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Nephrotic Syndrome and Glomerulonephritis Fontanilla, Crista Mae F.

Nephrotic and Nephritic

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Page 1: Nephrotic and Nephritic

Nephrotic Syndrome andGlomerulonephritis

Fontanilla, Crista Mae F.

Page 2: Nephrotic and Nephritic

NEPHROTIC SYDROME

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Nephrotic Syndrome• Primarily a pediatric disorder• Characteristic features are

– Heavy proteinuria (>3.5 g/24 hr in adults or 40 mg/m2/hr in children), – Hypoalbuminemia (<2.5 g/dL), – Edema – Hyperlipidemia

• Etiology– Primary or idiopathic– Secondary to systemic diseases– Hereditary caused by mutations in genes that encode protein

components of the glomerular filtration apparatus

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Pathophysiology• The underlying abnormality is an increase in permeability of

the glomerular capillary wall -> massive proteinuria and hypoalbuminemia.

• In minimal change disease, – T-cell dysfunction leads to alteration of cytokines, which causes a loss

of negatively charged glycoproteins within the glomerular capillary wall.

• In focal segmental glomerulosclerosis, – a plasma factor, perhaps produced by lymphocytes, may be

responsible for the increase in capillary wall permeability.

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• Massive urinary protein loss -> hypoalbuminemia-> decrease in the plasma oncotic pressure and transudation of fluid from the intravascular compartment to the interstitial space.

• The reduction in intravascular volume – Decreases renal perfusion pressure-> activating the renin-angiotensin-

aldosterone system-> stimulates tubular reabsorption of sodium– Stimulates the release of antidiuretic hormone-> enhances the

reabsorption of water in the collecting duct.• Serum lipid levels (cholesterol, triglycerides) are elevated

– Hypoalbuminemia stimulates generalized hepatic protein synthesis, including synthesis of lipoproteins

– Lipid catabolism is diminished, as a result of reduced plasma levels of lipoprotein lipase, related to increased urinary losses of this enzyme

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A. Idiopathic Nephrotic Syndrome

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Treatment:• Sodium intake should be reduced by the initiation of a low-sodium diet

and may be normalized when the child enters remission. • Children with severe symptomatic edema (large pleural effusions, ascites,

or severe genital edema) should be hospitalized. • Fluid restriction may be necessary if the child is hyponatremic. • A swollen scrotum may be elevated with pillows to enhance the removal

of fluid by gravity. • Diuresis may be augmented by administration of chlorothiazide or

metolazone followed by furosemide.• IV administration of 25% human albumin followed by furosemide is often

necessary when fluid restriction and parenteral diuretics are not effective.

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• Children with onset of nephrotic syndrome between 1 and 8 yr of age are likely to have steroid-responsive MCNS; steroid therapy may be initiated without diagnostic renal biopsy.

• Children with features that make MCNS less likely (hematuria, hypertension, renal insufficiency, hypocomplementemia, age <1 yr or >8 yr) should be considered for renal biopsy before treatment.

• In children with presumed MCNS, prednisone should be administered (after confirming a negative PPD test) for at least 4 consecutive weeks.

• An initial 6-wk course of daily steroid treatment may lead to a lower relapse rate.• 80 to 90% of children will respond to steroid therapy (urine trace or negative for

protein for 3 consecutive days), by 2 wk. Majority of children who will respond to prednisone therapy will do so within the first 4 wk of treatment.

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• Children who continue to have proteinuria (2+ or greater) after 8 wk of steroid therapy are considered steroid resistant, and a diagnostic renal biopsy should be performed.

• Cyclophosphamide prolongs the duration of remission and reduces the number of relapses.

• An additional option for the child with complicated nephrotic syndrome is high-dose pulse methylprednisolone.

• Cyclosporine or tacrolimus are also effective in maintaining prolonged remissions and are useful as steroid-sparing agents.

• Mycophenolate may maintain remission in children with steroid-dependent or frequently relapsing nephrotic syndrome.

• Most children who respond to cyclosporine, tacrolimus, or mycophenolate therapy tend to relapse when the medication is discontinued.

• ACE inhibitors and angiotensin II blockers may be helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients.

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B. Secondary Nephrotic Syndrome

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C. Congenital Nephrotic Syndrome• Infants who develop nephrotic syndrome within the

first 3 months of life.• Most common cause is Finnish-type

– Present with massive proteinuria (detectable in utero by increased α-fetoprotein), a large placenta, and marked edema, prematurity, respiratory distress, separation of the cranial sutures, persistent edema, recurrent infections, and progressive renal failure with death by the age of 5 yr.

– ACE inhibitors, indomethacin, and unilateral nephrectomy may diminish proteinuria and ameliorate the nephrotic state

– Require chronic dialysis and kidney transplantation• Diffuse mesangial sclerosis

– Rapid loss of renal function, with end-stage renal disease developing within months to years

• Other causes are congenital infections such as syphilis, toxoplasmosis, rubella, and cytomegalovirus– May improve or resolve with treatment of the

underlying infection

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GLOMERULONEPHRITIS

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Acute Poststreptococcal Glomerulonephritis

• This is a classic example of the acute nephritic syndrome • Characterized by

– Sudden onset of gross hematuria, – Edema, – Hypertension– Renal insufficiency

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Etiology and Epidemiology• It follows infection of the throat or skin by certain “nephritogenic” strains

of group A β-hemolytic streptococci. • It follows streptococcal pharyngitis during cold weather months and

streptococcal skin infections or pyoderma during warm weather months. • Although epidemics of nephritis have been described in association with

both throat (serotype 12) and skin (serotype 49) infections, this disease is most commonly sporadic

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Pathology

Glomerulus from a patient having poststreptococcal glomerulonephritis appearing enlarged and relatively bloodless and showing mesangial proliferation and exudation of neutrophils

Electron micrograph in poststreptococcal glomerulonephritis demonstrating electron-dense deposits (D) on the epithelial cell (Ep) side of the glomerular basement membrane. A polymorphonuclear leukocyte (P) is present within the lumen (L) of the capillary. BS, Bowman space; M, mesangium

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Pathogenesis• Mechanisms of immune injury include:

– Circulating immune complex formation with streptococcal antigens and subsequent glomerular deposition

– Molecular mimicry whereby circulating antibodies elicited by streptococcal antigens react with normal glomerular antigens

– In situ immune complex formation of antistreptococcal antibodies with glomerular deposited antigen

– Complement activation by directly deposited streptococcal antigens

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Clinical Manifestations• Most common in children aged 5–12 yr and uncommon before the age of

3 yr• Typical patient develops an acute nephritic syndrome 1–2 wk after an

antecedent streptococcal pharyngitis or 3–6 wk after a streptococcal pyoderma.

• The severity varies from asymptomatic microscopic hematuria with normal renal function to acute renal failure.

• Patients may develop various degrees of edema, hypertension, and oliguria.

• Patients may develop encephalopathy and/or heart failure owing to hypertension or hypervolemia.

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• Encephalopathy may also possibly result from the direct toxic effects of the streptococcal bacteria on the central nervous system.

• Edema results from salt and water retention; nephrotic syndrome may develop in 10–20% of cases.

• Nonspecific symptoms such as malaise, lethargy, abdominal or flank pain, and fever are common.

• The acute phase generally resolves within 6–8 wk. • Although urinary protein excretion and hypertension usually normalize by

4–6 wk after onset, persistent microscopic hematuria may persist for 1–2 yr after the initial presentation.

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Diagnosis• Urinalysis demonstrates RBCs ,proteinuria, and polymorphonuclear

leukocytes. • A mild normochromic anemia may be present from hemodilution and low-

grade hemolysis. • The serum C3 level is usually reduced in the acute phase and returns to

normal 6–8 wk after onset.• A positive throat culture report may support the diagnosis or may simply

represent the carrier state. • Rising antibody titer to streptococcal antigen(s) confirms a recent

streptococcal infection.

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• Antistreptolysin O titer is commonly elevated after a pharyngeal infection but rarely increases after streptococcal skin infections.

• The best single antibody titer to document cutaneous streptococcal infection is the anti-deoxyribonuclease (DNase) B level.

• The clinical diagnosis is quite likely in a child presenting with acute nephritic syndrome, evidence of recent streptococcal infection, and a low C3 level.

• Renal biopsy should be considered only in the presence of acute renal failure, nephrotic syndrome, absence of evidence of streptococcal infection, or normal complement levels. It is also considered when hematuria and proteinuria, diminished renal function, and/or a low C3 level persist more than 2 mo after onset.

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DISEASESPOSTSTREPTOCOCCAL GLOMERULONEPHRITIS IGA NEPHROPATHY

GOODPASTURE SYNDROME

IDIOPATHIC RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)

Clinical manifestations

Age and sex All ages, mean 7 yr, 2 : 1 male

10–35 yr, 2 : 1 male 15–30 yr, 6 : 1 male Adults, 2 : 1 male

Acute nephritic syndrome

90% 50% 90% 90%

Asymptomatic hematuria

Occasionally 50% Rare Rare

Nephrotic syndrome 10–20% Rare Rare 10–20%

Hypertension 70% 30–50% Rare 25%

Acute renal failure 50% (transient) Very rare 50% 60%

Other Latent period of 1–3 wk

Follows viral syndromes

Pulmonary hemorrhage; iron deficiency anemia

None

Laboratory findings ↑ ASO titers (70%) ↑ Serum IgA (50%) Positive anti-GBM antibody

Positive ANCA in some

Positive streptozyme (95%)

IgA in dermal capillaries

↓C3–C9;normal C1, C4

Immunogenetics HLA-B12, D “EN” (9)[*] HLA-Bw 35, DR4 (4)[*] HLA-DR2 (16)[*] None established

Differential Diagnosis

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Renal pathology Light microscopy Diffuse proliferation Focal proliferation Focal diffuse ➙

proliferation with crescents

Crescentic GN

Immunofluorescence Granular IgG, C3 Diffuse mesangial IgA Linear IgG, C3 No immune deposits Electron microscopy Subepithelial humps Mesangial deposits No deposits No depositsPrognosis 95% resolve

spontaneouslySlow progression in 25–50%

75% stabilize or improve if treated early

75% stabilize or improve if treated early

5% RPGN or slowly progressive

Treatment Supportive Uncertain (options include steroids, fish oil, and ACE inhibitors)

Plasma exchange, steroids, cyclophosphamide

Steroid

DISEASESPOSTSTREPTOCOCCAL GLOMERULONEPHRITIS IGA NEPHROPATHY

GOODPASTURE SYNDROMEIDIOPATHIC RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)

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Prevention• Early systemic antibiotic therapy for streptococcal throat and skin

infections does not eliminate the risk of glomerulonephritis.• Family members of patients with acute glomerulonephritis should be

considered at risk and be cultured for group A β-hemolytic streptococci and treated if culture positive.

• Family pets, particularly dogs, have also been reported as carriers.

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Treatment• Management is directed at treating the acute effects of renal insufficiency

and hypertension. • Although a 10-day course of systemic antibiotic therapy with penicillin is

recommended to limit the spread of the nephritogenic organisms, antibiotic therapy does not affect the natural history of glomerulonephritis.

• Sodium restriction, diuresis usually with intravenous Lasix, and pharmacotherapy with calcium channel antagonists, vasodilators, or angiotensin-converting enzyme inhibitors are standard therapies used to treat hypertension.

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Prognosis• Complete recovery occurs in more than 95% of children with acute

poststreptococcal glomerulonephritis.• Mortality in the acute stage can be avoided by appropriate management

of acute renal failure, cardiac failure, and hypertension. • Infrequently, the acute phase may be severe and lead to glomerular

hyalinization and chronic kidney disease. • Recurrences are extremely rare.

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ENDThank You.