Clinical aspects of proteinuria

Question 1

Normal protein handling by kidneys

Answer 1

• Only the smallest plasma proteins can get thru the GBM (most are immunoglobins)
• Plasma proteins account for 50% of protein excretion in urine, the other 50% are non-plasma proteins such as Tamm-horsfall glycoproteins (constituent of matrix in casts)
• Microalbuminuria is urinary albumin btwn 30-300mg/24hrs
• The filtered proteins are small (less than 60kD), linear (or round) and flexible, and most are positively charged
• Normally, most of the protein that is filtered is reabsorbed

Question 2

Properties of capillary wall

Answer 2

• Luminal membrane of endothelial cells is negatively charged
• The GBM contains type 4 collagen (target of Abs in anti-GBM/goodpasture’s and mutation target in Alport’s syndrome) and other negative charges: heparin sulfate, proteoglycans
• Slit diaphragm and podocyte membrane covered by sialoglycoproteins (gives podocytes negative charge)
• Loss of sialoglycoproteins (and resulting loss of negative charge of podocytes) can lead to increased protein excretion

Question 3

Fusion of epithelial foot processes

Answer 3

• Spaces btwn foot processes that create the slit diaphragm are normally maintained by the repulsion of negative charges
• When the charges are lost the foot processes tend to collapse and foot processes are fused together
• Loss of negative charges also facilitate the accumulation of immune-complexes in glomerular mesangium (contributes to glomerulosclerosis)

Question 4

Glomerular proteinuria

Answer 4

• Due to increased glomerular permeability from loss of negative charges along the GBM or alteration of normal GBM structure
• In this proteinuria, albumin is usually the dominant protein in urine (selective proteinuria)
• Less frequently there is proteins of higher molecular weight (non-selective proteinuria)
• Minimal change disease is more associated w/ selective whereas focal and segmental glomerulosclerosis tends to be non-selective

Question 5

Tubular proteinuria

Answer 5

• Renal cells in PT have a prominent lysosomal system responsible for reabsorption of proteins that pass thru the GBM
• Thus diseases that affect tubular functions (falcon syndrome, analgesic nephropathy) may result in decreased reabsorption and proteinuria
• Characterized by increased excretion of low MW proteins

Question 6

Overflow proteinuria

Answer 6

• Due to excessive production and filtration of proteins across the GBM
• Increased urinary excretion of proteins of low MW and size
• Ex: hemoglobinuria, myoglobinuria, monoclonal light chains (MM pts)

Question 7

Types of proteinuria

Answer 7

• Constant: occurs both during day and night
• Orthostatic: occurs only during the day but not at rest
• Transient: typically concurrent with an acute illness and will resolve upon resolution of the illness

Question 8

Nephrotic syndrome

Answer 8

• Sx of the syndrome: proteinuria >3.5gm/day, hypoalbuminemia, edema
• Other possible Sx: hyperlipidemia, Ca disturbances, hypercoagulability, thyroid dysfxn
• Hypoalbuminemia is due to the loss of negative charges in the GBM (selective proteinuria)
• There is renal loss of protein, along w/ tubular degradation leading to further protein loss
• Hepatic synthesis of albumin increases to compensate for hypoalbuminemia
• Occasionally other larger proteins (IgG) can be lost too (non-selective)

Question 9

Edema from nephrotic syndrome

Answer 9

• 2 hypothesis: underfilling and overfilling
• Hypoalbuminemia may cause a decrease in effective arterial blood volume which stimulate neural hormonal factors to reabsorb Na and H2O (for the 1/3rd of pts that have hypovolemia)
• In overfilling (2/3rds of pts have hypervolemia), the cause of renal Na retention is unknown (thought to be due to proteinuria), but its not due to RAAS b/c renin and aldo levels are normal and ACEIs do not prevent the Na reabsorption

Question 10

Other Sx seen in nephrotic syndrome

Answer 10

• Metabolic derangements: alteration of Ca and vit D, reduced IgA and IgG (increased IgM), increased susceptibility to infection, malnutrition
• Hyperlipidemia: increase in all non-HDL lipoproteins (HDL normal), with increase in LDL/HDL ratio (increased LDL synthesis, reduced catabolism)
• Hypercoagulability can often cause renal vein thrombosis or PR
• Hypercoagulability usually due to decreased AT/APC/APS or factor 5 leiden mutation

Question 11

Etiologies of nephrotic syndrome

Answer 11

• Most are idiopathic, but many are secondary to diabetic nephropathy, amyloidosis, SLE, neoplasia, drugs, infection
• Idiopathic forms based on histology: minimal change disease, membranous glomerulonephritis, focal and segmental glomerulosclerosis, membranoproliferative glomerulonephritis, IgA nephropathy

Question 12

Distinguishing nephrotic vs nephritic

Answer 12

• Nephrotic syndrome has a larger degree of protein urea (usually >3.5g/day), little if any hematuria, and show oval fat bodies (Maltese cross)
• Nephritic syndrome has less proteinuria if any (usually <3.5g/day), more hematuria, and RBC casts
• For nephritic syndrome, check if there is normal or low complement levels