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Mohamad A. Sobh, MD, FACP
Prof. & Head of Nephrology
Urology & Nephrology Center
Plasma Protein Delivery to the Nephrons
Protein conc. in plasma = ~70 g/L
Renal plasma flow = 625 ml/min
X 1440 (min/day) = ~900 L/day
Protein delivery / day = 63000 g/day
= 63 kg/day
Renal Handling of Proteins
Despite the delivery of many grams of plasma proteins to the nephrons each day , protein is
normally present in only small quantities in the urine – due to:
1-The glomerulus restricts the filtration of proteins
2-The tubules reabsorb most of the filtered proteins
Glomerular Restriction of Proteinuia
Glomerular capillaries are highly efficient sieving filter:
Free water 150-180 L/day + electrolytes & other solutes (<10’000 Daltons) are freely filtered
Retain the permeation of macromolecules of the size or greater than albumin (cut-off 1.5
nm)–on the basis of size, charge, shape and deformability .
1- Endothelial cell fenestra (1000A)
2- -ve charged BM: type IV collagen network filled with polyanionic heparan
3- -ve charged epithelial cells with foot prcesses (200-300A in between) covered
by slit diaphragm with openings 4x14 nm
However, hemodynamic factors also play a role in glomerular handling of
500-1000 mg of albumin is filtered by the glomeruli each day – yet only 30
mg/day reaches the final urine, the balance being absorbed by the proximal
Many low-molecular weight proteins and peptides are freely filtered by the
glomerulus and are similarly reabsorbed & degraded by the renal tubules; e.g.
lysozymes, ribonuclease, light chains, B2 microglobulin, insulin, GH, & PTH
Normal Urinary Protein Excretion
Normally, urinary protein excretion is <150 mg/day in
adults & <140 mg/m2/day in children
It is usually not detected by ordinary methods
It is composed of :
o Mucoproteins (Tamm-Horsfall glycoprotein): 70 mg
o Blood group related substances: 35 mg
o Albumin : <30 mg
o Immunoglobulin: 6 mg
o Mucopolysaccharides : 16 mg
o Other ptns e.g. hormones & enzymes: v. small amounts
Measurement of Proteinuria
Heating, or adding glacial acetic acid, , trichloroacetic acid or sulfosalicylic acid (SSA, the most
Turbidity may be graded by comparing to (urine + water): trace=20mg/dl, 4+=1g/dl or
measured by turbidometry
It detects both albumin, globulin and BJ proteins
+Ve precipitation with negative dipstick in globulinuria or BJ proteinuria
Tetrabromophenolphthalein , induce a color change with protein . sensitive to albumin more
than other proteins as globulin and mucoproteins and fails to detect bence jones proteinuria
Trace: <30, 1+:>30, 2+: >100, 3+: >500 mg/dl
False +ve: high SG, alkaline urine, UTI, antiseptics
- Total 24-hour urinary protein
- Urinary protein/creatinine (U Pr/Cr) ratio (mg/mg or g/g)
Urinary albumin/creatinine ratio is more accurate, especially in low-range proteinuria (<500 mg/d) but
Proteinuria is a secretion of an abnormal amount of protein in urine.
Normal protein excretion per 24 hours in adults is less than 150 mg. Most
of this protein is albumin and Tamm Horsfall protein with smaller amounts of
False positive proteinuria by dip stick occurs mainly when urine is alkaline
and very concentrated; or if the stick test is left in urine for long time.
False negative proteinuria is observed when protein excretion is mainly Bence
Jones proteinuria and when urine is very diluted.
Bence Jones protein which is the light chain fraction of immunoglobulin
appears in abnormal amounts in urine in cases of multiple myeloma, clots at
temperature 45-55°C, above and below that range it dissolves in urine. Presence of
Bence Jones proteinuria should be confirmed by immunoelectrophoresis.
The causes of Bence Jone's proteinuria include: multiple myeloma,
amyloidosis, adult Fanconi syndrome, benign monoclonal gammopathy and
Is a secretion in urine of ammount of
albumin that is more than the physiologic
one (>3o mg/d), but less than the
detection lemit of the clinical depsick
When first discovered was used as early
marker for diabetic nephropathy, but now
it is considered also as marker of
endothelial cell injury.
It is measured by RIA , ELISA ,and
Selectivity of Proteinuria
This test is done to evaluate the degree of damage in the GBM
through comparing the amount of a large mol. Wt. protein in urine
to that of another small mol. Wt. protein. If the damage is little,
most of the filtered proteins will be of small mol. Wt. , while if the
damage is large both large and small protein will pass easy.
This is done by comparing the clearance of IgG to that of
transferrin: CIgG/Ctransferrin .
A value < 0.1 is selective while > 0.2 is non selective. Selective
proteinuria is usually seen in MCN while non selective is seen in
lesions as MCGN.
Test for selectivity was introduced to avoid doing kidney biopsy.
This can be considered sometimes when biopsy is risky but can
not be generalized.
Orthostatic (Postural) Proteinuria
Proteinuria present in the upright position only that disappears with recumbent position. Mostly
below 2g/day – occasionally heavier
Seen in90% of young men presenting with isolated proteinuria
Entirely benign, transient in 80%
Persistent Isolated Proteinuria
Isolated proteinuria persistent in all samples tested in both recumbent and upright states
Seen in 5-10% of isolated proteinuria in healthy men
Almost always a sign of structure renal disease with some risk of progression – although
prognosis is not bad in all cases
Assessment will show a wide variety of renal lesions; e.g. GN
Proteinuria in association with high fever, strenuous exercise, exposure to cold, emotional stress,
congestive heart failure, and other acute medical diseases
This proteinuria disappears as soon as the precipitating factors has resolved
It is glomerular in type due to changes in renal hemodynamics
No progressive renal disease
Mechanism of proteinuria
There are four known mechanisms for proteinuria:
1. Abnormality in permeability of the glomerular basement membrane
because of glomerular disease or abnormal glomerular hemodynamics ,
usually albumen ( glomerular )
2. Increased concentration of small molecular weight protein in blood
(MW 60000- 70000) e.g. hemoglobin, myoglobin and immunoglobulin light
chains. These will pass easily through the normal GBM ( overflow )
3. Tubular disease with inadequate reabsorption of normally filtered
proteins of MW <60000 e.g. B2-microglobulin ( tubular ).
4. Secretion by renal tubular cells of Tamm-Horsfall protein (urinary
glycoprotein) ( secretory ).
Causes ( D.D) of Proteinuria
I. Functional proteinuria:
There is no organic change in the kidney tissue: it is usually less than 1 gm/d and is
reversible. Possibly, it is due to hemodynamic changes or to minor glomerular disease
which are reversible.
c. Orthostatic proteinuria
d. Miscellaneous (Thyrotoxicosis, severe anaemia, CNS lesions)
II. Tubular Proteinuria : Patients with proteinuria of 0.5-3.5 gm/d ,
Usually caused by tubular or tubulointerstitial diseases
a.Acute interstitial nephritis.
b.Chronic interstitial nephritis such as bacterial (pyelonephritis), gouty nephropathy ,
analgesic nephropathy or nephrolithiasis.
c. Tubular diseases such as Fanconi syndrome, heavy metal intoxication (lead, cadmium),
multiple myeloma, hypokalaemic nephropathy, polycystic kidney disease and medullary
cystic kidney disease.
III.Glomerular Proteiuria : Patients with proteinuria of more than 3.5 gm/d
Usually caused by glomerular disease.
A. Primary glomerular disease:
Minimal change disease
Immunoglobulin A nephropathy
B. Secondary glomerular disease:
Acute poststreptococcal glomerulonephritis
Collagen vascular diseases, HUS, TTP
Metabolic diseases: DM, Amyloidosis, etc.
Drugs (gold, nonsteroidal anti-inflammatory drugs, heroin, penicillamine)
Infections (human immunodeficiency virus; hepatitis A, B, C)
Symptoms & Signs of Proteinuria
Usually detected initially on routine urinalysis as an unexpected finding
Patients may be completely asymptomatic
Or may have many symptoms according to the magnitude of the proteinuria
and/or the level of renal function:
Foamy or frothy urine
Varying grades of edema
Nephrotic syndrome: proteinuria >3.5 grams/day classically presents with edema,
hypoalbuminemia, and hypercholesterolemia
Patients with glomerulonephritis may be asymptomatic or have hematuria, edema
of new onset, pulmonary symptoms, hypertension and/or azotemia
Complications of Proteinuria
Increased hepatic lipoprotein
Increased platelet aggregability
Increased tubular protein
Possible tubular dysfunction
Loss of proteins carrying
vitamins, hormones and minerals
Trace mineral deficiencies
Vitamin D deficiency
Loss of immunoglobulins
Reduced cellular immunity
Increased susceptibility to
Athersclerosis, CAD, & CVD
Alterations in coagulation
Renal vein thrombosis
Negative nitrogen balance
Alteration in drug metabolism
Proteinuria and Progression of CKD
1-Persistently increased protein excretion is usually a
marker of kidney damage
2-Proteinuria is a good predictor of progressive CRF
3-The rate of decline of renal function is proportional to
the severity of proteinuria
4-Proteinuria may cause tubular atrophy and intrstitial
5-Transudation of protein and proteinaceous material →
glomerular cells proliferation and increase synthesis of
extracellular matrix (ECM) components →
Investigations of a case of proteinuria
1.Characterization of proteinuria:
After diagnosis of proteinuria by dip stick test, it should be confirmed by
quantitative estimation of 24 hours proteinuria. Further assessment may
include electrophoresis or immunoelectrophoresis to determine the type of
abnormal protein excreted.
For pus cells (to diagnose U.T. infection), RBCs and casts (to diagnose
glomerular disease), also urine volume (oliguria or polyuria), pH of urine,
specific gravity and test for glucosuria; and aminoaciduria and B2
microglobulin (may help in the diagnosis of tubular disease).
3. Blood and serologic examination:
A. Kidney function tests: serum creatinine, creatinine clearance,
electrolytes (Na, K, Ca, Po4).
B. Total protein, albumin, cholesterol to diagnose nephrotic syndrome.
C. Serologic examination e.g. for anti-DNA and complement component C3
and C4 for diagnosis of lupus erythematosus.
4. Radiologic assessment including:
a. Examination of the kidney for its size, state of
parenchyma, the presence of stone, back pressure
change or pyelonephritic changes. It is achieved
through ultrasound examination, plain X-ray, and CT.
b. Investigations to discover malignancy which could
be the etiologic cause of proteinuria e.g. skeletal
survey for multiple myeloma, X-ray chest and
bronchogram or CT scan for bronchogenic
5. Renal biopsy will give the final answer for
the diagnosis of the kidney lesion causing