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PRESENTER: Dr. Devang B. Pandya SUBJECT SEMINAR |
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REFERENCES Pediatric nephrology by Arvind Bagga
NELSON textbook of pediatrics 19th edition
GHAI essential pediatrics 6th revised edition and 7th edition
4. Wikipedia internet site
5. E-medicine internet site
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HEMOLYTIC URAEMIC SYNDROME |
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Definition H.U.S. is characterized by the acute onset of
1.Microangiopathic hemolytic anemia
2.Acute renal insufficiency
3.Thrombocytopenia |
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SUB-GROUPS D+ HUS(typical):( 95%)
It is associated with diarrheal prodrome
D– HUS (atypical):
It is not associated with diarrheal prodrome
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EPIDEMIOLOGY Incidence :
D+ HUS - 2.1 cases per 100,000 persons per year, with a peak incidence in children who are younger than 5 years.
D- HUS -2 cases per year per 100,000 total population.
In D+ HUS, the mortality rate is between 3% and 5%.
In cases of D- HUS, overall mortality rate approaches 26%.
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ETIOLOGICAL CLASSIFICATION Infection induced:
Bacterial
Vero toxin producing E.COLI (O157:H7): causing HUS in 80-90% of patients in developed countries.
Shiga toxin producing shigella dysenteriae type 1: causing HUS in developing countries(MC cause in india)
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Bacteria in GIT tract by contaminated food
Toxin production by bacteria and it will act by inhibiting protein synthesis
A unit B unit
B1 B2
after binding it will internalize
And cause
ENDOTHELIAL INJURY
binds with bowel wall
receptors and inflammatory cells
to reach circulation
Binds to Gb3 receptors
in kidney endothelial cells |
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Others:
Neuraminidase producing Strept. Pneumonia:
Neuraminidase cleaves sailic acid present on the membranes of endothelial cells, RBCs and platelet and so they reveal cryptic antigen known as THOMSON FRIEDREICH
Endogenous IG M antibodies recognize them and cause microvascular angiopathy
Salmonella
Bartonella
Viral
Coxsackie, influenza,echo,varicella,EBV and HIV
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Reservoir of infecting organism:
Intestinal tract of domestic animals(usually cows)
Source of organism:
Uncooked meat
Unpasteurized milk
Swimming in infected water source
Cheese or raw spinach contaminated with meat
Person to person is rare
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B. GENETIC:
1.ADMATS 13 deficiency:
Mechanism:
It is zinc containing metalloproteinase that cleaves vWf large multimers to monomers and by this reduces its activity.
So if there is deficiency of ADAMTS 13 there is increased platelets aggregation and it will form micro thrombi in small vessels.
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2. Complement factor H or 1 deficiency or mutation:
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Membrane cofactor protein mutation(MCP):
Mechanism:
CD 46 gene encodes for MCP that reduces the activity of C3b and C4b and so prevent damage by complements. |
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C. Medication induced:
Calcineurin inhibitors(cyclosporin,tacrolimus)
Cytotoxic drugs: mitomycin C,cisplatin, gemcitabine
Clopidogrel and ticlopidine
Quinine
OC pills |
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Conditions associated with micro vascular injury:
S.L.E.
Anti-phospholipid syndrome
Following BMT
Malignant hypertension
HELLP syndrome associated with pre-eclampsia |
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PATHOGENESIS Main event:
ENDOTHELIAL CELL INJURY
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Normally, the vascular endothelial lining presents a non-reactive to circulating blood cells.
Due to negative charge on endothelial cell surface which repels negatively charged platelets and RBCs.
In HUS, there is disturbed coagulant-anticoagulant status and it causes platelet aggregation (consumptive thrombocytopenia) and fibrin deposition in capillaries. |
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These damaged vessels cause mechanical injury to passing RBCs through it and that causes hemolysis.(microangiopathic hemolytic anemia)
Due to glomerular capillaries and arteriolar injury there is reduction of GFR and it cause uremia.(renal insufficiency) |
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PATHOLOGIC FINDINGS IN KIDNEY BIOPSY LIGHT MICROSCOPY
At early stages,
Thickening of capillary walls due to swelling of endothelial cells or interposed mesangial cells with sub endothelial widening.
This occludes the capillary lumen and gives bloodless appearance.
Than separation of endothelium from underlying basement membrane and lying of new basement membrane like material(by endothelial cells or mesangial cells) result in DOUBLE CONTOUR appearance of the capilarry walls |
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Later, there is formation of platelet and fibrin thrombi in afferent and efferent arteriols and it causes fibrinoid necrosis
Later, these micro thrombi will cause severe ischemic changes and glomerular sclerosis and it will spread to adjacent glomerulus.
Immunofluroscene:
May be deposits of IgM and C3 along with capillary walls |
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Clinical presentation TYPICAL HUS:
HISTORY:
--Age: pre school and school children
--Prodrome illness 3 days or 3 weeks back characterized by
Fever
Abdominal pain
Vomiting
Diarrhea(often bloody)
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Clinical features: (acute onset)
-Pallor
-oliguria
-hypertension
-lethargy mild CNS involvement
-irritability
-petechiae or purpura(rare)
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These symptoms after prodrome usually indicate onset of HUS.
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In HUS, mostly the prodrome and main features overlap with each other.
We can make the rough estimate from the hydration status of the patient that if patient present with DEHYDRATION the acute gastroenteritis predominate and if patient present with OVERHYDRATION the renal insuffiency and anemia predominate. |
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ATYPICAL HUS:
-- older children
--no prodrome
--insidious onset and may be relapsing
--gross hematuria
--severe hypertension
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COMPLICATION RENAL:
-Acute renal failure due to anuria
-End stage renal disease(in 9% of patients)
2. CNS:
severe involvement is seen in <20% os cases
-SEIZURES (most common)
-small infarcts in basal ganglia and cerebral cortex
-severe intracranial bleeds
-focal neurological deficit
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CVS:
-cardiac failure
-severe hypertension
-pericarditis
-Arrhythmias
GIT:
-Severe inflammatory colitis
-intussusceptions
-intestinal perforation
ENDOCRINE:
Permanent or transient IDDM due to focal pancreatic necrosis
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DIAGNOSIS Laboratory criteria:
The following are both present at the same time during illness:
Anemia(acute onset) with microangiopathic changes like,
Schistocytes, burr cells or helmet cells on PS AND
2. Renal injury(acute onset) characterized by hematuria usually microscopic, proteinuria usually low grade or elevated creatinine levels.
>/= 1mg% in child< 13 years or
>/=1.5mg% in child>/= 13 years or
>/= 50% rise over baseline
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Thrombocytopenia can usually detected early in the illness in the range of 20,000 to 1lakh/cumm, but it can be normal or even high afterwards.
If platelet count obtained within 7 days after onset of the acute gastrointestinal illness is >/= to 1.5 lakhs/cumm, other cause should be considered. |
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CASE CLASSIFICATION Probable:
-An acute illness diagnosed as HUS that meets the laboratory criteria in a patient who does not have a clear history of acute or bloody diarrhea in the preceding 3 weeks OR
An acute illness diagnosed as HUS that has
Onset within 3 weeks after onset of acute or bloody diarrhea and
Meets the lab criteria except microangiopathic changes are not confirmed |
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Confirmed:
An acute illness diagnosed as HUS that meets
The laboratory criteria and began within 3 weeks after onset of episode of acute or bloody diarrhea. |
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DIFFERNTIAL DIAGNOSIS TTP:
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Other causes of ARF with microangiopathic hemolytic anemia and thrombocytopenia:
1.S.L.E.
Multisystem involvement
ANA, anti DNA and anti SMITH antibody positive
2.Malignent hypertension
Hypertensive emergency
Papilloedema
Vital systems involvement
3.Renal vein thrombosis
Deranged coagulation profile
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Investigations in suspected HUS HB= low
WBCs= neutrophil leucocytosis upto 30,000/cumm
PS= broken and deformed RBCs
Schistocytes, burr cells or helmet cells
4.Platelet count: decreased in early illness(normal within 2-3 weeks)
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5. Serum electrolytes: due to acute renal failure or severe hemolysis
6.Blood urea and creatinine: elevated
7.Urine analysis:
Microscopic hematuria, proteinuria
8.Coagulation profile: usually normal
9. Coombs test: usually negative but usually positive in strept.pnemonia
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For atypical HUS and familial cases:
Serum c3 and c4 levels
Factor H, Factor 1 and CD 46 level(MCP)
Antibodies to Factor H
IF TTP SUSPECTED:
ADMATS 13 Activity or antibodies to ADAMTS 13 |
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TREATMENT TYPICAL HUS:
There is no any specific treatment for HUS
Supportive treatment:
Fluid and electrolytes maintenance
Treatment of hypertension
Packed cells transfusion
B. Dialysis:
50% of patients needs during
acute phase of illness |
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There is no any role of
Anti- coagulants risk of bleeding
Anti- platelet
Anti-fibrinolytics or
Antibiotics if given it causes toxin release and aggravate the condition.(NO ANTIBIOTICS)
But if HUS caused by strpt pnemonia(pneumonia or empyema) specific antibiotics to be given to control the infection. |
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Indication of plasmapheresis in TYPICAL HUS:
Severe CNS involvement.
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ATYPICAL HUS:
-Plasmapheresis
-FFP transfusion
-ECULIZUMAB |
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PROGNOSIS Bad prognostic factors:
1.Atypical presentation
2.Secondory to strept. Pneumonia(20% mortality)
3.Familial causes
4.Higher neutrophil count
5.Anuria> 14 days |
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Most of the patients recover completely within 1 year without any residual renal insufficiency so overall prognosis is good.
During early illness:
<5% mortality
After dialysis therapy <5% patients become dependant on it.
Chronic renal insufficiency(20-30%) of cases. |
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HENOCH SCHONLEIN PURPURA |
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BACKGROUND First Heberden described a 5-year-old boy with "bloody points" over the skin of his legs, abdominal pain, bloody stools and painful subcutaneous edema.
This may be the first published case of Henoch-Schonlein purpura.
However, the illness is named after the 2 German physicians who further characterized this vasculitis. |
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Johan Schonlein described the association of non-thrombocytopenic purpura and joint pain, which he called purpura rheumatica.
Than his student, Eduard Henoch, noted the gastrointestinal and renal involvement in this disease.
So, the name was given henoch schonlein purpura.
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DEFINITION
It is a systemic leukocytoclastic vasculitis characterized by deposition of immune complexes(Ig A antibodies) in
1. Skin(palpable purpura)
2. Joints(arthritis)
3. GI tract(abdominal pain)
4. kidney(hematuria and proteinuria) |
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EPIDEMIOLOGY INCIDENCE:
14-20 per one lakh children per year
AGE:
3-10 years(95% of cases)
It is the most common vasculitis of childhood
SEX: M:F ratio= 1.2-1.8:1
Seasonal: more in fall and winter
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TRIGGERING FACTORS(30%) Infections:
About 50% of patients have a preceding upper respiratory illness (URI).
streptococci group A, hepatitis B, herpes simplex virus, parvovirus B19, Coxsackievirus,adenovirus, Helicobacter pylori, measles, mumps, rubella, Mycoplasma and numerous others
Drugs: vancomycin,cefuroxime, ACE inhibitors enalapril and captopril, anti-inflammatory agent diclofenac,ranitidine and streptokinase.
Foods
Insect bites
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PATHOGENESIS preceding URTI(group A strept)
it will cause immune reaction
deposition of immune complexes(Ig A1 C3)
in ARTERIOLES,
CAPILLARIES
AND VENULES. |
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PATHOLOGY Skin biopsy:
Vasculitis(neutrophils and monocytes) of dermal capillaries and post capillary venules.
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Kidney biopsy:
Endocapillary proliferative GN(may be focal segmental process to extensive crescent formation)
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Immunofluoroscene:
Ig A deposition in wall of small vessel and also lesser amount of C3,FIBRIN and Ig M. |
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CLINICAL PRESENTATION SKIN:
Hallmark of HSP is RASH. (95-100%)
Pink macule or wheals
petechiae
palpable purpura or large ecchymoses.
These lesions are usually symmetric and mostly in lower limbs and buttocks lasting for 3 to 10 days but may recur even upto 4 months after initial presentation. |
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2. GIT (80%):
Abdominal pain(60 to 80%)
Vomiting
Diarrhea(mucus or blood)
Bleeding(30%) mostly due to intussusceptions
Mesenteric ishaemia or perforation
Paralytic ileus
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3.Musculoskeletal: (75%)
Non erosive
Oligoarticular
Knees and ankle
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4. kidney: (50%)(almost always after skin)
Microscopic hematuria(>50%)(hallmark)
Proteinuria(50%)
hypertension
ARF or CRF(1-2% in children)
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Other organs involvement |
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DIAGNOSIS 1.ACR criteria: (1990)
Two of the following must present
Palpable purpura
Age of onset<20 years
Bowel angina(postprandial abdominal pain and bloody diarrhea)
Biopsy demonstrating intramural granulocytes in small arterioles and/or venules. |
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2. PRES criteria:
Palpable purpura(in absence of coagulopathy or thrombocytopenia) PLUS
One or more of the following:
Diffuse abdominal pain
Arthritis or artharlgia
Biopsy of affected tissue demonstrating deposition of Ig A predominantly.
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Laboratory findings HB-may be mild anemia
TC-may be leucocytosis
ESR- may be elevated
Platelet count- usually elevated or normal(not low)
CRP- elevated
Urine routine- RBCs cast, proteinuria(10-20%)
Stool occult blood- may be positive
RFT- to exclude renal failure
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USG ABDOMEN: To rule out intussuception
(more often ileoileal)
DOPPLER testicular scan:
Normal or increased blood flow in Henoch-Schönlein purpura, in contrast to the decreased blood flow seen in testicular torsion
Biopsy of skin and kidney:
To support diagnosis
Coagulation profile: to exclude other causes |
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Differential diagnosis 1.Ig A nephropathy:
It almost exclusively affect young adults and only kidney.
2. ITP and TTP: normal or elevated platelet count exclude both
3.Acute hemorrhagic edema:
Usually <2 years
Trunk is spared
Only skin involvement
Biopsy
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4. Testicular torsion
USG Doppler shows reduced blood supply
5. DIC:
Deranged coagulation profile
6.Pancreatitis
Serum lipase level |
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Treatment Symptomatic:
Hydration
Nutrition
Analgesia (NSAIDs) but caution in renal insufficiency
B. Steroids:
Prednisolone
1mg/kg/day for 1 to 2 weeks and then tapered. |
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Chronic HSP(renal disease):
when cutaneous, gastrointestinal and/or renal manifestations persisted CONTINUOUS for more than or equal to 12 months
Azathioprin
Cyclophoshamide
Mycophenolate mofetil
Severe disease:
Sometime IVIG or plasma change are used.
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Complication Intestinal perforation
ARF or CRF
(so HSP patients who presented with renal involvement should be monitored for 6 months after discharge. |
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PROGNOSIS More than 80% of patients have a single isolated episode lasting a few weeks.
Recurrence: (30%) when fresh episode will occur atleast 3 months after resolution of all symptoms
Within 4 to 6 months
ESRD: 1-2%
HSP nephritis: 8% will go for ESRD
Chronic HSP: <5%
Abdominal pain usually resolve within 3 days
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GOOD PASTURE DISEASE |
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HISTORY The disease bears the name of the American pathologist Dr. ErnesT Goodpasture of Vanderbilt University, whose 1919 description is regarded as the first report on the existence of the condition. |
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DEFINITION It is defined as the triad of glomerulonephritis (usually rapidly progressive or crescentic), pulmonary hemorrhage, and anti-GBM antibody formation.
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ETIOLOGY GENETICS:
HLA DRB1(most common)
HLA DR2
HLA DR4-5
Environment:
Smoking
Chemicals(gasoline fumes or industrial solvent)
Infections:
URTI preced onset of GPS(20-60%) mostly influenza
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EPIDEMIOLOGY Age: at any age
Sex: no difference
Race: whites
It is rare in children. |
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PATHOGENESIS The presence of auto antibodies that react with the alveolus in the lung and the basement membrane of the glomerulus in the kidney.
Antigen: The GBM antigen responsible for this disease is a component of the non-collagenous domain (NC1) of the alpha-3 chain of collagen type IV |
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Anti-GBM antibodies interact with the GBM glycoproteins, almost exclusively the epitope of the noncollagenous domain (NC1) of the a3 chain of type IV collagen(type 2 HS)
Results in complement activation with glomerular infiltration of polymorphonuclear leukocytes (PMNs) and monocytes.
Fibrinogen leaks through the damaged GBM into the Bowman space, and it is polymerized to fibrin through procoagulant factors from activated monocytes, resulting in crescent formation |
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PATHOLOGY Renal disease: crescent formation
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Lung: pulmonary hamorrhage
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CLINICAL PRESENTATION Onset:
Hemoptysis(most common)
Dyspnoea
Fatigue
Weakness
Dry cough
Hemoptysis precedes the onset of renal disease by 8-12 months. (2/3 cases)
This interval can be as long as 12 years
before nephritis develops.
Pallor(most common clinical sign)
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Renal disease:
Gross hematuria (10-40%)
Edema (25% )
Hypertension (4%)
It can vary from hematuria and proteinuria with normal renal function to severe oligoanuric renal failure |
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Pulmonary disease:
Hemoptysis (82-90%):
It can vary from blood-tinged sputum to profound bleeding.
Cough (40-60%)
Exertional dyspnea (50% )
This likely reflects both lung parenchymal involvement and anemia from pulmonary hemorrhage.
Fatigue and weakness (40-60%)
Respiratory failure signs: like tachypnoea,hypoxia and cyanosis
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DIFFERNTIAL DIAGNOSIS SLE
Multisystem involvement
ANA, anti DNA and anti- smith
2.HSP
Tetrad
Ig A deposition in skin and kidney
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3. WG:
ENT manifestation(90%)
Other system involvement like eyes,joint or skin
C ANCA positive in 95% of cases
MPA:
Skin involvement is common
P ANCA(70%)
No anti GBM antibody |
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DIAGNOSIS Laboratory findings:
HB- anemia
TC-may be leucocytosis
ESR- mild elevation
Urine routine: hematuria proteinuria
RFT- to exclude renal failure
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Serology:
Assessments of anti–glomerular basement membrane (anti-GBM) titers and antineutrophil cytoplasmic autoantibodies (ANCA) titers through indirect immunofluorescence testing.
The ANCA titer is usually perinuclear antineutrophil cytoplasmic autoantibody (p-ANCA) from antimyeloperoxidase antibody.
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Immunofluroscene of kidney biopsy:
Linear immunoglobulin G (IgG) deposition along the glomerular capillary walls
Linear C3 also seen in 2/3 of patients.
CXR : for pulmonary hemorrhage |
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CT scan: to detect focal area of bleeds
PFT: To assess pulmonary hemorrhage by demonstrating accelerated diffusion capacity of the lungs for carbon monoxide (DLCO).
A progressive decline in vital capacity or total lung capacity suggests developing interstitial fibrosis.
Pulse oximetry:
all patients with suspected anti-GBM disease who may have hypoxemia from their parenchymal lung injury |
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TREATMENT Aim:
The removal of the pathogenic antibody AND inhibit production of new antibody formation.
Plasma exchange:
plasma exchange of a single plasma volume on a daily basis for at least 5 days, followed by a change to alternate day for an additional 6-7 treatments.
Replacement is usually with fresh-frozen plasma or 5% albumin.
Anti-GBM titers should be monitored to demonstrate removal. |
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2.Corticosteroids and cyclophosphamide:
Prednisolone(3 months)
Cyclophosphamide(6 months)
3. Rituximab:
It is anti CD20 that reduce antibody production.
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PROGNOSIS If untreated prognosis poor.
Sometimes before diagnosis child can present as severe pulmonary disease and death can occur.
Mortality rate: (7-40%)
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NEXT TEACHING PROGRAMME:
JOURNAL CLUB
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