65. 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.