Tubular proteinuria

Tubular proteinuria

Unlike glomerular proteinuria, where protein excretion can reach 20g/24h and consists mainly of albumin, tubular proteinuria is generally less than 1-2 g/day. Along with albumin there is also larger proportion of proteins of <60 kDa.

Protein	Normal	Glomerular disease	Tubular disease
Total protein (g/day)	<0.15	>2.5	<0.5-1.0
Albumin (gm/day)	<20	>500	<500
α1-microglobulin (mg/day)	<10	Normal/slightly increased	Moderately increased
Β2-microglobulin (mg/24h)	<0.35	Normal/slightly increased	Moderately increased

In renal tubular disease reabsorption of protein together with water, ions, glucose and amino acids is impaired. In tubular disease increase in excretion of low molecular weight protein is greater than that found for larger proteins like albumin e.g. higher clearance of β₂-microglobulin. The albumin to β₂-microglobulin ratio becomes 1:2. 

During this condition there is direct tubular damage mediated by autoimmune or infection, drugs (phenacetin, paracetamol, NSAID), toxins and any pathology leading to glomerular proteinuria. Tubular proteinuria, together with defective reabsorption may form part of the Debre-de Toni-Fanconi syndrome which can be inherited or acquired as a consequence of other inherited metabolic defects.

Increased β₂-microglobulin excretion was first described in cadmium workers, and markers of tubular proteinuria are now used to monitor occupationally exposed subjects. Many drugs like NSAIDS, paracetamol can also cause glomerular and tubular damage.

Methods of assessing tubular damage:

Measurement of urinary proteins as markers of tubular damage falls into two categories: measurement of large molecular weight proteins such as enzymes or brush border antigens released by damaged tubules, and measurement of low MW proteins filtered at glomerulus and normally reabsorbed by PCT.

High molecular weight protein markers of renal tubular damage:

Renal tubular damage causes the release of enzymes not normally filtered by glomerulus and these are lactate dehydrogenase, GGT and ALP. The most widely employed for monitoring tubular damage is N-acetyl β-D-glucosaminidase (NAG) which is a lysosomal enzyme (150 kDa) found in PCT cells. It has been used as marker of acute rejection in renal transplant patients. Its release is increased during nephrotic syndrome, tubulointerstitial nephritis, metal poisoning, DM, hyperthyroidism, etc.

Low molecular weight protein markers of renal tubular disease:

During glomerular disease, tubules are presented with increased load of Low MW proteins which exceed the absorption threshold of tubules. These are retinol binding protein (21 kDa), α₁-microglobulin (31 kDa), β₂-microglobulin (11.8 kDa, this is unstable at urine pH<5.5). Lysozyme (muramidase) was the first Low MW marker of tubular function but its concentration increases during leukemia, inflammation. Increased excretion of β₂-microglobulin was first identified in patients with cadmium poisoning and with Wilson’s disease but increased level are also found in liver disease and malignancies like myeloma and B-cell lymphomas. RBP (85 kDa) complexes with vitamin A and prealbumin in plasma and only small proportion is free to be filtered by glomerulus. RBP is also excreted by kidneys and is stable in urine. α₁-microglobulin is more stable in urine than β₂-microglobulin and is widely used tubular marker.

Proteinuria of prerenal origin:

Proteinuria of prerenal origin has been defined as the occurrence in the urine of abnormal amounts of any plasma protein filtered by glomerulus in the absence of any glomerular or tubular abnormality. The term is applied to overflow proteinuria such as Bence Jones proteinuria, hemoglobinuria, myoglobinuria where plasma concentrations of these proteins are increased.

Myoglobinuria causes during rapid destruction of striated muscle (rhabdomyolysis) which releases myoglobin. As its molecular weight is 17 kDa it is filtered rapidly by glomerulus.

Haemoglobinuria occurs during intravascular hemolysis. In case of myoglobinuria and hemoglobinuria, these are degraded and there is formation of ferrihaemate within the tubules which damages tubular epithelial cells.

Bence Jones proteinuria, the presence in urine of immunoglobulin light chains is frequent finding in multiple myeloma and other B-cell malignancies. Normally kidneys catabolizes the light chain but in excess light chains are filtered, they are toxic to both proximal and distal renal tubules and contribute to development of Fanconi syndrome, renal tubular acidosis and renal failure in patients with multiple myeloma.