Proteinuria & nephrotic syndrome Flashcards
GN/Primary & secondary causes of nephrotic syndrome
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
Proteinuria- causes
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)
Nephrotic syndrome - outline features, causes, investigations & treatment
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
Renal tubular defects
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)
Alport syndrome
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).