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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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What is your diagnosis?

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Type of Edema

Non Pitting Edema

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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.

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NS APSGN

• HTN -ve +ve

• Urine Color dark yellow Cola color

• Proteinuria Severe Moderate

• Pulmonary Edema -ve +ve

• Edema Pitting nonpitting

pale pink

cold warm

• Size of Heart small Large

• Hematuria not persist Macro/Micro

micro

• C3 Nr Low

• Renal Failure -ve +ve

• ECF Low High