CANINE HEALTH ONLINE Q & A DR. MERYL LITTMAN

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1 Littman, Meryl. Canine Health Online Q & A (March 2003) : The transcript of a question and answer session with Dr. Littman from the AKCCHFOnline program. She addresses questions about Fecal API tests, kidney infection, diet, hindquarter weakness in PLN-affected dogs, Heska ERD tests, and the status of her DNA research project for Wheaten Terriers. Fecal API test, PLN, ERD test, Laboratory Tests, Nutrition, DNA, Kidney disease CANINE HEALTH ONLINE Q & A DR. MERYL LITTMAN Reprinted with permission from Canine Health Online, a program of the AKC Canine Health Foundation sponsored by the Nestle Purina Company. To participate in this free online forum, visit or start at the Foundation home page, Please explain the inconsistent results of the Fecal API tests. How is it possible to have 1 or 2 days test results in the normal range and another day over the normal range? Is it worse to have 2 days above the normal range than to have one day? Are there degrees of severity in the abovenormal numbers? How is a breeder to evaluate the results? Should a dog that has tested 1 day (or 2 days) above normal be taken out of the breeding program? The criteria for PLE include low serum albumin and low serum globulin. These proteins are lost into the stool (feces) because of a permeability change in the intestine. The permeability change may be functional, without obvious morphologic changes under the microscope, or they may ultimately be seen on biopsy samples as inflammatory bowel disease, lymphangiectasia, or lymphangitis. Even before the serum proteins drop, a very sensitive test on the feces (fecal API) may show that there is a permeability change in the gut, allowing for leakage of the blood protein API. This protein is about the size of albumin and leaks wherever albumin leaks. Since albumin gets digested in the intestine just like other proteins in the diet, we can t test for the amount of albumin in the stool. But since API is a protease inhibitor, it doesn t get digested as readily, and we can test for it in the feces. The hope was that the fecal API test would be the earliest warning of future PLE. However, as you said, sometimes we have more questions than answers. The fecal API test is very sensitive (but not specific for PLE), and can be elevated by various things such as parasites (intestinal worm infestation), ulcerations, gastrointestinal inflammation or infection, as well as food allergy, inflammatory bowel disease, and PLE. There is some variation in fecal protein loss daily. Three tests are done to help show how consistently protein is getting lost, and what the highest value is. At NCSU, Dr. Shelly Vaden is studying a colony with a very high incidence of PLE/PLN. In that family, the puppies with mean or maximum fecal API of greater than 15 ug/g eventually showed PLE more often than the puppies with lower abnormal fecal API results. Although the fecal API testing appeared to be helpful in testing younger dogs (and not older dogs) in that family, we are still gathering information on a wider number of dogs in other families where the onset of PLE/PLN might be delayed or more variable. Currently, we are looking at fecal API test results annually throughout the life of our informative family members. All in all, I still think the fecal API test is very useful, and recommend it for all Wheatens. As we do more testing and gain experience, we will be able to interpret more wisely. The fecal API testing is done at Texas A&M and veterinarians may call there and consult with specialist Drs. David Williams and Jorg Steiner to help interpret the test results. Although the fecal API and MA testing are the earliest warning tests we have for PLE and PLN, respectively, I think that people should remember that the tests are sensitive but not specific. Either test can be elevated due to other things besides PLE or PLN. So they need to be interpreted carefully by the vet and consultant. For instance, this partial list (not in a particular order) might be of interest: Examples of causes for fecal API elevation: parasites (intestinal worm infestation) gastrointestinal ulceration oral ingestion of blood (e.g, nosebleed, bleeding gums) gastrointestinal inflammation or infection

2 food allergy inflammatory bowel disease gastrointestinal neoplasia PLE carrier state (as seen in siblings of Crohn's disease patients) Examples of causes for MA elevation: urinary tract infection urinary tract inflammation urinary tract neoplasia steroid use Cushing's disease phenylpropanolamine use hypertension fever hard exercise vaginal discharge tick-borne diseases neoplasia PLN It s a flip-of-the-coin in my opinion about whether to use a hypoallergenic diet in an asymptomatic dog with mildly elevated fecal API results. We really don t know if it s necessary. Realize that abnormal fecal API test results may be seen in normal relatives of affected animals. For instance, normal littermates of Irish Setter dogs with inherited gluten enteropathy may have abnormal fecal API test results, and also healthy human siblings of patients with Crohn s disease may have abnormal fecal API test results. By close monitoring, we need to learn whether the fecal API test results may reveal a carrier state that doesn t necessarily progress to full-fledged disease. Some breeders may want to adhere to a very strict standard of normal screening test results in an effort to avoid carriers in their lines. However, we may lose too many dogs that way, lose genetic diversity, and dogs with perhaps other good traits. I am not rigid on this point and leave the decision up to the individual breeder. It is frustrating, but at this time, since we do not completely understand the mode of inheritance of the traits, the influence of genes/environment, and because none of the screening tests we use are solid predictors of future health, I am at a loss as to how to answer that question. That is why the DNA bank and continued research is so important. If we find genetic markers, we hope to answer these questions with more confidence. Are there any preventative measures to prevent kidney infections? Does each kidney infection damage the kidneys even more? Kidney infections (pyelonephritis) in dogs usually sneak up on us and are not easily preventable. Infections might come to the kidneys via the blood stream (perhaps from infection from elsewhere in the body, such as dental disease), or may ascend from the bladder (cystitis) or prostate gland (prostatitis). Dogs with urinary stagnation, stones, and conformation or developmental problems of the urinary tract may be predisposed to urinary tract infection, and dogs immunosuppressed because of disease or medications (Cushing s, Diabetes, steroid or chemotherapy administration) may be predisposed to kidney infection. A kidney infection due to Leptospirosis (acquired from exposure to infected urine from wildlife) might be prevented by use of the new 4-serovars Leptospira vaccine, but not by the old 2-serovars vaccine. Kidney infections can be acute (with sudden signs of anorexia, lethargy, polyuria/polydipsia, vomiting, possibly fever, possibly kidney pain or arched back), or infection may be chronic, simmering, and occult, eventually causing chronic renal failure. If urinary tract infection is suspected, we obtain urine samples for urinalysis and urine culture and sensitivity with a fine needle into the bladder (cystocentesis) or with a catheter. We use antibiotics for kidney infections much longer (6 weeks) than we do for bladder infections (10 days) and then we want to be sure and monitor the urinalysis and urine cultures 1 or 2 weeks off the antibiotics and again a month later. Monitoring is important, and the culture results help us to understand if the same bacteria is cultured, we may not have treated long enough or with the right antibiotic, or if a different bacteria is cultured each time, there may be stagnation, mechanical, or immunosuppressive reasons underlying it.

3 Each kidney infection may damage the kidney in a transient or permanent way, depending on the severity of the infection and response to treatment. If not too much damage has been done, the kidney can heal well, and since the dog has plenty of renal reserve, we don t usually see problems such as renal failure until 75% of the kidney mass is lost. If damage leaves scar tissue (fibrosis), the kidneys become irregular and eventually shrunken. These changes can be seen by imaging studies (radiographs, ultrasound). If my Wheaten has several food intolerances (wheat, corn, soy, barley, chicken and turkey) what is the likelihood that he might develop PLE/PLN when he's older? He also has inhalant allergies, hip dysplasia and has had one bout of ear infections thus far. We know that dogs with PLE often have food allergies, but we don t know chicken or egg, in other words, whether the permeability change in the gut occurs as a primary problem, leading to food allergy, or whether the inflammation due to food allergy leads to the permeability change. There are no real studies about this but my impression is that yes, dogs with food allergies may be at a higher risk for PLE/PLN. Dogs with IBD (inflammatory bowel disease) are also probably at a higher risk, since this histopathologic change is seen in about 67% of the SCWT dogs with PLE. Time will tell whether a hypoallergenic diet for dogs with food allergies might prevent the onset of PLE/PLN. Close monitoring with the recommended screening tests are important. If your dog has abnormal fecal API test results on one diet, I would change to a more hypoallergenic diet (usually a hydrolysate diet such as Hill s Z/D Ultra, Purina s HA-CNM, or 3M s EXclude) and test again 2 months later on that diet. Normalization of the fecal API test results on the right diet (and/or medication) is hopefully associated with fewer clinical signs of food allergy (vomiting/diarrhea or pruritus/itchy skin). Sometimes dogs with food allergies need medications in addition to hypoallergenic diet, such as steroids (Prednisone), metronidazole (Flagyl), mast cell stabilizer (Cromolyn), azathioprine (Imuran), etc. Sometimes changing the bacterial flora of the gut with antibiotics (such as tylosin/tylan) is helpful. There is probably an inherited predisposition for hypersensitivity or immune dysregulation in Wheatens, in other words, the immune system is not working properly. The umbrella of these problems might encompass a variety of diseases, such as various types of allergies and/or immune-mediated diseases, such as lupus, IMHA (immune-mediated hemolytic anemia), myasthenia gravis, Addison s disease, etc. I believe that a genetic predisposition for hypersensitivity might be triggered by environmental exposure to certain allergens, maybe food, antigens from infections, inflammations, etc. Another possibility is that food allergies may not cause PLE/PLN, but since both problems are fairly common in the breed, and we have a small gene pool (most Wheatens here are related to the few dogs that were used as breeding stock in the s), we might often see food allergies and PLE/PLN together in the same dog or same family of dogs. What type of diet (not K-D vet diet) should be fed to a Wheaten with serious renal problems? Is weakness in the hindquarter related to PLE or PLN? By serious, I guess you mean severe renal failure? When dogs have moderate or severe renal failure, I usually want to feed them a low-protein, low-phosphorus diet. There are many of these available now, made by various companies. We need to look at each case individually to see if the dog should be on a moderate diet or a severely restricted diet, and also to decide whether a hypoallergenic diet is a good idea or not. There are no diets that I know of on the market that are both hypoallergenic as well as lowprotein/low-phosphorus. So I often recommend using a hypoallergenic diet and adding potatoes or rice to decrease the % protein content. Or we make up home-cooked recipes for the individual s needs with the help of our veterinary nutritionist. Other supplements/medications often given to dogs with renal failure include omega-3 fatty acids, phosphate binders (aluminum hydroxide), antihypertensives, anti-emetics, anti-ulcer medications, etc. If the renal failure is due to PLN, we want to use ACE (angiotensin-converting enzyme) inhibitors which have been shown to decrease the amount of protein lost in the urine, and a tiny dose of baby aspirin as an antithrombotic, to decrease the risk of thromboembolic events. Some dogs with renal failure need other medications, such as Doxycycline for Lyme nephropathy or Leptospirosis, or other antibiotics for pyelonephritis (kidney infection). Every case needs to be evaluated as an individual. Your question reminded me of an important point I d like to make here. Hind leg weakness in SCWT dogs may be related to orthopedic, neuromuscular, cardiac, or metabolic problems. But did you know that it could be associated with PLN? This is due to the hypercoagulable state in that condition, and a saddle thrombus (clot), which may form at the level of the bifurcation of the aorta, as it divides for the hind leg

4 circulation. The dogs have poor or absent femoral pulses. They may not be able to walk. The toes may be cold and the leg muscles may be stiff or painful. PLN is one of the few things associated with saddle thrombus in the dog, and the dog may not even be in renal failure yet (there may be normal serum creatinine and BUN). The urinalysis, urine protein/creatinine ratio, and the serum albumin test results will help in making the diagnosis. What is the difference between the Heska ERD test and urine protein/creatinine ratio and routine urinalysis? Is there one preferred for dogs and bitches who are going to be bred? The main differences are that the ERD test can be done quickly, in-house (in your vet s office), but it only gives an estimation when it is positive (low, medium, high positive). The ERD is sensitive, so if the reading is negative, I trust it. But if the ERD is positive at all (showing some protein), I would follow it up with the more exact test, the urine protein/creatinine ratio (Up/c), because although it needs to be sent out to a lab, it gives us better quantification of the amount of protein in that urine sample, based on the ratio with excreted creatinine. If the Up/c is abnormal, we can monitor it closely as we make adjustments with diet, medications, etc. Since I work at the University where I can get Up/c testing done immediately, I don t use the ERD test here. But I certainly see a place for it in local veterinary practices. For breeding animals, I prefer the more exact test, the Up/c. If an animal has a urogenital discharge, the protein content in a free catch sample may be higher than if the sample is taken by cystocentesis. A routine urinalysis should be interpreted along with the ERD or Up/c. A urinalysis tests for specific gravity, dipstick for protein, blood, sugar, etc, and the microscopic sediment examination shows cells, casts, crystals, etc. The dipstick square for protein, along with the sample s specific gravity, gives us the roughest estimate of whether the ERD or Up/c test might be abnormal. Protein in the urine may be due to inflammation or infection in the urinary tract, and if the sediment looks active or inflammatory, the Up/c or ERD should be repeated after the infection has been cleared and the sediment is quiet or inactive. What is the current status of your research project on DNA? Currently we have funding from the AKC-CHF for our project entitled: Longitudinal field studies of families of Soft-Coated Wheaten Terriers affected with protein-losing enteropathy (PLE) and/or proteinlosing nephropathy (PLN) and the foundation of a DNA bank. This study involves following the health status of members of certain informative families, including affected dogs as well as their healthy relatives (littermates, sire/dam, aunts/uncles, and grandparents). Their DNA is collected (blood or tissue) and their health is monitored annually throughout their lives by the screening tests we recommend for all Wheatens (complete blood count (CBC), biochemical profile (Chemscreen), urinalysis (U/A), urine protein/creatinine ratio (Up/c) and/or microalbuminuria (MA), and fecal alpha-1 protease inhibitor (fecal API) testing). We are currently funded for the first 2 years, but since there is no age limit for these diseases, the dogs will need to be followed closely all their lives, so we can match their phenotypes (health status) with their genotypes (DNA). By comparing the genes of sick dogs with those of healthy dogs, our goal is to find genetic markers for these terrible diseases. Even though your dog might not be a member of an informative family, we recommend the screening tests be done annually, with good record keeping. We also recommend DNA be saved and frozen if possible (puppy tails/dewclaws, neutered organs, 10 ml of blood in purple top tubes, or fresh-frozen tissue taken at necropsy). Breeders can help by keeping followup health records and current contact information of old and new owners, so that the health status of each dog can be known and so that its DNA (genotype) will be matched with its eventual health (phenotype). Although not predictive, the screening tests help identify affected animals as early as possible so that medications or special diets can be started, and hopefully help to prolong good quality life. Eventually, more information about the dog s phenotype is obtained from tissue samples after death (formalin-fixed kidney and small intestine), and necropsy is helpful to understand what kinds of illnesses affected the individual and the kinds of diseases to which the breed is predisposed. The DNA from healthy ancestors is very important for our DNA bank. Besides the representation of members of the informative families, we need representation from geriatric (14-16 yrs old) SCWT dogs who are documented to be free of PLE/PLN, based on the screening tests and necropsy. The Open Registry has been very helpful to us in identifying possible informative families, and seeing patterns in inheritance of various problems in the breed. Owners and breeders have been cooperating in sharing information with us, including pedigrees, medical records, and samples (blood, urine, feces, and

5 eventually, tissue samples). This truly is a team effort. We need the support of the breeders, or we won t get the information we need to help the breed. If you know of a Wheaten that has been diagnosed with PLE, PLN, inflammatory bowel disease, renal dysplasia/juvenile renal disease, renal failure, or Addison s disease, and is not already on the OR, please contact me so that we can keep the OR as complete and up-to-date as possible. Thank you all for helping with our studies and for sharing information openly with one another.