erythematosus, vasculitis,

Henoch
-
Schönlein purpura, Goodpasture syndrome, Wegener

granulomatosis

o

Primary glomerular diseases
-

Membranoproliferative GN (MPGN), Berger

disease

(ie, immunoglobulin A [IgA] nephropathy), "pure" mesangial

proliferative GN.
3

o

Miscellaneous
-

Guillain
-
Barré syndrome, radiation of Wilms tumor,

diphtheria
-

pertussis
-
tetanus vaccine, serum sickness



Differential Diagnoses

Glomerulonephritis,
Crescentic

Goodpasture Syndrome

Glomerulonephritis, Diffuse Proliferative

Hemolytic
-
Uremic Syndrome

Glomerulonephritis, Membranoproliferative

Nephritis, Interstitial

Glomerulonephritis, Poststreptococcal

Nephritis, Lupus

Glomerulonephritis, Rapidly
Progressive



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Laboratory Studies



Urinalysis and sediment examination

o

These tests are crucial in the evaluation of patients with acute nephritic
syndrome.

o

Look for protein, blood, RBCs and WBCs, dysmorphic red cells,
acanthocytes, cellular (ie, RBC, WBC)

casts, granular casts, and oval fat
bodies. In some instances, marked sterile pyuria is present.

o

Finding RBC casts is an almost pathognomonic sign of GN.

o

Urine electrolytes, urine sodium, and fractional excretion of sodium (FENa)
assays are needed to
assess salt avidity.



Blood, urea, and nitrogen (BUN); serum creatinine; and serum electrolytes
(especially serum potassium level)



Complete blood cell count



Erythrocyte sedimentation rate



Complement levels (C3, C4, CH50)

o

Low C3 levels are found in almos
t all patients with acute poststreptococcal
nephritis; C4 levels may be slightly low. Hypocomplementemia is noted

in
73.9% of adult patients.

o

Type III cryoglobulinemia may be present.



Twenty
-
four

hour urine test for total protein and creatinine clearance:

Remember
that creatinine clearance is a "steady
-
state" measurement. The creatinine clearance
may not reveal the true picture because of rapidly changing renal function; therefore,
it is better to wait until renal function has stabilized before performing
creatinine
clearance.



Antistreptolysin
-
O titer (ASOT) or streptozyme titer: Increasing titer levels confirm
recent infection. In patients with skin infection, anti
-
DNase B titers are more sensitive
than ASOT for infection with
Streptococcus
.



Antibody to
NAPR: Levels are elevated in streptococcal infections with GN but not in
streptococcal infections without GN.



If MRSA is the inciting agent, then hypocomplementemia is usually not present, but
plasma immunoglobulins, especially IgA, are markedly elevated.


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Qualitative estimation of proteinuria: Determination of high
-
molecular weight (HMW)
protein, like fractional excretion of IgG (FEIgG), and low
-
molecular weight (LMW)
protein, like alpha
-
1
-
microglobulin, may help predict the clinical outcome and may
help
in guiding steroid and immunosuppressive therapy, especially in patients with
primary glomerular diseases with nephrotic syndrome.


Imaging Studies



Abdominal ultrasound

o

Assesses renal size

o

Assesses echogenicity of renal cortex

o

Excludes obstruction

Procedures



Generally, a renal biopsy is not necessary for a diagnosis of acute PSGN; however,
in most cases, it is important because histology guides both prognosis and therapy.


Histologic Findings

Diffuse endocapillary proliferative changes are found.
The most common histologic patterns
are diffuse (72.1%), focal (12.8%), and mesangial (8.1%) proliferative GN in adults.
4
In
postinfectious GN, the glomerulus is hypercellular with marked cellular infiltration (ie,
polymorphonuclear neutrophils, monocytes)
. Immunofluorescence may show fine, granular
deposits of immunoglobulin G in a "starry sky" appearance. Large subepithelial deposits may
be observed on electron microscopy.


Treatment

Medical Care

Treatment of acute PSGN is mainly supportive because there
is no specific therapy for renal
disease. Treat the underlying infections when acute GN is associated with chronic infections.



Antimicrobial therapy


o

Antibiotics (eg, penicillin) are used to control local symptoms and to prevent


spread of infection
to close contacts.

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o

Antimicrobial therapy does not appear to prevent the development of GN,



except if given within the first 36 hours.



Loop diuretic therapy


o

Loop diuretics may be required in patients who are edematous and



hypertensive in order to remove excess fluid and to correct hypertension.


o

Relieves edema and controls volume, thereby helping to control volume
-



related elevation in BP.


o

Vasodilator drugs (eg, nitroprusside, nifedipine, hydralazine, diazoxide) may


be used if severe hypertension or encephalopathy is present.


o

Glucocorticoids and cytotoxic agents are of no value, except in severe cases


of PSGN.

Diet



Sodium and fluid

restriction
-

For treatment of signs and symptoms of fluid retention

(eg, edema, pulmonary edema)



Protein restriction for patients with azotemia
-

If no evidence of malnutrition

Activity

Recommend bed rest until signs of glomerular inflammation and ci
rculatory congestion
subside. Prolonged inactivity does not benefit in the patient recovery process.

Medication

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to
eradicate the infection.

Antimicrobials (antibiotics)

In
streptococcal infections, early antibiotic therapy may prevent antibody response to
exoenzymes and render throat cultures negative, but may not prevent the development of
PSGN.


Penicillin V (Pen VEE K, V
-
Cillin K)

More resistant than penicillin G to hydro
lysis by acidic gastric secretions and is absorbed
rapidly after oral administration. 250 mg of penicillin V = 400,000 U of penicillin.

Dosing

Adult

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500,000 U PO q6
-
8h


Pediatric

25,000
-
90,000 U/kg/d PO in 3
-
6 divided doses

Interactions

Probenecid can incr
ease effects; coadministration of tetracyclines can decrease effects;
aminoglycosides show synergistic bactericidal effect in vitro against some strains of
enterococci and viridans streptococci

Contraindications

Documented hypersensitivity

Loop diuretics

Decrease plasma volume and edema by causing diuresis. The reduction in plasma volume
and stroke volume associated with diuresis decreases cardiac output and, consequently, BP.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride
-
bin
ding cotransport system,
inhibiting sodium and chloride reabsorption in ascending loop of Henle and distal renal
tubule.

Rapidly absorbed from the GI tract. The diuretic effect is apparent within 1 h of PO
administration, peaks by second h and effect lasts

for 4
-
6 h. Following IV administration
diuresis occurs within 30 min; duration of action is about 2 h; 66% of dose is excreted in the
urine.

Dosing

Adult

Edema:

Initial: 40
-
80 mg PO, titrate to satisfactory diuresis in 20
-

to 40
-
mg increments q6h; not to
exceed 200 mg per dose; once effective single dose determined, may repeat qd/tid

Hypertension:

20
-
40 mg PO bid; titrated to desired response; if 40 mg PO bid does not lead to clinically
significant response, add another antihypertensive agent rather than i
ncreasing the dose

Pediatric

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0.5
-
1 mg/kg PO/IV; not to exceed 2 mg/kg PO qd or 1 mg/kg IV qd; in newborn and
premature babies, daily dose should not exceed 1 mg/kg

Interactions

Metformin decreases concentrations; furosemide interferes with hypoglycemic eff
ect of
antidiabetic agents and antagonizes muscle
-
relaxing effect of tubocurarine; auditory toxicity
appears to be increased with coadministration of aminoglycosides and furosemide; hearing
loss of varying degrees may occur; anticoagulant activity of warfa
rin may be enhanced when
taken concurrently with this medication; increased plasma lithium levels and toxicity are
possible when taken concurrently with this medication; potentiate hypotensive effect of
various antihypertensive agents; may enhance the neph
rotoxicity of cephaloridine; sucralfate
may reduce absorption; increases risk of salicylate toxicity; NSAIDs, probenecid,
anticonvulsants may attenuate effect of furosemide

Contraindications

Documented hypersensitivity; hepatic coma, anuria, and state of s
evere electrolyte depletion

Complications



Renal failure (rare)



Pulmonary edema



Generalized anasarca and hypoalbuminemia (secondary to severe proteinuria)



Hypertension



Hypertensive encephalopathy


Prognosis



Prognosis of acute PSGN is generally excellent in children.



Within a week or so of onset, most patients with PSGN begin to experience

spontaneous resolution of fluid retention and hypertension.



C3 levels may normalize within 8 weeks after the first
sign of PSGN.



Proteinuria may persist for 6 months and microscopic hematuria for up to 1 year after

onset of nephritis.



Eventually, all urinary abnormalities should disappear, hypertension should subside,

and renal function should return to normal.


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In adults with PSGN, full recovery of renal function can be expected in just over half

of patients, and prognosis is dismal in patients with underlying diabetic

glomerulosclerosis.



Few patients with acute nephritis develop rapidly progressive rena
l failure.



Nephritis associated with MRSA and chronic infections usually resolves after

treatment of the infection.



Immunity to type M protein is type
-
specific, long
-
lasting, and protective. Repeated

episodes of PSGN are therefore unusual.



Appro
ximately 15% of patients at 3 years and 2% of patients at 7
-
10 years may have

persistent mild proteinuria. Long
-
term prognosis is not necessarily benign. Some

patients may develop hypertension, proteinuria, and renal insufficiency as long as 10
-

40 years

after the initial illness.


Patient Education



Counsel patients about the need for the following measures:

o

Salt restriction during the acute phase to control edema and volume
-
related


hypertension

o

BP monitoring at periodic intervals

o

Ongoing lon
g
-
term monitoring of patients with persistent urinary abnormalities


and elevated BP

o

Consideration of protein restriction and angiotensin converting enzyme



inhibitors (in

patients who show evidence of persistent abnormalities or in


those who deve
lop late evidence of progressive disease)

o

Early antibiotic treatment of close contacts


SKILLS

:

History taking about
acute glomerulonephritis

s
ee
a
ttachment


SCENARIO

:

An 7
-
year old boy, present with hematuria. A history of a recent throat infection + 14 days
before admission. Physical examination revealed temperature is 37,20C, blood pressure
140/100 mmHg, periorbita edema +. Laboratory examination revealed albumin, cho
lesterol
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was normal. BUN : 168 mg/dl, creatinine serum : 4,8 mg/dl. ASO titer : 400 iu/ml, CRP :
negative. Urinalysis revealed albumin +2, dysmorphic erythrocyte, erythrocyte/granular casts
: +, leucocyte 3
-
5 /hpf. What is the diagnosis in this patient ?

T
ASK
:

1.

Discuss a problem of
the scenario








2.

Explain the possibility mechanism, why the patient suffered from those symptoms?









3.

Can you draw
the

symptoms
in your patient?






4.

What will the patient suffer from the next complication? How?



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5.

What is your opinion about the laboratory result?


6.

Do you need further examination to confirm your hypothesis about the patient problem?
What for?





A
SSESSMENT
:

Assessement system consist of: formative and summative ssessement.

1.

Formative
assessement
: s
tudent activity during discussion

2.

Summative assessement: MCQ examination after the completion of teaching
-
learning process.

3.

PBL assessment in the last semester



S
UGGESTED READING
:

1.

Yoshizawa N. Acute glomerulonephritis. Intern Med. Sep 2000;39(9):687
-
94.

2.

Ahn SY, Ingulli E. Acute poststreptococcal glomerulonephritis: an update. Curr Opin

Pediatr. Apr 2008;20(2):157
-
62

3.

Oda T, Yamakami K, Omasu F, et al. Glomerular plasmin
-
like
activity in relation to

nephritis
-
associated plasmin receptor in acute poststreptococcal glomerulonephritis. J

Am Soc Nephrol. Jan 2005;16(1):247
-
54.

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4.

Wen YK, Chen ML. The significance of atypical morphology in the changes of spectrum

of
postinfectious glomerulonephritis. Clin Nephrol. Mar 2010;73(3):173
-
9.

5.

Nasr SH, Markowitz GS, Stokes MB, et al. Acute postinfectious glomerulonephritis in the

modern era: experience with 86 adults and review of the literature. Medicine (Baltimore).

Ja
n 2008;87(1):21
-
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