Saturday, November 10, 2012

PROTEINURIA and it's types:

PROTEINURIA

Every 24 hour 65 kg protein goes to kidney and only 150 mg appear in urine. The glomerular barrier to filtration includes arterial fenestrated epithelium, glomerular basement membrane which is gel like structure, and overlying are epithelial cells called podocytes with numerous foot processes that interdigitated and envelop the outer surface of glomerular membrane. The foot processes are separated by slit diaphragms which form the final barrier to plasma proteins. The whole of the glomerular membrane carries net negative charge due to glycoproteins, sialic acid heparin sulfate with great density of charge at slit diaphragms.

The glomerular membrane selectively allows passage of water and low molecular weight solutes in the tubule and restricts passage of larger molecular weight plasma proteins. The negative charge of membrane restricts the passage of negatively charged plasma proteins forming electrochemical retention of plasma proteins (charge barriers especially starts in GBM and higher at slit diaphragm). Thus filtration of solutes depends upon their molecular size, shape and charge. Although some proteins are filtered e.g. albumin.

Most of proteins are reabsorbed in PCT and some are metabolized in tubular cell (e.g. 10-60% albumin). Only very small proteins with molecular weight <66 kDa (ie. Less than albumin mol. Wt.) normally reaches the urine (E.g. amylase, 48 kDa, myoglobin, 17.8 kDa, etc.).

Proteinuria occurs when filtered load increases and this may be due to glomerular damage, increased glomerular permeability, increased circulating concentration of LMW proteins or decrease in reabsorptive capacity due to tubular damage. There are 3 main types of proteinuria.

Glomerular:

Increased glomerular permeability. There is damage in basement membrane may be due to immune complex deposition, diabetic nephropathy. HMW proteins excretion is increased e.g. albumin, IgG.

Overflow: 

Increased plasma concentration of relatively freely filtered proteins. Bence Jones proteins in myeloma, lysozyme in leukaemia, amylase in pancreatitis, myoglobin in rhabdomyolysis, etc.

Tubular: 

Proximal tubular damage which leads to decreased reabsorption. This type of proteinuria also occurs due to decreased nephron number and there is increased filtered load per nephron. Proteins excreted are low molecular weight proteins like α1-microglobulin, β2-microglobulin, retinol binding protein, etc. Due to damage of tubular epithelial cells there is release of enzymes like ALP, N-acetyl-β-D-glucosaminidase). There is also distal tubular damage and during this proteins excreted are Tamm Horsfall glycoprotein, glutathione S-transferase (nephrogenic aminoaciduria)

Proteinuria can be detected by dipstick method which can detect >150 mg of protein in urine. 

Proteinuria >300 mg/day is pathological. Proteinuria above 1g/day implies glomerular proteinuria. Proteinuria has been shown to be a potential risk factor for progression of renal disease. It is also used for screening purpose to identify persons with silent kidney damage. There should be 50 to 60% loss of renal mass before appearing symptoms or alteration of biochemical markers.

There are at least 3 proteins present in urine that are renal origin they are Tamm Horsfall glycoprotein, urokinase and secretory IgA. THG is a glycoprotein and comprises 68% protein, 31% carbohydrate and 0.5 to 1.0% lipid. THG is secreted from the loops of Henle and the DCT. It traps albumin, red blood cells, tubular cells or cellular debris present in tubular fluid. It has protective role in trapping damaging material in urinary space, recently, the capacity of THG to bind E. coli has led to suggestion of its role for defense against UTI. Urokinase is a proteolytic enzyme that converts plasminogen to plasmin which in turn breakdown fibrin and has role in removing fibrin from the renal microvasculature and possibly in removing urinary casts. sIgA is produced by lymphocytes which is transported to tubular epithelial cells and secreted to lumen with secretory peptide which is a transport protein.

In the National kidney Foundation Guidelines, urine albumin is recommended as a sensitivity marker for chronic renal disease due to diabetes, glomerular disease and hypertension and α1 and β2-microglobulin as sensitive markers of tubulointerstitial disease.

Proteinuria is renal disease:

Proteinuria is the most frequent clinical finding in renal disease and quantitation of proteinuria is valuable test in monitoring renal damage. Urine protein is derived from plasma and from kidneys themselves. Measurement of low concentrations of specific proteins such as albumin, IgG or transferrin, predominantly reflecting glomerular function and α1-microglobulin or retinol binding protein, reflecting tubular reabsorptive function, are now used as early markers of primary renal disease (e.g. glomerulonephritis) and secondary renal disease (e.g. due to DM or hypertension).

Conventionally proteinuria is classified into glomerular proteinuria, tubular proteinuria, nephrogenic proteinuria (e.g., due to THG, BM and tubular proteins), proteinuria of prerenal origin (e.g. overflow proteinuria like light chains disease, myoglobinuria, haemoglobinuria, lysozyme in leukaemia and amylase in pancreatitis) and postrenal proteinuria due to obstruction of the urinary tract or inflammation like in UTI.
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