(renal protein loss due to inflammation)
Most of the time when kidney disease is discussed, renal insufficiency or chronic kidney failure is the subject. In renal failure, the kidney loses its ability to conserve the body’s water while it removes the body’s daily toxin build up. Excessive water consumption is seen as an early sign of trouble as large amounts of water are required to make enough urine. Eventually toxins build up despite increased water consumption. Weight loss ensues. The classical metabolic changes that result are collectively called uremia or uremic poisoning.
Glomerular disease is different. Glomerular disease is more of a filtration problem rather than a failure to get rid of harmful toxins; in fact, glomerular disease is all about inappropriately losing protein through the kidneys. While it is certainly possible to have uremia without glomerular disease and glomerular disease without uremia, in many cases glomerular disease seems to be a situation that can progress to uremia.
What is a Glomerulus Anyway?
The glomerulus is the microscopic kidney area that separates urine from blood. Blood comes in the afferent arteriole, is filtered in a tuft of capillaries, and then exits through the efferent arteriole. The fluid that has been separated out is channeled into the tubules of the nephron for further treatment. Let us emphasize that the filtration membranes are delicate.
With glomerular disease, holes are punched out in this filtration system, which allow large molecules (like the proteins that your body needs to keep) to enter the urine flow and be urinated away into oblivion.
How does the Glomerulus get Leaky?
Sources of chronic inflammation are believed to be the ultimate cause of the problem. The chronic inflammatory state leads to the circulation of antigen:antibody complexes in the blood and these complexes stick in the delicate glomerular membranes like flies on fly paper. Once stuck there, they call in other inflammatory cells, and soon a hole is eaten into the membrane by the ensuing reaction. The holes in the filtration membranes are big enough for proteins to traverse.
There are many possible sources of chronic inflammation that could be generating antigen:antibody complexes. Chronic ear or skin infections could be the cause. Long-standing dental disease could do it. A latent more internal infection might be the cause (such as heartworm, feline infectious peritonitis, prostate infection, or Ehrlichiosis). Even a tumor might generate enough of the immune system’s attention to lead to this sort of reaction.
Kidney failure is one thing but when it is compounded by glomerular protein loss,
survival is substantially reduced and prognosis is much worse.
How is the Diagnosis Made?
There are several common scenarios that might lead to the diagnosis of glomerular disease.
Protein found in a Routine Urinalysis
A urinalysis examines a urine sample for some of its chemical contents and properties. Protein content is one of the parameters checked and found to have a small, medium or large amount. On a urinalysis report this will be designated as “+,” “++,” or “+++.”
This seems like it would be easy enough to interpret but unfortunately there is more to the story. A small amount of protein in a well-concentrated sample may be normal while the same amount of protein a dilute (reduced concentration) sample would be highly significant. How dilute or concentrated the urine is depends on the patient’s water consumption. We need a method to examine urine protein that is independent of the patient’s water consumption.
To complicate matters, protein in urine may result from inflammation or infection in the urinary bladder (or even blood contamination of the sample) and not be related to the kidney at all. To determine what is going on, there are two tests that your veterinarian may discuss:
- Urine culture
- Urine protein:creatinine ratio
The urine culture should find any latent infections (infection and its associated inflammation easily increases protein in the bladder). The urine protein:creatinine ratio quantifies the amount of protein loss in a way that is not dependent on the patient’s water consumption. It is helpful to do the culture first as a bladder infection will elevate the urine protein:creatinine ratio well into the abnormal range and lead to the wrong diagnosis if infection is not ruled out.
If the urine sediment is active, meaning there are inflammatory cells in the sample, then the patient most likely has infection and the urine should be cultured. If the urine is dilute from the patient’s excess water consumption, it may be wise to culture the urine to rule out a more latent infection.
Alternatively, if the sediment is not active (especially if the sample is not also dilute), a recheck urine sample in a couple of weeks to see if the urine protein is persisting might also be a fair idea. If there is still protein in the urine 2 to 4 weeks later, further tests are definitely in order.
Screening for Protein Loss after Diagnosing Kidney Failure
After kidney failure has been discovered, if urine testing has not yet been done, performing urine tests can lead to important additional information. Again we come to the same two tests:
- Urine culture
- Urine protein:creatinine ratio
In the kidney failure patient, urine is generally dilute because kidney failure includes inability to concentrate urine and conserve water. This means that clues that there is an infection (visible bacteria, white blood cells etc.) will be diluted out. The only way to find a latent infection is to culture the sample. If a pet has both an infection and kidney failure, there is a good chance that the infection is inside the kidney. This means the antibiotic course must be much longer (4-6 weeks) than it would be for a simple bladder infection. It also means there may be potential for the kidney to heal with time and for function to be regained. Prognosis improves with documented infection.
On the other hand, glomerular disease accompanying kidney failure is very bad news. The kidney insufficiency is likely to progress much faster when the urine protein:creatinine ratio is abnormal.
Low Blood Albumin Level found on a Blood Panel
Albumin is one of those proteins that the body really wants to conserve. There are plenty of substances the body needs to circulate that are not water soluble, which means they will not simply dissolve in the bloodstream and be pumped around by the heart. Substances that will not dissolve in water bind to albumin, and the albumin carries them around like passengers on a subway train. Albumin also is important in keeping water in the bloodstream. This sounds odd but blood is a liquid and without enough water in it, it sludges and clots abnormally. Furthermore, if water is not held in the blood vessels, it leaks into other body cavities such as the chest and abdomen, and fills these cavities with liquid.
There are very few ways that albumin can be depleted.
- When an inflammatory process occurs and globulin levels rise due to antibody production, albumin levels will drop so that the overall blood protein level does not get too high. This is normal compensation and should not lead to a dangerously low albumin level.
- Albumin can be lost from the intestinal tract in diseases called protein-losing enteropathies. These conditions tend to lose albumin as well as other blood proteins through GI tract leakage.
- Albumin is a product of the liver. If the liver fails, there may not be adequate albumin produced.
- Albumin can be lost through the holes in the kidney membranes caused by glomerular disease. Fairly advanced glomerular disease is required to produce a drop in blood albumin. One would need to beware of nephrotic syndrome (see below) and treatment would be needed.(Note that a ratio is one number divided by another. If the ratio is 2:1, the laboratory will say it is 2.0.)
- Urine protein:creatinine ratio of <1.0 in a stable animal with normal kidney function tests (normal blood creatinine) can be periodically monitored.
- A urine protein:creatinine ratio of 1-2 warrants investigation into a possible underlying cause.
- A urine protein:creatinine ratio >2 warrants not only investigation but also intervention.The International Renal Interest Society classifies the urine protein:creatinine ratio a little differently for animals that are azotemic (have an elevated blood creatinine level):• Ratios <0.2 are considered normal• Ratios of 0.2-0.5 in dogs and 0.2-0.4 in cats are considered borderline proteinuric and warrant a test 2 months later to see if the condition is progressing.• Ratios >0.5 in dogs and >0.4 in cats are considered proteinuric and require intervention.
A biopsy of the kidney is needed to confirm the diagnosis of glomerulonephritis and further classify the glomerular inflammation. This is an invasive and potentially risky procedure and recently the usefulness of the information gleaned from biopsy has been questioned.
It is much more practical to monitor the urine protein:creatinine ratio though this is not as easy as it sounds, either. You need to get an idea of the baseline urine protein:creatinine ratio, which means that at least a couple of samples should be checked. (The International Renal Interest Society recommends running the ratio on three samples over a 2-week period.) After this, how often the ratio should be rechecked depends on how the patient is doing and how the serum creatinine level is doing.
The urine protein:creatinine ratio varies by up to 30% above or below
baseline as a matter of course. A significant change in the ratio caused by
disease progression (up) or response to therapy (down) must be greater than 30%.
If Intervention is Recommended what does that Mean?
There are several aspects to treatment and some or all of them may be instituted depending on the needs of the patient.
Low Protein, Low Sodium Diet
Most commercial renal diets would fit in this category. It seems paradoxical that a disease that causes body protein to be lost would be treated with a protein-restricted diet, but in fact supplementing protein causes albumin to drop faster.
These medications have been shown to reduce renal protein loss. Typically enalapril is recommended for dogs and benazepril for cats. These medications reduce blood flow to the kidneys, so care must be taken in patients with elevated creatinine ratios to be sure the uremia does not worsen. Lower doses are used and monitoring becomes more important.
Asprin in low doses can be used to reduce the tendency for blood to clot by inactivating blood platelets. Again, it is important to use low doses so as not to disturb the kidney’s circulation by disrupting the prostaglandin balance, which could happen with anti-inflammatory doses of aspirin typically used for pain. In patients for whom nephrotic syndrome is a concern (see below) one definitely needs to be concerned about increased blood clotting tendency.
Omega 3 Fatty Acid Supplementation
Most commercial kidney diets are fortified with omega 3 fatty acids. These anti-inflammatory fats have been shown to improve survival of dogs with renal disease. It is unclear how helpful they are for cats but studies are ongoing.
In severe cases of glomerular disease, a complication called nephrotic syndrome can result due to the extreme urinary protein loss. Patients with nephrotic syndrome develop:
- High blood pressure
- Tendency to form abnormal blood clots
- Edema (swelling) especially of the legs and potentially fluid accumulation in a body cavity.
Nephrotic syndrome is defined as the combination of: significant protein loss in urine; low serum albumin; edema or other abnormal fluid accumulation; and elevated blood cholesterol level. This complication is severe and suggests a poor prognosis, especially if creatinine levels are elevated in the blood. Diuretics may be needed to supplement the other treatments listed above.
Renal Amyloidosis: The Other Glomerular Disease
There is an additional glomerular disease that bears mentioning and this is renal amyloidosis. Here instead of antigen:antibody complexes damaging the tender glomerular membranes, an abnormal protein called amyloid is deposited in the kidney. This condition is far less treatable and more rapidly progressive.
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