Brian is a 52 year old teacher who had been feeling unwell for several months. He had not been sleeping at all well, often getting up in the night to urinate, and was feeling extremely fatigued. He also noticed that his ankles seemed swollen. Eventually, when he felt his symptoms were interfering with his work and social life he was persuaded to visit the GP who referred him for blood and urine tests. This revealed Brian was suffering from nephrotic syndrome. A renal biopsy was ordered by the consultant and the cellular pathology report.
The nephrotic syndrome is defined as a collection of abnormal events caused by the heavy loss of protein in the urine. Hence the often need for Brian to urinate. The protein is excreted in the urine faster than its manufacture in the body. This causes the protein concentration in blood plasma decrease significantly leading to edema which associates to plasma osmotic pressure being low. This is displayed as a sign of fatigue in Brian. Numerous kinds of different renal diseases are responsible for the cause of nephrotic syndrome. The protein is leaked mainly through the damaged basement membrane in the injured glomerulus. One of the main proteins called albumin is lost in large amount in the urine than the other main protein called globulin due to the albumin molecule being smaller in size. The osmotic pressure of the plasma comes to a certain level where large quantity of fluid is leaked into certain body cavities and tissues from the capillaries. This is one of the main reasons of the patient, Brian's ankle being swollen.
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Before a biopsy was ordered, the patient, Brian was presented with the nephrotic syndrome with the help of clinical features.
Firstly, the signs start with swellings in different parts of the body, such as Brian's ankle. This is usually described as dependent edema in adults. Secondly, the colour of the urine varies according to the concentration of protein that has been leaked into the urine. This is noticed by dark coloured or foamy urine. Thirdly, signs of nephrotic syndrome are presented by complications caused by thrombosis in areas such as calf veins or pulmonary embolus. Finally, the history of the patient can be related to the signs of nephrotic syndrome such as non steroidal anti inflammatory drug intake or the patient's diabetic history. Hypertension and anemia is noticed in patients with diabetic nephropathy which is associated with reduced kidney functions.
One of the main physical signs of nephrotic syndrome is edema which is developed initially around legs or eyes. Eventually, it starts spreading and its weight being increased and the development of ascites and effusions. Also, hematuria is observed in some patients with nephrotic syndrome.
The major signs and symptoms of nephrotic syndrome are the different levels of proteinurea, hypoalbuminemia, peripheral edema and hyperlipidemia.
High levels of proteinura are noted as more than 3.5g of protein in the urine within a day in a patient with nephrotic syndrome. Moreover, the albumin level is significantly low in the blood (Hypoalbuminemia). Also high level of cholesterol is found in blood.
The significance of the cellular pathology laboratory in the diagnosis of nephrotic syndrome is relied on the combination of symptoms, blood and urine tests and physical examinations.
Following are the diagnostic tests that are carried out for the identification of nephrotic syndrome.
This is the test used to detect proteinurea in urine. The physician measures the quantity of proteinurea present in the urine sample if the test turns out positive. This test is done in a 24 hour time period. Unfortunately, carrying out this test is slow and tiresome. Therefore, estimates of the protein in urine produced in 24 hours is calculated using the spot urine protein:creatinine ratio. This ratio is estimated in grams. This makes collecting the spot urine sample easier than the 24 hour urine sample. This can be used to track proteinurea over time.
The urine sample may contain different findings in the urine sample of the patient with nephrotic syndrome. This is further evaluated by centrifuging the sample and discarding the liquid that is separated. A microscope is then used to examine the elements found in the sample. This process is called urine sediment examination. However, they are not specific to the cause of nephrotic syndrome.
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A low blood albumin level is found in patients with nephrotic syndrome (less than 3g/dL). Levels of cholesterol and triglyceride are increased as the lipid production is increased which is caused by the decrease of protein in blood. Proteins that control cholesterol level can also elevate levels of lipid if the protein is lost in the urine.
Other types of blood tests are also carried out to identify the cause of nephrotic syndrome. This is done to treat the underlying diseases that cause nephrotic syndrome. These include the blood tests for syphilis, lupus, hepatitis C, hepatitis B, cryoglobulins, and HIV. Nephrotic syndrome can also be caused by abnormal antibodies produced by multiple myeloma and monoclonal gammopathy diseases. This is identified using electrophoresis and immunofixation tests. Infections are indicated by low blood complement levels caused by diseases like lupus.
The blood creatinine level is measured to identify the kidney function. Decreased function is observed by increased creatinine levels.
Radiology tests are done before the kidney biopsy to make sure that there are no abnormalities in kidneys. These include obstructions or scarring in kidney. The results obtained from these tests do not help to find the cause of the nephrotic syndrome but ensure the safety of the patient before a biopsy. Therefore imaging of kidneys using MRI or CT scan is generally not required.
A kidney biopsy is used to identify the specific underlying cause of the nephrotic syndrome. It consists of a small tissue sample taken from the kidney and observing it under the microscope. An ultrasound image is used to locate the site of biopsy. The tissue sample is obtained with the help of a biopsy needle which is inserted through a tiny cut after anesthetia. The severity of the kidney tissue is assessed by pathologist and nephrologist. Kidney biopsy is only done if the symptoms of nephrotic syndrome persist even after few weeks of drug intake.
All these diagnostic tests enable us to identify the mechanisms involved in the development of the disease that cause nephrotic syndrome.
Usually less than 0.1% of albumin passes through the filtration barrier of glomerulus. The normal concentration of albumin present in glomerular space is 3.5 mg/L. This amount of concentration leads to around 500 mg per day of albumin in the urine after glomerular filteration in a healthy human. A glomerular disease is indicated if the concentration is above that of the normal level.
The filtration barrier of the glomerulus include glomerular epithelium, fenestrated endothelium and glomerular basement membrane
Fig 1. Glomerular barrier.
Endothelial fenestrae and filtration slits helps in the process of plasma and solute filtration. Podocytes and filtration slits plays an important role in the identification of genetic diseases such as congenital nephrotic syndrome of the finnish type. In this disease a protein of the filtration slit is mutated. Similarly, in children with steroid resistant focal glomerulosclerosis, a protein called podocin is abnormal. This helps in the identification of specific cause of the disease.
The cause of proteinurea can be narrowed to endothelial, podocyte or basement membrane damage. Selective proteinurea is when there is more than 80% of albumin in urea. It has a net negative charge. Therefore albuminurea is caused when the negative charge of the glomerular membrane is lost. Whereas, non selective proteinurea is affected mainly by the defect in permeability and not the net charge.
Hypoalbuminemia and albuminuria is caused by the gradualy increased permeability of glomerulus. Plasma colloid osmotic pressure is lowered by the hypoalbuminemia. This in turn causes increased filtration of transcapillary leading to the development of edema. However, the protein content determines oncotic pressure.
Fig 2. Edema Formation
"Massive proteinuria induces tubulointerstitial inflammatory infiltrate with stimulation of vasoconstrictive mediators (angiotensin II) and inhibition of vasodilatory substances (e.g., nitric oxide). In the glomeruli, proteinuria causes a reduction in glomerular ultrafiltration coefficient (Kf) and single nephron glomerular filtration rate (SNGFR). As a consequence, there is a net increase in tubular reabsorption and a reduction in filtered sodium load that result in primary sodium retention and a tendency to "overfilled" intravascular volume and increased capillary hydrostatic pressure (PC). The decrease in plasma oncotic pressure (PCOP) favors fluid movement outwards from the vascular compartment and thereby buffers the changes in blood volume induced by primary sodium retention." (Bruneau S, 2009)
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Underlying cause of nephrotic symptoms are classified into primary and secondary, primary being kidney specific disease and secondary being expression of general systemic illness. However, glomerular injury is heavily involved in all features.
Amyloidosis and paraproteinemias
Viral infections (eg, hepatitis B, hepatitis C,HIV )
The biopsy results of Brain show IgG deposition along the basement membrane. This helps us to further narrow down our choices to two causes under glomerulonephritis also known as membranous nephropathy.
Glomerulonephritis is an inflammation of the glomeruli caused by an antigen-antibody reaction within the glomerular capillaries. The interaction of antigen and antibody activates compliment and liberates mediators that attract polymorphonuclear leukocytes. The actual glomerular injury is caused by destructive lysosomal enzymes that are released from the leukocytes that have accumulated within the glomeruli. The antigen-antibody reaction within the glomeruli may take place in two ways. In most cases, the antigen and antibody interact within the circulation, forming small clumps called immune complexes. These are deposited in the walls of the glomerular capillaries as the blood filters through the glomeruli. Glomerulonephritis that occurs in the way is called immune-complex glomerulonephritis. Less commonly, the glomerular inflammation is caused by an autoantibody directed against the basement membranes of the glomerular capillaries. This type of glomerulonephritis is called antiglomerular basement membrane glomerulonephritis.
Glomerulonephritis caused by autoantibodies directed against glomerular basement membrane is a type of autoimmune disease. It is a relatively uncommon cause of acute glomerulonephritis. In some patients, the anti-GBM antibodies may also injure the basement membranes of the pulmonary capillaries and may cause intrapulmonary hemorrhage as well as acute glomerulonephritis. It is possible to distinguish immune-complex glomerulonephritis from anti-GBM glomerulonephritis by observing kidney tissue obtained by renal biopsy. Anti-GBM nephritis is characterized by a relatively uniform layer of antibody and complement deposited along the inner surface of the glomerular basement membranes.
Almost all the underlying causes to the nephrotic syndrome can be identified using the light and electron microscope. However, a very few diseases such as lipoid nephrosis can be easily ignored under a light microscopy leading to an error in diagnosis. Lipoid nephrosis is also known as minimal change disease. This is the disease where the diffuse loss of visceral epithelial cells foot processes lead to the nephrotic syndrome. It does not involve immunoglobulins or immune complex depositions. The anion production in glomerular basement membrane is reduced due to abnormal secretion of lyphokines by T cells. This makes the glomerulus more permeable to serum albumin with the help of electrostatic repulsion reduction. This may also favour the foot process fusion. With the help of an electron microscope, effacement of the foot processes is identified.
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