Glomerulonephritis

(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 as 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 represents more of a filtration problem rather than a failure to excrete harmful toxins; in fact, glomerular disease is all about losing protein inappropriately 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 represent a situation that can progress to uremia.

WHAT IS A GLOMERULUS ANYWAY?

nephron

This illustration shows the “nephron” which is the functional unit of the kidney. The kidneys have thousands upon thousands of these and they serve to filter the blood, add in toxins to get rid of, and balance the blood’s electrolytes and pH by adding and subtracting salts. The round tuft-like structure at the head of the nephron is the “glomerulus,” where blood is filtered.

The delicate membranes of the glomerulus, allow salts and very small molecules to pass through while cells and large molecules (like proteins) stay in the blood. Later areas in the nephron balance the salts and small molecules to make sure we keep and dump them in appropriate amounts but the glomerulus is the filter that allows our body’s blood proteins to be conserved. Let’s take a closer look:

glomerulus drawing

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 filteration membranes are very delicate.

When glomerular disease exists, holes are punched out in this filtration system allowing large molecules (like the proteins that one’s 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 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, 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 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.

    cushings2

    To complicate matters more, protein in urine may be a reflection of 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 culture of the urine 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 culture should be pursued. If the urine is dilute from the patient’s excess water consumption, it may be prudent to culture the urine to rule out a more latent infection. Alternatively, if the sediment is not “active” (and 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 2-4 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 a 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 very dilute because failure includes inability to concentrate urine/conserve water. This means that urinalysis clues that infection is present (visible bacteria, white blood cells etc.) will be diluted out. The only way to find a latent infection is to culture the sample. If infection and kidney failure are present together, 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 thus 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 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.

  • When an inflammatory process occurs and globulin levels rise due to antibody production, albumin levels will drop in compensation 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 an actual drop in blood albumin. One would need to beware of “nephrotic syndrome” (see below) and treatment would be needed.

 

  • 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
    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 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 absolutely confirm the diagnosis of glomerulonephritis and classify the glomerular inflammation further. 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. One needs 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 3 samples over a two 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.

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.

Aspirin

    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.

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.

NEPHROTIC SYNDROME

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 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 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. We hope to have a supplemental section on this special situation in the near future.

Page last updated: 7/17/10