Proteinuria

Protein in urine: Cause, Types and testing procedure

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Normally little proteins are found urine. All proteins in urine come from plasma as ultra filtrate in glomerulus. But normally, filtration barrier in glomerulus do not allow proteins to escape from plasma.

Glomerulas
Glomerulas

Filtration barrier

There are three structures that separate the capillary lumen from glomerular lumen

Filtration Barrier
Filtration Barrier
  1. The capillary endothelial cell wall: the endothelial cell wall are not tight everywhere. There is fenestration between cells or the junction of the cells. This fenestration is 70-100nm in diameter.
  2. The Glomerular Basement membrane (GBM): a network of collagen on which visceral layer of epithelial cells of glomerulus rests. These cells are called podocytes.
  3. The visceral epithelial cells: There are slits between foot process of podocytes, which are about 20-30nm in diameter.

All these three layers of filtration barriers prevents large proteins (molecular weight >67kDa) molecules to pass from capillaries. So, normally-almost no albumin passes through filtration barrier. Only smaller proteins (MW <20kDa) are filtrated freely.

Plasma protein

Normal proteins components in plasma, called plasma proteins are as follows

  • Albumin-55%
  • Globulin:
    • Alpha1 globulin-5.3% (Antitrypsin, TBG, Transcortin)
    • Alpha2 globulin- 8.6% (Hepatoglobulin, ceruloplasmin, macroglobulin)
    • Beta globulin- 13.4%( beta transferring, beta lipoproteins)
    • Gamma globulin- 11% (Antibodies)
  • Fibrinogen: (a fibrous proteins with a molecular weight 3,40,000.) -6.5%

Proteinuria

When proteins in urine are present, it is called proteinuria.

Normally, small amounts of proteins are found in urine. Some of these are filtrated and some of these are secreted by tubular cells-like Tamm Haorsfall mucoprotein.

If filtration barrier are damaged, albumin passes to urine as albumin constitutes about 70% of plasma proteins. Depending on the damage severity, large amount of proteins can be excreted in urine.

Normal protein excretion daily – 150 mg/day

  • Albumin 10-30 mg.
  • Rest is other protein, like
    • Beta 2 microglobulin,
    • Ig- light chain, & lysozyme
    • Tamm Haorsfall mucoprotein secreted by DCT cells & ascending loop of henle.

Strip method is sensitive to albumin

Acid sensitive method detects all proteins.

Proteinuria may be of several types

Selective proteinuria- due to loss of anionic albumin due to damage of GBM.

Functional  proteinuria- [<500mg/day] , found in

  • Dehydration
  • heavy exercise
  • Congestive cardiac failure
  • Cold weather
  • Fever

Postural proteinuria [ <1000 mg] may occur due to change in posture  – occurs 3-5% healthy adult.

Quantification:

as per quantity of proteins excreted, proteinuria are classified into several group

Heavy proteinuria  [>4gm/day] , as in-

  • Nephrotic syndrome
  • Severe heart failure
  • Renal vein thrombosis
  • Acute, rapidly progressive & Chronic Glomerulonephritis
  • Diabetes mellitus
  • Hypertension
  • Drugs
  • Neoplasm
  • Amyloidosis.

Moderate proteinuria– [ 1-4 gm/day] –may be due to all cause of heavy proteinuria, and-

  • Degenerative,
  • Malignant,
  • Inflammatory cause of lower urinary tract.

Minimal proteinuria [<1 gm/day] – occurs in

  • Chronic pyelonephritis
  • Interstitial nephritis
  • Renal tubular disease

Qualitative categories

depending on site of pathology, proteinuria may be classified as-

Glomerular proteinuria –[ >3-4gm/day]

  • large non selective protein appears.
  • Albumin, transferring, prealbumin etc.

Tubular proteinuria [ 1-2g/day]  – due to loss of re absorptive capacity of tubules.

These proteins are usually low MW.

Beta 2 micro globulin is indicator of tubular damage.

  • Occurs in fanconi`s syndrome,
  • Wilson`s disease,
  • pyelonephritis,
  • renal transplant rejection etc.

Overflow proteinuria

  • Due to excess in blood. Such as Hb, Immunoglobin, Myoglobulin loss.
  • They may cause renal damage.

Bence Jones proteinuria-

It is light chain of Immunoglobulin.

  • Associated with Multiple myeloma,
  • malignant lymphoma, and
  • macroglobulinemia.

Microalbuminuria-

Albumin above normal level but below the dipstick detectable level.

100-200mg/L are indicator of early glomerular damage.

Test for urine protein

Qualitative test

Heat & acetic acid test  -this is the most common test

Heat Test
Heat Test

Procedure:

  1. Take  urine in a test tube almost 2/3rd filled
  2. heat upper part
  3.  If cloud appear.
  4. Add 3% acetic acetic acid 2-3 drop
  5. If coagulum persists then presence of Albumin confirmed.
  6. If coagulum disappears – possible cause of cloudiness is presence of phosphates.

Result – in case of proteinuria

Proteinuria
Proteinuria
  • Negative_- no cloud
  • Trace  – barely visible cloudiness
  • 1+ à definite cloud without granular deposit [ < 0.1%]
  • 2+ à heavy granular cloud without flocculation [ 0.10-0.25%]
  • 3+ à dense cloud with flocculation [ 0.25-0.5% ]
  • 4+ à thick, curdy ppt. With coagulation [. .5%]

Sulphosalicylic acid test :

Take 2ml Urine and add equal volume 3% Sulphosalicylic acid à invert test tube & mix à stand 10min.

Reading similar like heat & acetic acid test.

Heller’s Nitric acid test:

Take 1ml concentrated fuming Nitric acid à add 2ml Urine by the side of TT à whitish ring appears at the junction due to formation of metaprotein.

Dipstick method

Dipstick Method
Dipstick Method

Detect albumin in strip changing colour.  Detect as low as 20mg% albumin in urine.

Quantitative test

Esbach`s method by Esbach`s Albuminometer

  • Take filtered acidified urine up to U mark of albumin meter àadd reagent up to R markà stand for 24 hours.
  • Take reading after 24 hours.
  • Reading are expressed as gm/L.
  • Result divided by 10 will give mg%.
  • Result X 24 hours urine quantity will give à 24 hrs total urine excretion

Other special situation:

 Protein/createnine ratio: pcr

24 hours urine collection may not be possible. In that case single sample with estimation of protein/createnine ratio (PCR) give valuable information about the progression of the kidney disease.

Microalbuminuria:

Describe excretion of small amount of albumin in urine. The presence of albumin in urine is a clear sign of glomerular disease and can identify very early stage of disease progression.

Bence jones proteinuria

Bence-jones proteins are immunoglobin light chains and secreted by plasma “B” lymphocytes. These are found in various conditions, like

  • Multiple Myeloma
  • Plasmacytoma
  • Waldrenstrom macroglobinaemia

Selective proteinuria

When low molecular weight proteins like Albumin(MW-66000) and Transferrin(MW-76000) are selectively excreted through kidney, but higher molecular weight proteins do not. This condition is called “Selective Proteinuria”. It is found in

  • Minimal change glomerulonephritis
  • Membranous glomerulonephritis
  • Focal-segmental glomerulonephritis
  • Almost all cause of nephritic syndrome.

Poorly selective proteinuria

When there is high molecular weight protein excretion in addition to albumin.

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