GLOMERULONEPHRITIS

(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. It is also not the kind of kidney disease we are going to be discussing on this page.

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 inappropriate urinary protein loss.

This depiction of a nephron shows a glomerulu and blood vessels (part of the nephron). The kidney has millionsof nephrons all doing the kidney's work. (original graphic by marvistavet.com)

WHAT IS A GLOMERULUS ANYWAY? Consider for a moment what an important resource protein is to your body. Your blood, for example, is full of very necessary circulating proteins handling clotting, fluid balance, transporting other chemicals etc. Your body went to a lot of trouble to build those proteins and you can't afford to waste them. If you were to lose them, your body would have to break down muscle in order to recreate them because that is how important they are. On the other hand, your blood carries an assortment of metabolic wastes that you need to get rid of. You need to filter out these bad materials without losing what is valuable. The glomeruli (you have millions of them) are in charge of keeping your blood proteins where they belong: in the blood, while allowing for smaller wastes and extra fluid to filter out and be made into urine. There are other "valuables" in your blood besides cells and protein but other areas of your kidney handle those. The illustration on the left shows the “nephron” which is the functional unit of the kidney. There are millions of these making urine every moment of every day. Only about 30% of them must be working in order to maintain normal kidney function; the rest form a "back up system" so that we will have plenty of extra nephrons should some of them get plugged with debris, damaged by scarring or infection, or starved for oxygen during a traumatic event.

The glomerulus, which in a way looks like a little dandelion tuft, is where our interest lies today. Blood flows through an "afferent arteriole" into the glomerulus. Inside the glomerular tuft, the blood vessel narrows into a complicated spiral of tiny capillaries, so small that the blood cells pass through single file. The capillaries are gripped by special cells called "podocytes." Like hands, the podocytes have tiny fingers (ironically called "foot processes") which encase the capillaries. Fluid and small molecules can flow in between the "fingers" while cells and large molecules (like proteins) cannot pass through.

The cells and large molecules/proteins exit the glomerulus through an "efferent arteriole" and return to normal circulation. This first step in filtration is driven both by blood pressure as well as by the protein content of the blood.

Now imagine what would happen if there were holes punched in that filtration system so that protein can pass through the "fingers". This is what happens in glomerular disease.

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 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 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.

HOW IS THE DIAGNOSIS MADE?

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 reported as 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. Further, we need to determine if any protein in the urine is truly coming from the kidneys; after all, a bladder infection or other bladder condition might generate urine protein. To help distinguish renal protein loss, the rest of the urinalysis will be helpful. When one is confident that other issues with the urinary tract have been excluded, it is time for a urine protein: creatinine ratio (we will come back to this).

Urine Dipstick test for urinary protein among other things. (Photocredit: J3D3 via Wikimedia Commons)

Low Blood Albumin Level found on a blood panel

(Photocredit: CDC Public Health Image Library)

Albumin is one of those proteins that the body really wants to conserve and here's why. There are plenty of substances the body needs to circulate that simply are not water soluble. How do we circulate these things if they won't dissolve in water? We bind them to a carrier protein that will circulate and carry them as if they were commuters on a city bus. The albumin molecule is that city bus, carrying important biochemicals around your body. There's more. 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.

Your body prioritizes the maintenance of its albumin levels and will not allow them to drop. When the albumin levels are down, a very serious protein loss is afoot. It could be intestinal or liver-related but glomerular protein loss is going to be one of the first conditions to rule out. If there is no protein in the urine, the focus shifts to other organs but if there is protein in the urine, it must be quantified and that means a urine protein: creatinine ratio.

Interpretation of the Urine Protein: Creatinine ratio

The urine protein: creatinine ratio compares the amount of protein in the urine to the amount of creatinine, one of the metabolic wastes filtered by the kidneys. By using this ratio, it does not matter how dilute the urine is or how concentrated it is. The ratio allows for protein loss to be quantified and then we can tell how significant the protein loss actually is. 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.

Determining how serious a patient's protein loss is depends on overall kidney function as well. In other words, a protein-losing kidney that is effectively removing the daily load of toxins and wastes is in less trouble than a protein-losing kidney that is failing.

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?

If it is at all possible, the inciting chronic inflammation source should be sought and addressed. Abdominal ultrasound, chest radiographs and specialized blood tests are typically employed. As for the glomerular protein loss itself, 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.

ACE inhibitor

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.

Omega 3 Fatty Acid Supplementation

Addition of omega 3 fatty acids to the regimen appears to improve the protein loss situation and supplementation is recommended. Most renal diets are already fortified with these anti-inflammatory fats but additional use is felt to be beneficial.

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. The two commonly used medications are losartan and telmisartan.

Spironolactone

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). In dogs it might be used when ACE inhibitors or ARB's have not controlled the proteinuria. It is not a medication for cats.

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 and blood test monitoring will be periodically (at least quarterly) recommended in hope of achieving and finally maintaining these results.

NEPHROTIC SYNDROME

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.

BIOPSY THE KIDNEY?

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. Biopsy is most commonly recommended for patients with UPC ratios >3.5 or with significant proteinuria combined with low albumin levels or high blood pressure.

Kidney biopsy showing an inflamed glomerular tuft. (Photocredit: Nephron via Wikimedia Commons)

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. 

This page is also part of the Chronic Renal Failure Center.
Other Pages in the Chronic Renal Failure Center:

• Kidney Failure: Where to Begin
• Fluid Therapy In Renal Insufficiency
• Dietary Therapy
• Appetite Management
• Renal Anemia/Red Blood Blood Cell Loss
• High Blood Pressure
• Calcium/Phosphorus Balance
• Glomerular Disease: Urinary Protein Loss (this page)
• Dialysis
• Kidney Transplants
• External Links for Further Information

 Page last updated:6/5/2022