10: Nephrotic Syndromes

Question 1

Nephrotic syndrome overview

Answer 1

• Albuminuria (>3-3.5 g/day)
• Hypoalbuminemia (proteinuria + ↑albumin catabolism)
• Hyperlipidemia
• Edema (low oncotic pressure 2/2 hypoalbuminemia + high hydrostatic pressure 2/2 ↓plasma volume –> RAAS activation –> Na retention)
• Thrombotic tendency
• ↑risk infx

Question 2

Therapy of edema in NS

Answer 2

• Low salt diet
• Loop diuretic (furosemide)
  
  • Start with low dose
  • Add 2nd if necessary (thiazide)
• Goal = 1-2lb edema loss/day

Question 3

Lipiduria

Answer 3

• Micro/UA: oval fat bodies, maltese crosses (cholesterol ester)

Question 4

Treatment of hyperlipidemia

Answer 4

• Tx high risk pt: high LDL, low HDL, unlikely to rapidly remit
• Induce remission of proteinuria (**ACEi (captopril, enalapril, lisinopril) **or ARBs (candesartan, valsartan, losartan), immunosuppressives) –> ↑protein –> ↓chol
• Dietary therapy
• Medical therapy (HMGCo-reductase inhibitors [statins])

Question 5

Pathologic processes leading to glomerular injury and proteinuria

Answer 5

• Increased glomerular pressure reults in proteinuria and fibrosis
• Block afferent arteriole effects of AngII with ACEi
• Block efferent arteriole effects of AngII with ARB (higher density angiotensin AT1 receptors)

Question 6

Minimal Change Disease (Lipoid Nephrosis; Nil Disease; Childhood Nephrosis)

Answer 6

• Gross: pale, lipid-rich kindeys
• LM: normal
• UA: oval fat body (polarize to see maltese cross)
• IF: no reactants detected
• EM: foot process effacement, intracellular transport vesicles
• Pathogenesis: immunologic derangements (viral infx, immunization, Hodgkin’s dz) –> circulating lymphocytotoxins (permeability factors) –> podocyte alterations, loss of anions in GBM
• Epi: 5-10% adults w/ NS, 85% kids (2-6yo) w/ NS (therefore assume MCD and tx)
• Presentation: sudden onset of heavy proteinuria and edema; ↑BP 30%, microhem 30%, mild ↑creatinine
• Course: responds to corticosteroids (prednisone)

Question 7

Focal Segmental Glomerulosclerosis (FSGS)

Answer 7

• Involves subset of glomeruli (focal) and portion of glomerular tuft (segmental)
• IF: Segmental staining IgM and C3
• EM: podocyte effacement and detachment (–> nonselective proteinuria)
• LM: lesions may progress to global glomerulosclerosis + extensive tubular atrophy & interstitial fibrosis –> ESRD
• Causes: circulating permeability factors; secondary forms:
  
  • Genetic: mutations in podocyte genes (nephrin, podocin)
  • Viral (HIV infx)
  • Drugs (heroin)
  • Adaptive (elevated glomerular capillary pressure, flow 2/2 renal agenesis, reflux nephropathy, obesity)
• Epi: >20% NS in AA, 2/3 adult NS (1/3 present w/ proteinuria)
• Clinical: ↑BP >30%, microheme >30%, renal dysfunct 50%; predictors of ESRD = ↑proteinuria, ↑creatinine, interstitial fibrosis, collapsing GN
• Tx: steroids (50% remit); for others, use immunosuppresives
• Recurs in 1/3 transplant kidneys

Question 8

Membranous glomerulopathy

Answer 8

• LM: diffuse capillary, GBM thickening
• EM: spike and dome appearance w/ subepi deposits
• IF: granular IgG and C3
• Pathogenesis: subepithelial in situ immune complex formation (Ab bind locally formed/planted Ag [PLA2R] - 70% pts w/ primary MGN); secondary MGN cationic antigen deposited in GBM due to:
  
  • Infx (hep B/C, syphilis, malaria, schistosomiasis)
  • Drugs (gold, penicillamine)
  • Collagen vascular dz (SLE, mixed conn tissue dz)
  • Neoplasia (lung, breast, colon, stomach carcinoma)
• Tx:
  
  • conservative therapy (edema, hyperlipidemia)
  • corticosteroids
  • alternating steroids - cytotoxics
  • immunomodulatory agents
    
    • cyclosporine, tacrolimus
    • mycophenolate
    • ACTH, rituximab
• ​​Risks: thrombosis (35%)

Question 9

Thrombotic abnormalities in the nephrotic syndrome

Answer 9

• ↑coagulation tendency (platelet hyperaggregability, high fibrinogen and fibrinogen-fibrin transfer, ↓fibrinolysis, low anti-thrombin III)
• DVT, renal vein thrombosis (RVT), pulmonary emboli
• Membranous NS greatest risk (up to 35%)
• Most RVT asymptomatic, but may have flank pain, microheme, low GFR

Question 10

Diabetic glomerulonephropathy

Answer 10

• **Diffuse **and **nodular **forms
  
  • Diffuse =
  • Nodular = Kimmelsteil-Wilson (KW) nodules
• ​EM: diffuse mesangsclerosis & thick GBM
• Gross: large kidney (2/2 ↑matrix in all renal compartments)
• Types of diabetes mellitus
  
  • I: insulin-dep, juvenile onset (<5%)
  • II: non-insulin dep, maturity onset (>95%)
• Pathogenesis: glycosylation of GBM (w/ advanced glycation end [AGE] products) causes:
  
  • ↑circulating plasma proteins –> defective mesangial clearing –> mesangial sclerosis
  • ↓sialic acid content –> ↑cationic charge –> proteinuria
  • ↑disulfide bonding in GBM collagen –> ↓GBM degradation, ↑GBM synthesis –> GBM thickening
• Stages
  
  • 1: hyperfiltration
  • 2: clinically silent
  • 3: incipient nephropathy
  • 4: overt nephropathy
  • 5: ESRD
• Prevention:
  
  • BP goal of <130/80
  • Inhibition of RAAS
  • Blood sugar control
  • Metabolic manipulation

Question 11

Amyloidosis

Answer 11

• LM: congo red stain shows apple-green birefringence under polarized light
• EM: amyloid fibrils infiltrating GBM
• IF: lambda light chain (AL)
• Gross: end-stage kidney large and pale
• Causes:
  
  • Dysproteinemias (primary, “AL”); precursor protein = light chains
  • Longstanding inflammatory/infx states (secondary; “AA”); precursor = SAA-protein