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39. Laboratory findings in proteinuria and haematuria

Proteinuria

Proteinuria refers to pathological amounts of protein in the urine, defined as urinary protein content of > 150 mg per day. Physiologically, 50 - 150 mg protein is excreted in urine per day, most of which secreted by the tubuli with only small amounts filtered through the glomeruli. 99% of filtered proteins are reabsorbed in the tubuli.

Most normal plasma proteins are not filtered in the glomeruli because they are too large for the glomerular pores and they are negative, just like the filter surface. The small amount of protein that is filtered are small in size (below 65 kD) and are reabsorbed by proximal tubular cells where they are metabolized.

Proteinuria is often a sign of kidney damage, except orthostatic proteinuria, which is physiological. The amount of albumin in the urine, albuminuria, is used to stage chronic kidney disease.

Etiology

Different types of proteinuria can be distinguished based on the underlying pathology and resulting distinguishing clinical features.

Glomerular proteinuria (300 - 20000 mg/day) occurs because of damage to the glomeruli. It can occur because of diabetes mellitus (diabetic nephropathy), nephrotic syndrome, preeclampsia, or chronic hypertension. The damage usually allows for large proteins (like albumin) to be filtered.

Tubular proteinuria (150 - 2000 mg/day) occurs due to tubular injury, for example due to acute tubular necrosis or interstitial nephritis. Only small (< 65 kD) proteins will be lost, like alpha-1 microglobulin and beta-2 microglobulin. The tubular injury prevents the physiological reabsorption of small proteins which are (physiologically) filtered through the glomeruli.

Overflow proteinuria (150 - 2000 mg/day), sometimes called prerenal proteinuria, occurs when a small protein (which is physiologically filtered but usually completely reabsorbed in the tubuli) is produced to such an extent that the tubuli cannot reabsorb all of it. This occurs in multiple myeloma (which produces immunoglobulin light chains, called Bence Jones proteins) and rhabdomyolysis (myoglobin). It may also be physiological if it only occurs when standing, called orthostatic proteinuria, which may occur because of compression of the renal vein while standing, as well as after exercise.

Postrenal proteinuria (300 - 1000 mg/day) can occur due to urinary tract infection.

Classification

Proteinuria can be classified according to quantity of proteins in the urine. Because albumin is the most abundant protein excreted in urine, we usually classify proteinuria by the amount of albumin. Urinary albumin excretion varies throughout the day and depends on how concentrated the urine is. Measuring the albumin/creatinine ratio (ACR) rather than the albumin concentration mitigates the latter of these issues and is therefore used rather than urinary albumin concentration, but the gold standard is 24-hour measurement of urinary protein concentration

Name Equivalent chronic kidney disease stage Albumin excretion per day Albumin to creatinine ratio
Normal or mildly increased proteinuria A1 < 30 mg < 30 mg/g
Moderately increased A2 30 - 300 mg 30 - 300 mg/g
Severely increased A3 > 300 mg > 300 mg/g
Nephrotic range proteinuria > 3500 mg

According to the result of the urinary dipstick analysis:

Urinary dipstick analysis Albumin excretion per day Approximate equal albumin to creatinine ratio Albumin concentration in urine
Negative < 150 mg < 30 mg/g < 10 mg/dL
Trace 150 mg - 200 mg 30 - 300 mg/g 15 mg/dL
1+ 200 - 500 mg 30 mg/dL
2+ 500 - 1500 mg > 300 mg/g 100 mg/dL
3+ 1500 mg - 5000 mg 300 mg/dL
4+ > 5000 mg >1000 mg/dL

Consequences

Proteinuria is a sign of pathology, usually kidney damage. Glomerular filtration of protein damages the glomeruli further and so eventually causes progressive kidney damage. Proteinuria, even small amounts, is associated with cardiovascular disease. Massive proteinuria (especially nephrotic proteinuria) can cause hypoproteinaemia, which may affect muscle growth, immune system function, and may cause oedema.

Haematuria

Haematuria refers to the presence of blood in the urine. We distinguish between microscopic haematuria, when the concentration of blood is too low to be macroscopically visible, and macroscopic haematuria (also called gross haematuria), where the concentration is so high that the urine is visible coloured red. Haematuria is defined as the presence of > 3 RBCs per field of view at 400x when examining a urine sample under the microscope, or by it's detection by laboratory methods.

Haematuria may be a sign of kidney or urinary tract pathology, including glomerulonephritis, urinary tract infection, and bladder cancer. In many, however, haematuria is transient or no underlying pathology can be found.

Severe gross haematuria, especially when there is concurrent urinary retention or voiding of blood clots, is a urological emergency as it may cause bladder tamponade.

Etiology

We distinguish two types of haematuria, glomerular haematuria and nonglomerular haematuria. Glomerular haematuria is secondary to glomerular disease. Nonglomerular haematuria is much more common.

Gross haematuria:

Classification

Macroscopic haematuria, also called macrohaematuria or gross haematuria, is the name of haematuria where the reddish colour change of the urine is visible to the naked eye. This is due to a high concentration of blood per unit urine.

Microscopic haematuria, also called microhaematuria, where the urine is mixed with so little blood that it cannot be seen macroscopically but it can be measured on biochemical tests.

Diagnosis and evaluation

The gold standard is microscopic evaluation of the urine, with 3 or more RBCs per high-power field usually being thought of as pathological. A urine dipstick test can also be used to semiquantitatively evaluate haematuria.

Glomerular and non-glomerular haematuria have some differing features. Glomerular haematuria usually has RBC casts in the urine, as well as dysmorphic RBCs in the urine. These dysmorphic RBCs have blebs on the surface and irregular morphology. In case of glomerular disease, there is often also concomitant proteinuria. RBC casts are absent for non-glomerular haematuria, and the RBCs in this type have normal morphology.

Other causes of bleeding, like menstruation and haemorrhoids, should be excluded. To rule out transient microhaematuria, microhaematuria should be confirmed with a second analysis after 1 month.

Because malignancy may be an underlying cause, patients with otherwise unexplained macrosopic haematuria must be thoroughly evaluated for malignancy. In Norway, referral for malignancy evaluation for microscopic haematuria is indicated if there is 2+ or more on the urinary dipstick test (or > 2 RBCs per field of view on microscopy) on three separate tests with 1 month in-between. The first step is usually to rule out bladder malignancy with cystoscopy.