Post on 29-Aug-2018
transcript
1/16/2014
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Nephrotic vs Nephritic
syndrome
Hooman N .MD
IUMS
3 y/o male presents to the ER with fever, abdominal pain, and has had “puffy” eyes for the past 2 days.
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Measurement of Proteinuria
• Semiquantitative
– Dipstick
– Turbidometric SSA – TCA - NA
• Quantitative– Turbidometric methods+photometer/nephrometer
– Ultraviolate spectrophotometry
– Biuret method (more sensitive)
– Micro kjeldahl method ( research – most accurate)
• Qualitative measures– Electrophoresis
– Immunodiffusion
– ELIZA
Dipstick
Interpretation Negative0 = no
Trace = < 30 mg/dL
1+ = 30 mg/dL
2+ = 100 mg/dL
3+ = 300 mg/dL
4+ = 2000 mg/dL
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Method Sulfosalicylic Acid
Interpretation turbidity ( 0 mg/dL)
Trace = slight turbidity
(1-10 mg/dL)
1+ = print can be read (15-30 mg/dL)
2+ = through which heavy black lines on white
background can be seen
3+ = white cloud with fine precipitate through
which heavy black lines cannot be seen (150-300
mg/dL)
4+ = flocculent precipitate
(> 500 mg/dL)
Method
Dipstick Turbidometric
Concentrated urine False + False +
Dilute urine False - False -
Urine PH>8 False + False -
Contamination antiseptic False + No effect
Tolbutamide metabolites No effect False +
Penicillin , Cephalosporin No effect False +
Sulfisoxazole metabolites No effect False +
Phenazopyridin False + No effect
contrast media No effect False +
Measurement of ProteinuriaQuantitative Methods
• Timed Urine Collection
– Overnight
– 24- Hour• Lack of consistency
– Activity
– Other factors
• Improper timing –– OVER – COLLECTION , UNDER-COLLECTION
• Incomplete bladder emptying , Neurogenic bladder , Incontinency
• Radio contrast media (FP)
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Measurement of Proteinuria Quantitative
Methods
• UPr/UCr (T.Prot vs. albumin)
– Random
– First morning– Lower creatinine excretion in
» Female
» Age
– Variable creatinine excretion in NB
– Hydration
– Total Urine Protein(g/m2/d)=0.063x(UPr/Cr)
– Up/Ucr = daily protein excretion in gram (Cr excretion
is = 1 gr/day) adult
– Have to be corrected for age , sex, body weight
Case 1:
• A previously well 3 yr F
• CC: facial puffiness (few days ago)
• PE: BP=92/55,PR 20 ,HR=90, T 37
• HN-Heart- Lung & Abdomen= Nr
• Ext 2+ pulses
• U/A 4+ protein , SG 1.030 ,
• Blood ; Prot 2g/dl , S Alb 1.4 g/dl , Cholestrol 350 mg/dl
• BUN – Cr nr
• WHAT IS THE DIAGNOSIS?
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Definition
• Generalized edema
– Most commonly beginning as facial, particularly periorbital, and pretibial edema
• Hypoproteinemia (<2g/dL) – albumin<<globulin
– Albumin:Globulin < 1.0
• Proteinuria
– 3-4+ on urine dip
– Protein:Creatinine > 2.0 (first morning void)
– 24 hour protein > 50 mg/kg
• Hypercholesterolemia (>200mg/dL) – VLDL and LDL
Other Laboratory Findings
• Microscopic Hematuria
– if gross hematuria, must consider IgA nephropathy
• Hyponatremia
• Hypocalcemia
• Hyperkalemia - Hypokalemia
• Hypercoaguability – increased thrombin and decreased platelet inhibitors
– PTT
• Normal complement levels
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Additional Clinical Findings
• Abdominal Pain
• Ascites
• Oliguria
• Scrotal/Labial swelling
• Tachypnea
• Chest Pain
Etiology
• Primary (Idiopathic) Nephrotic Syndrome
(90%)
– Minimal Change Disease (80%)
– Focal Segmental Glomerulosclerosis (FSGS)
(10%)
– Mesangial Proliferation (5%)
– Mebranoproliferative Glomerulonephritis
(MPGN) (5%)
– Membranous Nephropathy (1%)
Minimal Change Disease
• Younger age
• Glomeruli appear normal or show minimal
mesangial increase
• Not usually associated with hematuria or
hypertension
• No association with renal failure
• Majority (90%) respond to steroids
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Overview of Primary Nephrotic
Syndrome
Min. change FSGS MPGN
Hematuria 10-20% 60-80% 80%
HTN 10% 20% 35%
Renal Failure None 10 years 5-20 years
Microscopy Foot process
fusion
Sclerotic
lesions
Variable
Immune None IgM Complement
Steroid
response
90% 15-20% Unknown
Adjunctive therapy
• Diuretics (Lasix, thiazides)
• Albumin – only if needed for volume
resuscitation or severe hyponatremia
• Sodium restriction (3 gm/kg)
• Fluid restriction (if hyponatremic)
• Ace inhibitors (if hypertensive)
• Statins (if hyperlipidemia is severe)
• Immunization – Pneumococcal, Varicella and
Flu
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Relapse and Resistance
• Most children (up to 80%) will go on to relapse several times = proteinuria >3d with edema
• Relapses are treated with a 2nd course of steroids– Frequent relapser 4 relapses in 1 year
– Steroid Dependent – if the relapse is during taper or within 28 days of initial course
– Steroid resistant – No initial response after 8 wks of steroid therapy. Most often FSGS.
• Other agents such as high dose methylprednisolone and cylcophosphamide may be used
When to consider biopsy?
• If initial presentation includes:
– Hematuria
– Hypertension
– Renal Insufficiency
– Hypocomplementemia
• Age <1 yr or >8-10 yrs
• Steroid resistant
Complications
• Infection
– Loss of immunoglobulins
– Immunosupressive therapy
– Protein malnutrition
– Edema / Ascites
*spontaneous bacterial peritonitis is most
common infection
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More Complications
• Thromboembolic events (2-5%)
– Arterial and Venous
– Increase in prothrombotic factors:
• Fibrinogen
• Hemoconcentration
– Decrease in fibrinolytic factors:
• Antithrombin III
• Proteins C and S
* Avoid aggressive diuresis and use of indwelling
catheters
Still more complications
• Hypothyroidism – loss of thyroid binding globulin
(TBG)
• Hypocalcemia – loss of vitamin D binding
globulin
• Steroid-associated
– Weight gain
– Gastritis
– Osteoporosis
– Cataracts
– Mood changes
– Diabetes
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In the clinic…
• 10 y/o boy with Gross Hematuria for 3 weeks
– With every void, with some frequency.
– Brownish red in color, now tea colored.
– Mild back pain for the past few days.
– No dysuria, no abdominal pain, no fever.
• 2 wks ago, Hx / of URI like picture, with sore
throat, no meds taken.
• No Rash, no cough.
• Resolved on its own.
• mild edema
• Creatinine 1 mg/dL
• BUN 96 mg/dl
• CBC= normal, with Hgb 10 gm/dL
• Pt. has BP’s 170/100
• ASO elevated at 760
• UA= large blood, and 3+ protein
• Multiple RBC casts on microscopic exam of urine.
What is the diagnosis?
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• Nephritic Syndrome
Differential Diagnosis
• Acute Postinfectious Glomerulonephritis
• IgA (±IgG) Deposition
– Systemic Lupus Erythematosus
– IgA Nephropathy - Berger's Disease
– Henoch-Schonlein Purpura (HSP)
• Ischemia/Infarction (ATN or papillary necrosis)
• Autoimmune Disease
• Membranoproliferative GN
Etiology
• Following infections by nephritogenic strains of
Group A ß hemolytic streptococci
– Pharyngitis (serotypes 1, 2, 4 and 12)
– Impetigo (serotypes 47,49, 57)
• Infection is uncommon in children <2 y/o
– Possibly due to decreased attachment of GABHS
to nasopharyngeal epithelial cells
• Close contact with potentially infected
individuals occurs in child care and grade
school
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Case definition for APSGNClinical cases need 4 criteria , Subclinical cases , only criteria 2,3
and 4
Clinically compatible illness with one or more of :
Oedema
Macroscopic hematuria
High blood pressure ( DPB>80 mmHg if 13 years of age or younger , or > 90 mmHg if older than 13 years)
Microscopic glomerular hematuria
RBC > 10/ml
Dipstick : hematuria of 2+ or more
Evidence of recent streptococcal infection
Positive GAS culture from skin or throat , or elevated ASO or anti-DNase B
Reduced serum complement level
M protein
•Colonization
•Resistance to
phagocytosis
Hyaluronic acid capsule
•Hide its own Ag
•Prevent opsonized phagoctosis by neutrophils /macrphage
LTA
Adhesins
protein M , F
Adhesins
Hyaluronidase
•Digest host connective tissue / own Capsule
Streptolysin s/o
oxigen – stable/labile leukocidin
Streptokinases
Fibrin lysis
Streptodronase
Deoxyribonuclease activity
Serology
• Anti-streptolysin O (ASO) Antibodies rise in ~75% of cases
• Titers of ASO rise within 10-14 days; declines over 1-6 months
• Anti-DNase B and Anti-hyaluronidase rise more quickly
• Elevation in any of the titers will detect ~100% of persons with recent strep infection
• Note that ASO titers rise in pharangitis, not in cutaneous disease
• Streptococcal antigen M serotypes 12,1, and 4 are especially associated with GN
• Anti-Streptokinase, M-protein specific tests, and anti-NADase can also be determined
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Pathogenesis
• Formation of immune complexes including antibodies and streptococcal antigens
• Localization (deposition) on subepithelial portion of glomerular basement membrane
• Initiate inflammatory response, including Complement deposition (reduced serum levels)
• This leads to localized mesangial and endothelial cell proliferation
Clinical Manifestation
• Rare before age 3
• Initial pharyngitis MAY present with:
– Fever, tonsillopharyngeal erythema, exudate,
swollen/tender adenopathy.
– Absence of rhinorrhea and cough
• 60-70% of children will present as such.
Clinical ManifestationLater…
• Malaise, Lethargy, Abdominal/Flank Pain, Fever are common.
• Typically an acute nephritic syndrome develops 1-2 wk after a strep pharyngitis
– Or 3-6 wks after strep pyoderma
• Nephritic Syndrome:
– Tea colored urine
• Only 1/3rd present with gross hematuria
• 2/3rd could be microscopic
– Facial/body edema
– HTN
– Oliguria
• Renal involvement ranges from asymptomatic microscopic hematuria to ARF.
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Further Manifestations
• Encephalopathy
– Hypertension is the commonest cause
– Toxic effects of strep on the CNS-rare• Heart Failure
– Secondary to HTN, and hypervolemia• Nephrotic Syndrome may develop in 10-20% of cases.
– Heavy proteinuria (40mg/m2/hr)
– Hypoalbuminemia (<2.5g/dL)
– Edema• Acute Phase resolves anywhere from 3 weeks to 2
months after onset.
– Hematuria (gross or microscopic) can continue for up to a year
Diagnosis
• UA
– RBC’s
– RBC Casts
– Proteinuria
– Leukocytes
• From inflammation, not a response to infection!!
• Normochromic Anemia
– Low grade hemolysis and Hemodilution
• Serum C3 is reduced
– Returns to normal 6-8 wks after onset
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Confirmation of Diagnosis
• Positive Throat Culture
– Can represent the carrier state
– Limited by:
• Poor culture technique
• Surreptitious abx use
– Rapid Strep:
• 76-87% sensitive
• 90-96% specific
• Elevated ASO
– Rarely elevated after strep skin infections
– Can indicate recent infection
• Anti-DNase B antigen
– Elevated in both pharygitis and pyoderma
– Your best bet
More tests…
• Anti-Zymogen titers
– Shown to be 88% sensitive, and 85% specific
in the diagnosis of strep infection with
glomerulonephritis.
– Hardly used
• Streptozyme test
– Detects ab to streptolysin O, DNase B,
hyaluronidase, streptokinase, nicotinamide-
adenine dinucleotidase
When to consider a Renal
Biopsy?• Usually not done, unless…
– Symptoms point towards SLE
– ARF
– Low C3 level for more than 3 mos after onset
– Clinical features do not resolve in 6-8 wks.
• REMEMBER: asymptomatic microscopic
hematuria can be expected for up to one
year)
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Complications
• ARF
• Volume overload
• Heart Failure
• HTN - 60% of patients
• Hyperkalemia
• Hyperphosphatemia
• Hypocalcemia
• Acidosis
• Seizures
• Uremia
Treatment
• 10 day course of ABX
– If throat culture positive, not for pyoderma
– Does not affect course or risk of GN
– Does limit the spread of nephritogenic organisms
• Na+ restricted diet
• Anti Hypertensive Meds
– Ca + channel blockers
– Vasodilators
– ACE inhibitors
• Management of ARF complications
Prognosis
• 95% children with complete recovery.
• Recurrence is rare.