Proteinuria & nephrotic syndrome Flashcards

1
Q

GN/Primary & secondary causes of nephrotic syndrome

A

PRIMARY
Minimal change disease
- 3yrs +, most common cause of INS in children
- 85% of children with idiopathic nephrotic syndrome
- Idiopathic, recent infection/vaccination, immune stimulus → bee sting
- T cells release GPF → effacement of podocytes
- Loss of negatively charged coat → loss of negatively charged protein
- Selective protein loss (albumin) → spares immunoglobulins
- Normal appearance on light microscopy/immunofluorescence
- Effacement of podocytes on electron light microscopy
- Steroid responsive

Focal segmental glomerulosclerosis (FSGN)

  • More common in adults
  • Idiopathic or secondary to drug abuse, HIV, interferon treatment, congenital malformations
  • 6yrs +, 10-15% of children with idiopathic nephrotic syndrome
  • Effacement of podocytes, hyalinosis (deposition of lipids and proteins in glomerulus)
  • Seen on light microscopy, immunofluorescence neg/pos for C3,C1, IgM- patchy changes- segmental, only some glomeruli affected
  • Inconstant response to steroids

Membranous nephropathy

  • Secondary to SLE, drugs (NSAIDs, penicillamine) infections (Hep B, syphillis),
  • Immune complex deposition between podocytes & mesangial cells
  • Blood: Positive serum IgG AB - PLA2R
  • Light microscopy: Diffuse capillary GMB thickening and immune complex deposition- expansions of GBM on silver methenamine staining, ‘spike and dome pattern’
  • Immunofluorescence: complexes
  • Poor response to steroids
  • ⅓ improve, ⅓ persistent NS, ⅓ ESRF by 5 yrs (worse if young, genetic cause, tubular atrophy on Bx), can have recurrent disease post transplant if genetic/rapid onset

Membranoproliferative GN (MPGN)

  • 10yrs +

SECONDARY
Diabetic glomerulonephropathy
- Glycated proteins obstruct glomeruli, efferent arteriole thickening & dilatation (increased pressure → hyperfiltration), matrix deposition & expansion ‘Kimmelsteil-Wilson Nodules’

Systemic amyloidosis

  • Tissue damage from abnormally shaped proterins
  • Amyloid pink on congo red staining, collect in mesangium
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2
Q

Proteinuria- causes

A

Proteinuria = >40mg/m2/hr (elevated protein creatinine ration >200)

Benign

  • Exercise, fever, dehydration, seizures, postural (tall, thin)
  • Mild, self resolving

Pathological

  • *1. Glomerular** = barrier disruption → excess protein through GBM
  • Larger proteins- ie albumin
  • *2. Tubular** = increased filtration, impaired reabsorption or secretion
  • Smaller proteins, RBP, microglobulin
  • Causes: ATN, pyelonephritis, toxins, structural disorders, Fanconi syndrome, Dent’s disease

Causes

  • *Primary:**
  • *-** GN: minimal change, FSGN, mesangiocapilliary/membranoproliferative GN
  • idiopathic membranous nephropathy
  • *Secondary:**
  • autoimmune/immunological: SLE, vasculitis (HSP, Wegners), allergy, amyloidosis
  • infectious: Hep B/C, HIV, malaria
  • endocrine: diabetes
  • cardiac: CCF, constrictive pericarditis
  • vascular: renal vein thrombosis
  • malignancy
  • *Hereditary/syndromic**
  • Denys Drash
  • Nail-patella syndrome
  • Shimke immune-osseous dysplasia
  • Pierson-Lowe syndrome

Investigations

  • Urine: UCR, ACR
  • Blood: total protein, albumin, FBE, ASOT, C3,4, dsDNA, lipids- cholesterol
  • Imaging: renal utrasound
  • Biopsy (if suspecting GN)

Urine ACR/PCR affected by concentration, infection, level of creatinine (lower in infants)

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3
Q

Nephrotic syndrome - outline features, causes, investigations & treatment

A

Proteinuria (albumin) + hypoalbuminemia (<25g/L) + oedema + hypercholesterolemia (>250dg/dL)

90% idiopathic (INS)

  • Isolated glomerular pathology (podocyte sclerosis) in absence of systemic disease
  • GN- 85% minimal change, 10-15% FSGN
  • Associated HLA-DR7, B8, B12

10% non-idiopathic

  • Membranous nephropathy
  • Membranoproliferative GN
  • Vasculitis- SLE, HSP/immune complex deposition- post infectious GN

More likely to be genetic if younger age (congenital <3mo) or familial

Pathophysiology

  • Increased glomerular permeability → excess excretion of proteins → low serum protein levels
  • Low serum protein leads to reduced plasma oncotic pressure = fluid shift vessels → interstitial fluid = oedema
  • Reduction in BV leads to RAAS activation
  • Low protein = increased lipoprotein synthesis/decreased metabolism = increased serum lipids (cholesterol, TG), frothy urine
  • Loss of clotting factors (antithrombin III), increased F6,7,8,10 & fibrinogen → thrombotic state
  • Loss of immunoglobulins (IgG, C3 activator) → recurrent infections, risk of cellulitis, SBP, sepsis, disseminated VZV
  • Relapsing may suffer vit D deficiency, hypothyroid (loss in urine)

Acute
Relapsing- >40mg/m2/hr for >3 days, remission <4mg/m2/hr, frequent = >2x in 12mo

Assessment

  • Oedema: pleural effusion, abdominal pain/SBP, skin breakdown/infection
  • Volume depletion: oliguria, dizziness, peripheral cyanosis, hypotension, tachycardia
  • Thrombosis: DVT/PE, renal vein thrombosis (palpable mass, nephritic sx), cerebral vein thrombosis, mesenteric thrombosis
  • Heavy proteinuria on dipstick 3-4+, urine microscopy- possible hyaline casts
  • Hypoalbuminemia (<25)
  • Urine:creatinine ratio (can compare trend in steroid therapy)
  • Urinary sodium (decreased <10mmol in volume depletion)

Bloods: FBE, UEC, LFT, C3+4 (low in SLE, MPGN), ANA/dsDNA, Hep B/viral serology

Biopsy if steroid resistant (4-6wks of therapy), red flags age extremes, HTN, haematuria

Exclude other causes of oedema - PLE, CCF, liver disease

Less consistent with INS

  • Age <1, >12
  • Systemic symptoms (fever, rash, joint pain)
  • Persistent HTN, macroscopic haematuria
  • May have microscopic haematuria

Treatment
Salt restriction
Daily weights/dipstick
IV 20% albumin with frusemide if intravascular depletion, symptomatic oedema
- Prednisolone: 60mg/m2/day daily dose 4/52 then taper over 3mo → longer duration may reduce rate of relapse
- 80-90% will respond to steroids
- Of steroid sensitive cases, 80% will have >1 relapse
- Prophylaxis- oral penV (infection), ranitidine (gastric ulcers)

Steroid therapy

  • Steroid sensitive: remission after <4wks steroid
  • Steroid dependant: 2x relapses on steroid therapy or within 14d of steroid cessation
  • Steroid resistant: failure to resolve after 1mo pred 60mg/m2/day
  • To treat relapse- 60mg/m2/d until remission (<4 protein) then 40mg/m2/d for 1mo
  • Consider side effects pf long term steroids

Second line treatments

  • Cylophosphamide
  • Calceneurin inhibitor
  • MMF
  • Rituximab
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4
Q

Renal tubular defects

A

Defects in renal tubules that affect acid base and electrolyte balance

PCT

  • reabsorbs: HCO3, glucose, amino acids, uric acids, water, most Na+/Ca2+, K+, Cl-, PO4-
  • secretes: PO4+, H+

DLH:
- reabsorbs water

TAL:
- reabsorbs: K+, Na+, Cl- (NKCC2), Ca2+, most Mg2+

DCT:
- reabsorbs Na+/Cl- (cotransporter), Ca2+, some Mg2+

CD:

  • reabsorbs Na+ (eNACs)
  • secretes K+(principal cells) /H+ (intercalated cells)

Fanconi syndrome
Reabsorption defect in PCT
- Hereditary: Wilsons (accumulation of Cu), tyrosinemia (accumulation of tyrosine/byproducts), glycogen storage disorders
- Acquired: ischaemia, hypovolemia, multiple myeloma, nephrotoxic drugs (i.e cisplatin)
- Proximal RTA (type 2): metabolic acidosis, low phosphate → osteopenia

  • *Bartter syndrome**
  • Autosomal recessive defect in NKCC2 cotransporter in ALH
  • Loss of sodium and potassium in urine → hypokalemia, hypercalciuria
  • Water loss → volume contraction → RAAS activation
  • Metabolic alkalosos (HCO3 reabsorption)
  • Can mimic loop diuretics
  • *Gittelman Syndrome**
  • Autosomal recessive defect in Na/Cl co-transporter
  • Decreased reabsorption NaCl → volume contraction → RAAS activation
  • Hypokalemia, metabolic alkalosis, hypocalciuria (Ca2+ dependant on Na+/H20), hypomagnesemia
  • Mimics thiazide diuretics

Liddles syndrome

  • Autosomal dominant, collecting tubule
  • Increases Na+ channel, mimics hyperaldosteronism (HTN, headaches, fatigue) - low aldosterone levels
  • Hypokalemia, hypernatremia, metabolic alkalosis
  • Rx amiloride
  • *Syndrome of apparent mineralocorticoid excess**
  • 11-bhydroxysteroid dehydrogenase deficiency (metabolises cortisol → cortisone), excess mineralocorticoid, mimics effects of aldosterone - levels low (HTN, headache, fatigue)
  • hypernatremia, hypokalemia, metabolic alkalosis
  • associated too much licorice
  • K+ diuretics, steroids (decreases endogenous)
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5
Q

Alport syndrome

A

Alport syndrome genetic cause of glomerular dysfunction is caused by mutations in genes encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen. This leads to abnormalities of the basement membranes of the kidney (glomerular disease), cochlea (sensorineural hearing loss), and eye (anterior lenticonus is pathognomonic).

Autosomal dominant: 5% (mutations in COL4A3 or COL4A4).

Autosomal recessive: 15% (mutations in COL4A3 or COL4A4).

Most cases are X linked (mutations in COL4A5 gene).

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