Types and Causes of Proteinuria

Proteinuria means the excretion of protein in the urine. A healthy person does not excrete proteins in the urine or the excretion of proteins is less than 150 mg per day. The proteins most commonly found in the urine are those derived from the plasma of blood and consist of a mixture of albumin and globulin. Predominantly albuminuria (excretion of albumin in urine) is detectable on routine urine analysis during a medical examination. Albuminuria could be organic (due to involvement of kidneys or other organs) or functional (due to physiological or biological stress on kidneys). The functional albuminuria is usually intermittent and not accompanied by any symptoms or evidence of kidney disease. Renal function tests and urinary deposits are found to be normal during the functional albuminuria. It may be connected with posture; being absent when the person is lying down and present when standing. The functional albuminuria usually clears up in early adult life and seems to be associated with the growth and development of kidneys. Any severe stress may also lead to transient albuminuria. Exposure to severe cold and excessive exercise or physical activity may cause functional or transient proteinuria. However, there is nothing to worry about as the functional albuminuria is self limiting with respect to the cause. Mild to moderate functional albuminuria may also be detected during last two months of pregnancy due to pressure on kidneys.

Organic albuminuria is of three types: 1) Renal Albuminuria - When the cause is the kidney disease. 2) Pre-renal Albuminuria - When the kidneys are affected secondarily to some other disease. Post-renal Albuminuria - When the protein is added to the urine after it has left the renal tubules.

1. Renal Albuminuria: It is found in all forms of kidney disease. The cause of renal disorder or kidney disease may be inflammatory (infectious), degenerative (immunological) or destructive (toxic or malignant). The plasma globulin and red blood cells (RBCs) may also be excreted along with albumin during some renal disorders. The urine would be smoky in color if macroscopic hematuria (blood in urine) is also associated with proteinuria. The cases of acute glomerulonephritis may excrete 0.5 to 2.0 percent (0.5 g to 2.0 g/dl) protein in the urine, whereas the cases affected by chronic glomerulonephritis generally excrete less than 0.5 percent (0.5 g/dl) protein in the urine. The amount of protein excreted daily would vary depending on the volume of urine voided daily. The ratio of albumin to globulin excreted in the urine may vary from 10:1 to 5:1. A routine and quantitative urine analysis is required to evaluate the extent of excretion of proteins in the urine.

2. Pre-renal Albuminuria: It is found in a variety of conditions exerting stress on the kidneys. The pre-renal albuminuria usually disappears when the primary disease is cured. Impairment of renal circulation due to dehydration, diarrhea or vomiting, blood loss due to accidental injuries or anemia are the most common conditions, which could lead to pre-renal albuminuria.

3. Post-renal Albuminuria: The proteinuria or albuminuria is termed as post-renal albuminuria if protein is possibly added to the urine as it passes along the urinary tract after leaving the urinary tubules of the kidneys. The major causes of the post-renal albuminuria are the lesions of the renal pelvis or urinary bladder. Lesions of the prostate (in male patients) and urethra also lead to post-renal albuminuria. Admixture of discharges from the vagina (in female patients) and semen (in male patients) may also give positive tests for protein.

What Could Be The Cause Of Swelling On Face

The swelling on face or facial edema should be taken seriously if there is no history of insect bite, wasp sting or honey bee sting and when it is after a throat infection. The swelling on face or facial edema could be due to renal disorder (kidney disease). If on routine examination of urine of the patient, excretion of albumin or protein is detected; there is a need to consult a nephrologist for proper investigations. Blood biochemistry for blood urea, serum creatinine, serum proteins, serum electrophoresis, urine electrophoresis and 24-hour urinary protein should be done. Excretion of protein in 24-hours through urine will help the physician to assess the loss of proteins and possible course of action. Urine electrophoresis would show the type of protein being excreted in the urine. In a patient with nephrotic syndrome, serum electrophoresis would show hypoalbuminemia (low level of albumin in blood), hypogammaglobulinemia (low level of globulins in blood) and raised alpha-2 (a-2) globulin, and urine electrophoresis may show albuminuria (excretion of albumin in urine) or non-selective proteinuria (excretion of almost all the fractions of serum proteins in urine). Total serum protein and its fractions like albumin and globulin would show the altered albumin-globulin ratio. The normal albumin-globulin ratio (^Albumin/_Globulin) is 3:1 and it may be reversed in patients with swelling on face due to kidney disease.

The swelling on face or facial edema is directly associated with albuminuria (excretion of albumin in urine) and salt retention. The loss of blood albumin through urine hinders the return of fluid from the tissues into the blood and may thus lead to development of edema. It is well known that 68 to 70% weight of our body is due to water content in the blood and tissues. Around 12 to 14% of the total water volume of our body is in the blood and the rest is present in the tissues of the body. There is direct correlation between albuminuria (excretion of albumin in urine) and edema. Retention of Chloride is also a common accompaniment of edema. However, there may not be any retention of Chloride in majority of the cases with edema. The edema is perhaps the greatest problem confronting the students of nephrology. Pathological lesions in the kidney need to be evaluated microscopically through renal biopsy examination. Blood urea and serum creatinine may be normal. There may be salt retention without edema and edema without salt retention. The Chloride may collect in watery subcutaneous tissue due to some external factors also without involvement of any renal lesion.

Two forms of swelling on face or facial edema could be recognized and these are called nephritic edema and nephrotic edema. In nephritic edema the protein content of the edema fluid is over 1 gram/dl whereas in nephrotic edema the protein content of the edema fluid is always less than 0.1 gram/dl. Nephritic edema occurs in acute glomerulonephritis. The capillaries in the subcutaneous tissue become more permeable leading to leakage of proteins in the extra cellular fluid. Nephrotic edema occurs in the wet nephritis or second stage of nephritis, in nephrosis and also in renal amyloidosis. The edema is caused due to the great fall in the osmotic pressure of the blood due to constant loss of protein in urine; so, the fluid from the blood vessels escapes into the tissues in an effort to correct the viscosity of blood plasma.

Kidney Biopsy Evaluation and Clinicopathological Understanding

Kidney biopsy evaluation is must to understand the renal lesions in association with clinical picture. An adequate kidney biopsy should contain five to ten glomeruli and corresponding tubules and cortical tissue. The adequacy of needle biopsy of kidney depends on the expertise of nephrologist, performing the biopsy technique. Pathologist performs a methodic approach in the microscopic evaluation of kidney biopsy (renal biopsy). Patient may find microscopic description of glomeruli, tubules, blood vessels and interstitial tissue in the surgical pathology (histopathology) report of kidney biopsy. There are several categories of kidney diseases in which histomorphologic features obtained from renal biopsy may prove clinically helpful. Some such conditions are:

1. Nephritic syndrome and acute renal failure (Sudden impairment of renal function).
2. Nephrotic syndrome (Clinical picture characterized by marked edema, massive albuminuria, hypoproteinemia together with high blood cholesterol, normal blood pressure and absence of signs of renal failure)
3. Systemic diseases with associated renal disorders.
4. Evaluation of asymptomatic patients in whom routine laboratory examination has disclosed proteinuria (protein in urine) and/or microscopic hematuria (blood in urine).
5. Evaluation of prospective kidney donors, to be sure that they did not have any occult renal disease.
6. Assessment of renal microstructure of patients with renal transplant.
7. Evaluation of siblings of patients with hereditary renal disorders like Alport's syndrome.

The biopsies are classified by combining the clinical presentation, the histopathology, the immunopathology and ultrastructural pathology. There are several defined patterns of renal lesions and syndromes and these would be discussed separately.

Albumin & Casts in Urine and Associated Renal Lesions

Urine analysis is the cheapest and routine investigation which could be of great help to the clinician to reach at a diagnosis of a complex renal disorder. Albuminuria (excretion of albumin in urine) detected on heat test of the urine and the casts detected on microscopic examination of first morning specimen of urine reveal a lot about the associated renal lesions (pathological changes in kidney). Albuminuria we know definitely to be glomerular origin, although the tubules may also play their part in its production. It seems probable that this is mainly due to the glomerular basement membrane (GBM) which separates the epithelium of the tuft from the endothelium lining the capillaries, with increase of its permeability.

Casts are the microscopic accumulations of cells or coagulated proteins or lipids. Casts if present could be detected on microscopic examination of deposit obtained after centrifugation of urine. The casts must also be traced to the glomerulus, at least the essential hyaline matrix of the cast composed of coagulated albumin. Again the tubules add their contribution in the shape of epithelial cells and fatty and granular detritus which give to the casts their characteristic appearance. Careful examination casts is as informative as blood biochemistry investigations in cases of kidney disease. The cast gives a picture of the degenerative changes in the tubules. A hyaline cast indicates slight glomerular leakage without active tubular degeneration. Cellular casts denote marked activity of the morbid process. Granular casts denote moderate activity. The admixture of red blood cells (RBCs) is a sign of glomerular hemorrhage. We find that the study of casts is of remarkable importance in assessing the prognosis of a renal disorder. As long as there is considerable activity there is a scope for improvement. For such a study to be of value, the urine should be fresh. If the urine is alkaline or has been allowed to stand for long time, the casts may largely disappear. The absence of casts in an alkaline urine has not the same significance as when the urine is acidic. The acidity of the urine assists in the formation of casts. Deposition of casts in the tubules may lead to oliguria (low output of urine) leading to edema.