(Urinary Protein Loss Due to Kidney Inflammation)
When a patient, human or non-human, is said to have “kidney failure,” “renal insufficiency” or even “chronic renal failure,” what most people are talking about is a toxin build up when the kidney cannot adequately remove the body’s harmful wastes. This toxic state is called “uremia” and is associated with nausea, appetite loss, weight loss, listlessness and other unpleasant issues.
Glomerular disease is a completely different kind of kidney disease and may not involve any toxin build up at all. Glomerular disease is a disease of protein loss.
This depiction of a nephron shows a glomerulus and blood vessels
(original graphic by marvistavet.com)
The illustration above shows the “nephron” which is the functional unit of the kidney. Basically the nephron starts with a bulb called a “glomerulus” where blood is filtered. The cells and proteins stay on the blood side of the filtration membrane but water, toxins, and salts enter a complicated tubular system where urine is made and blood pH and electrolyte levels are balanced. Our discussion centers on the glomerulus at the top of the nephron so let’s take a closer look:
In this illustration the “blood side” of the filtration system is shown in red while the “urine side” is shown in yellow. Blood enters the glomerulus through the “afferent arteriole” and exits through the “efferent arteriole.” The tuft of capillaries in between is surrounded by cells called “podocytes” which grasp the capillaries with numerous fingers ironically called “foot processes.” These fingers have slits in between them through which the filtered fluid travels. Filtration is driven both by blood pressure as well as by the protein content of the blood.
Blood proteins are too large to pass through the slits and that is a good thing because proteins are important assets to the body and are complicated to make. Protein is conserved whenever possible.
In glomerular disease, holes are punched in the filtration system allowing proteins to pass into the filtered fluid. The tubular cells below are able to reabsorb some of the proteins but for the most part, the body’s precious blood proteins are urinated away into oblivion.
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 delicate glomerular membranes like flies in 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 are many possible sources of chronic inflammation which 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, Lyme disease, prostate infection, or Ehrlichiosis). Even a tumor might generate enough of the immune system’s attention to lead to this sort of reaction. If it is at all possible to identify and resolve the underlying cause of inflammation, this should be accomplished as other therapy is unlikely to fully resolve the protein loss.
Kidney failure is one thing but when it is compounded by glomerular protein loss,
survival is substantially reduced and prognosis is much worse.
There are several common scenarios that might lead to the diagnosis of glomerular disease but they all boil down to one (or both) of two findings: excess urine protein found on a routine urinalysis and/or low albumin found on a blood test.
Let’s start with excess urine protein found on a routine urinalysis
A urinalysis examines a urine sample for some of its chemical contents and properties. Protein content is one of the parameters that is checked and semi-quantified in 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 very normal while the same amount of protein a dilute sample would be highly significant. How dilute or concentrated the urine is depends on the patient’s water consumption and we need a method to examine urine protein that is independent of the patient’s water consumption. The test that is used to quantify urinary protein loss is called a Urine Protein:Creatinine Ratio. This test is often added after a urine sample has been found to have more protein than expected. It should be noted that urinary tract infection is associated with excess urine protein and this generally does not involve kidney disease. If bacteria or white blood cells are noted on the routine urinalysis, then most likely infection is responsible for the presence of urinary protein and this would be pursued instead of the urine protein:creatinine ratio.
(original graphic by marvistavet.com)
If the urine protein:creatinine ratio is found to be abnormal, ideally it is repeated in 2-4 weeks to be sure that the protein loss is persistent but this depends on how high the ratio is and whether or not there is a known inflammatory condition that would be expected to damage the glomeruli.
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 simply 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 basically a liquid and without enough water it sludges and clots abnormally. Further, if water is not held in the vasculature, it leaks into other body cavities such as the chest and abdomen, filling these cavities with liquid.
There are very few ways that albumin can be depleted and the easiest to pursue is glomerular disease. Fairly advanced glomerular disease is required to produce an actual drop in blood albumin but when one sees a low albumin level on a blood report, the next steep is to quickly check the urinalysis to see if there is a "negative" in the protein column or if there is a +1, +2, +3, or +4. If there is no protein in the urine, then other diseases that cause low blood albumin can be explored. If there is a positive protein level at all, the urine protein:creatinine ratio can be added next.
Interpretation of the Urine Protein:Creatinine ratio
As we have said, the urine protein:creatinine ratio allows for a quantitation of urine protein loss so that urine samples can be compared. Interpretation of the ratio depends on whether or not the patient has renal insufficiency/kidney failure/toxin build up or if the kidney function is normal. For patients with normal kidney function, the following guidelines are employed:
- Urine protein:creatinine ratio of <1.0 in a stable animal with normal kidney function
tests (normal blood creatinine) can simply be periodically monitored.
- A urine protein:creatinine ratio of 1-2 warrants investigation into a possible
- 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
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%.
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 is recommended for cats. These medications inherently 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.
Aspirin in very 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). Patients where nephrotic syndrome is a concern (see below) would definitely need to be concerned about increased blood clotting tendency; in fact, if the blood albumin level is <2.0 aspirin is definitely indicated. This is because the proteins that keep blood clotting tendency in the normal range are lost in the urine leaving the patient with proteins that promote clotting. In patients that have already experienced abnormal clotting or embolism, medications stronger than aspirin may be needed.
Omega 3 Fatty Acid Supplementation
Most commercial renal 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 still unclear how helpful they are for cats but studies are ongoing.
Angiotensin II Receptor Blockers (ARB's)
Angiotensin II Receptor Blockers are becoming more popular in human medicine and their use is trickling down to the management of canine glomerular disease. These medications work with ACE Inhibitors to further help reduce urinary protein loss though they can also be used alone. Like the ACE inhibitors they not only reduce urine protein loss but also lower blood pressure as well and seem to have some effect on reducing the clotting tendency. They are new to veterinary medicine and protocols are still being worked out.
Aldosterone is the hormone that acts on the kidney to retain sodium and water and get rid of potassium. Spironolactone is an antagonist of this hormone which means it increases urine production, causes some retention of potassium and removal of sodium. In humans, it has been found to reduce urine protein loss by 34% which makes it an attractive medication for this situation especially in patients with nephrotic syndrome (see below).
The goal in the management of urine protein loss is a 50% reduction in urine protein:creatinine ratio for dogs and a 90% reduction in urine protein:creatinine ratio for cats. A combination of the above medications is likely to be prescribed and urine monitoring will be periodically recommended in hope of achieving and finally maintaining these results.
In severe cases of glomerular disease, a complication called “Nephrotic Syndrome” can result due to the extreme urinary protein loss. Nephrotic syndrome is defined as the combination of 1) significant protein loss in urine 2) low serum albumin 3) edema or other abnormal fluid accumulation 4) elevated blood cholesterol level. This is a severe complication of glomerular disease and suggests a poor prognosis especially if creatinine levels are elevated in the blood. High blood pressure is a common complication of nephrotic syndrome. Patients also tend to form inappropriate blood clots (embolism) which can lodge in small blood vessels causing loss of circulation to entire organs or sections of organs. Nephrotic syndrome represents an advanced state of urinary protein loss and must be treated aggressively
There are pros and cons to this relatively invasive test. The kidney receives 25% of the blood supply at any given time which means it is highly vascularized and can bleed in an extreme way. Blood transfusion is needed for 10% of dogs and 17% of cats having this procedure and a 3% mortality rate has been reported. So why take the chance on this procedure? The main reason is to obtain information on prognosis. There are different types of glomerular disease and different types of glomerular inflammation all of which may have different associated expectations. There is a special type of glomerular disease called "amyloidosis" which involves abnormal protein (called "amyloid") infiltrating the kidneys and has a much more progressive and damaging course. Approximately, 50% of glomerular disease patients have diseases that can benefit from immune-suppressive therapy but the only way to identify these patients is with biopsy. Depending on how your pet responds to the therapies reviewed above, biopsy may be recommended.
When the kidney cannot retain blood proteins, the body loses its ability to carry out normal blood functions. In an attempt to replace these proteins, muscle is broken down and the patient becomes debilitated. Maintaining proper nutrition and using medication to palliate the protein loss are crucial to the management of this form of kidney disease. It is important for the pet owner to keep up the monitoring schedule and to stay in contact with the veterinarian as to the pet's progress and response to therapy.
Page last updated: 8/14/2014