Nephrotic Syndrome

·         Classical Findings

o        Protein >3.5g/dL

§         Normal protein excretion is 150 mg/day

o        Edema

o        Hypoalbuminemia

o        Hyperlipidemia

o        Lipiduria

Pathophysiology

·         Proteinuria can be caused by

·         Loss of negative charge on the Glomerular Basement Membrane (GBM)

o        The GBM has small minute pores which protein can get through. We have so little protein in the urine due to the charge of the GBM.

o        The GBM usually has a negative charge at pH 7.4 due to heparin sulfate and other acidic proteolgycans present.  This is extremely important in the charge dependent restriction of NEGATIVELY charged albumin, which is repelled from the BM and therefore not filtered into the urine. If the negative charge is lost then there is no repulsion and albumin can get through.

·         Increased pore size in the GBM

o        The cause of the increased pore size is unkown, but is probably due to a biophysical reaction in the basement membrane.

o        So even though albumin has a large molecule weight, it can pass through these large pores and appear in the urine

·         Loss of podocytes

o        Cells of the kidney include 3 types: epithelial, endothelial, mesengial cells

o        Podocytes (epithelial cells) form a slit diaphragm that acts as a size selective diffusion barrier and is involved in production of the slit pore proteins. If podocytes are lost then the passage of proteins will be allowed through.

·         Decreased synthesis of slit pore proteins (nephrin & podocin)

o        While not much are known about these proteins, they are involved in maintaining glomerular permeability.

o        These proteins are often loss in diabetics or in other proteinuric conditions.

·         Edema Formation

·         As a result of the reasons mentioned above, albumin is lost in the urine causing hypoalbuminia.

o        There is also retention of excess sodium

·         Since albumin is the major protein for oncotic pressure, plasma oncotic pressure will decrease.

·         This then leads to a decreased plasma volume and effective circulating volume (the amount of blood perfusing the kidney is smaller than normal)

·         This signals the release and action of 3 important players (seen in patients w/ volume depletion, liver failure or CHF à all of which have decreased effective circulating volume)

o        Renin-AII-Aldosterone system will lead to the absorbtion of Na.

o        Increased sympathetic tone will also lead to increased Na reabsorbtion

o        Increased ADH leads to the reabsorption of water in the cortical collecting duct.

·         Hyperlipidemia

·         Increased production in the liver leads to increased circulating levels of vLDL, IDL, and LDL. There is also an increase in HDL (good cholesterol)..

·         Decreased removal

o        There is decreased catabolism, and decreased activity of lipoprotein lipase which leads to increased levels of circulating cholesterol.

·         These will accumulate in vascular tissues leading to accelerated atherosclerosis formation

4 major causes of Nephrotic syndrome

• Systemic Diseases (nephrotic syndrome is secondary, so treat the systemic disease!)
  • Diabetes is the number one systemic cause in adults.
  • Lupus, amyloidosis
  • Cancer is actually a common cause in elderly (>55yrs) patients with isolated nephrOtic syndrome.
• Infections: bacterial, viral, parasitic
• Drugs:
  • NSAIDS are the major offender
  • Cox-2 inhibitors, Gold, Pencillamine or bucillamine, heroine, pamidronate
    • Pamidronate is a drug giving to inhibit bone resorption and the release of Ca. It is used to treat hypercalcemia. Associated with focal segmental glomerulosclerosis.
• Idiopathic: primary glomerular diseases
  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • Membraneous nephropathy
  • Membranoproliferative GN
  • All of these can also be caused by systemic diseases or medications so rule those causes out first! If its not anything else it must be idiopathic!

Diagnosis

• As always take a good history and do a thorough physical
• Serum chemistry, CBC, lipid profile
• Urinalysis!
• 24 hr collection for creatinine and protein
• Urinary protein electrophoresis: check for kappa and lambda chains to r/o multiple myeloma
• Cannot rely solely on hypoalbuminemia since other things like infection can cause it
• Serology
  • ASO (antistreptolysin O) titers to r/o post infection GN
  • ANA (antinuclear antibody) to r/o Lupus
  • VDRL to r/o syphilis as syphilis causes membraneous nephritis
  • Hepatitis B (associated w. membraneous neprhitis)
  • Hepatitis C (associated w. Proliferative nephritis)
  • Complement
  • CXR to r/o pulmonary renal syndrome
  • Renal ultrasound (to see size of kidney)
  • Renal biopsy (if the cause is believed to be idiopathic)

Complications

• Hypercoagulability and thromboembolism

o        antithrombin III, Protein S and Protein C are all important to inhibit thrombus formation but they are lost in the urine leading to hypercoagulabe states.                                   

• Infections
• Accelerated atherosclerosis due to hypercholesterolemia
• Acute renal failure due to heavy proteinuria
  • Skeletal abnormalities (loss of Ca in the urine)

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