Red blood cells are basically little microscopic bags of hemoglobin. They have no nucleus and thus no DNA. They have no internal structures and thus no ability to perform complicated metabolism. Despite their simplicity, their function is crucial: they carry hemoglobin, the iron-containing complex protein that allows for oxygen transport to the tissues, as well as carbon dioxide transport to the lung for removal. Inadequate red blood cell quantity means inadequate hemoglobin, which means inadequate oxygen delivery. In the whole patient, this translates to lack of energy, poor appetite, and pallor - basically an important reduction in life quality.
There are two important ways in which the kidney patient loses red blood cells. The first way is bone marrow suppression. The second way is bleeding. We will review both of these as well as hemodilution and what can be done about them. Maintaining a stable red blood cell quantity keeps the patient energetic and spirited and is crucial to staying alive.
Bone Marrow Suppression
Red Blood Cells
Red blood cells are basically small bags of hemoglobin.
Photo by NIH image libary, Drs. Noguchi, Rodgers, and Schechter of NIDDK
One of the functions of the kidney is the production of the hormone called erythropoietin (pronounced “urithro-po-eetin”). This hormone, often simply referred to as Epo, represents the command to the bone marrow to make more red blood cells. When the kidney is damaged, its ability to produce erythropoietin is compromised. Red cells are still produced but over time the red cell count drops.
A simple measurement of red blood cell count is called the packed cell volume or PCV. The packed cell volume is an expression of the percentage of the blood’s volume which is taken up by red blood cells. It can be measured using only a drop or two of blood and can be done while you wait in any veterinary office. The sample is spun in a machine called a centrifuge to separate the red cells, white cells, and serum. The blood tube is then read against a chart to get the packed cell volume. Alternatively, hematocrit or HCT can be evaluated by measuring the amount of hemoglobin in the sample using a blood analyzer. Both measurements are common in most small animal hospitals and testing can be done while you wait.
Practically speaking, PCV and hematocrit measure the same thing.
Blood sample in a PCV tube being read against a chart. This patient is not anemic. Photo by MarVistaVet
||37 - 55%
||43.3 - 59.3%
||24 - 45%
||29.3 - 49.8%
In renal patients, weakness becomes evident in dogs and cats when the packed cell volume drops below 20.
What Can we Do?
Thanks to genetic engineering, human erythropoietin is commercially available in an injectable form. This means that the hormone that the kidney has failed to make is replaced with injections. Injections are given three times a week at first but when the patient is more stable they can be backed off to twice or even once a week.
- The injections can easily be given at home.
- Treatment with erythropoietin injections is generally extremely effective as normal red blood cell counts are usually achieved within 4 weeks.
- An iron supplement must be given simultaneously so that the bone marrow will have the building blocks necessary to make red blood cells.
- Packed cell volume (or hematocrit) should be monitored weekly until the patient stabilizes, so at first the patient will need frequent veterinary visits. If this monitoring is skipped, it is easy for the red cell count to become too high, thickening the blood and causing high blood pressure, which in turn creates more kidney damage in addition to other problems.
- Cost of treatment is reasonable for small pets such as cats and smaller dogs but could be prohibitive for even a medium-sized dog.
- Because the product used is a human origin protein, it can induce a cat or dog to generate antibodies against it. When the immune system is stimulated in this way, it not only attacks the human erythropoietin but also the patient’s own erythropoietin, creating a severe anemia. If this happens, transfusions may be needed to manage the anemia. When the Epo injections stop, eventually the antibody production stops and the anemia resolves somewhat but Epo cannot be used in this patient again and periodic transfusions become the only means of managing anemia.
How often does this happen? In a presentation by Dr. Sheri Ross at the 2006 meeting of the American College of Veterinary Internal Medicine, she noted that in one study of dogs and cats with naturally occurring kidney failure, two of three dogs treated with erythropoietin for greater than 90 days and five of seven cats treated for greater than 180 days developed refractory anemia that was attributed to anti-erythropoietin antibodies. A clinically significant immunologic reaction to erythropoietin has been reported to occur in 20-70 percent of treated veterinary patients. A more commonly published statistic is that antibody production is a problem in 30-40 percent of pets using human erythropoietin but this complication poses a sobering thought. It is important not to use this hormone at the first sign of anemia but wait until it is really and truly needed.
Is Darbepoetin better than Erythropoietin?
Darbepoetin is a synthetic hormone meant to improve on the natural hormone, erythropoietin. The synthetic version lasts longer so is typically only used weekly. Less frequent use makes the product less likely to create the antibody problem described above. The cost of darbepoetin is substantially higher than for erythropoetin but ends up being similar given that darbepoeitin is used less frequency (i.e. the bottle costs much more but it lasts much longer). It appears that the changes made in the amino acid sequence have made darbepoetin less likely to generate anti-erythropoietin antibodies but in a patient that is already having a problem with antibodies, darbepoetin is close enough to Epo to be inactivated as well.
Why doesn't darbepoetin have the same problem with antibodies as human erythropoietin? For one thing, darbepoetin is used much less frequently so immunological exposure to the non-feline protein is reduced. For another, it appears that the changes in the amino acid sequence have made darbepoetin less likely to generate anti-erythropoietin antibodies. Still, in a patient that is already having issues with antibodies, darbepoetin is likely close enough to be inactivated as well.
Read more information on erythropoietin.
The calcium-phosphorus imbalance that goes with renal disease is reviewed elsewhere in this center but the bottom line is that the excess blood phosphorus that results in renal insufficiency leads to demineralization of bone and mineral deposits in soft tissues. Mineralization is inflammatory and, when it occurs in the GI tract, it leads to bleeding, ulceration, and pain. The renal patient cannot afford appetite loss, nausea or further blood loss so treatment is needed while other efforts are made to control phosphorus levels.
Beyond the phosphorus level, another problem is a hormone called gastrin. Gastrin is a hormone involved in food digestion and is a stimulus for the stomach to release acid. Normally, when the need for gastrin has passed, the kidney removes it from the circulation but in the kidney patient gastrin is not efficiently removed. The prolonged presence of gastrin also prolongs the stomach’s secretion of acid, which can lead to ulceration.
How do we Know there is Stomach/Intestinal Ulceration?
There are several clues in the lab work and in the patient’s physical appearance that tell us that additional therapy is needed to control this kind of blood loss.
- Horrendous inflammation in the mouth (odor, bloody or purulent drool, sticky discharge on the lips and chin) includes ulceration. When ulceration in the mouth is this bad, we can assume similar erosion is occurring deeper in the tract.
- A blood urea nitrogen (BUN) level that is more elevated than the creatinine is a sign of GI bleeding. The BUN partly depends on dietary protein. Bleeding into the GI tract provides the intestine with blood to digest and the BUN rises further. Some laboratories include a BUN:creatinine ratio to highlight this phenomenon (a ratio greater than 20 suggests intestinal bleeding).
- Uncontrolled phosphorus in and of itself suggests mineralization in the GI tract.
What Can we Do?
Medications for nausea and appetite stimulation can be used. The most important treatment, of course, is going to be control of the phosphorus level. Other treatments include the following:
When the mouth is purulent, there is probably secondary infection and antibiotics can help clear it. Antiseptic mouthwashes may also be of benefit.
Reducing stomach acid helps reduce pain and bleeding when the GI lining is ulcerated (at least in the stomach). At present there is no evidence that using antacids in IRIS stages 1-3 is beneficial, but it is really the more advanced stages where this becomes relevant.
Sucralfate is an oral medication that forms gentle webbing that is effectively a bandage over the ulcers, protecting them from further irritation.
Pets coming to the veterinarian in Stage IV or late Stage III kidney failure are often dehydrated. A typical scenario is a pet that had been drinking lots of water and eating fairly well who suddenly stops eating and is listless. Possibly it is even noticeable that the pet has lost weight (though this is often erroneously attributed to age). The owner waits a day or two to see if the pet will start eating again and get better on his own and when that does not happen, he is brought to the veterinarian. Once the diagnosis of kidney failure is made, fluid therapy will be recommended, possibly fairly aggressively to drive the toxin levels down quickly. When blood tests are rechecked, anemia that was not originally present may be apparent or an existing anemia may be worse.
This is not a big problem if the patient is not particularly anemic to begin with, but if the patient is already low on red blood cells or if fluid therapy is aggressive, by the end of hospitalization, or even in the middle of it, the patient may be feeling the low red cell count.
Are the fluids making the patient anemic? No. The patient is just as anemic as he was prior to fluid therapy but without dehydration, the true red blood cell count is revealed. Hemodilution does not create anemia so much as it unmasks anemia.
What Can be Done?
What we do not want to do is withhold fluids from a dehydrated patient. The first step in restoring or at least maximizing kidney function is to get the kidneys the blood supply they need and that means no dehydration can be permitted. If the patient is significantly anemic, either before or after rehydration, then they may need a blood transfusion to get their red cell count back to a more livable level quickly. Restoration and maintenance of the red cell count is part of the art of managing renal disease.