• Dietary Protein
  • Amyloidosis
  • Inflammatory Bowel Disease
  • Mast Cell Cancer
  • Streptococcal Toxic Shock

Much progress has been made in clinical nutrition in the past decade especially in the area of nutrition in the kidney failure patient. This is still an area of controversy between clinicians and nutritionists, but research is providing more insight concerning the role of dietary protein in the management of the kidney failure patient. What I hope to do here is provide a digest of this current state of affairs and let you make your own decisions.

* There is a link between dietary protein levels and the clinical signs of kidney failure.
* Once dogs have developed signs of uremia such as decreased appetite, vomiting, depression, electrolyte changes, GI ulceration, increased BUN and creatinine and weight loss, then decreasing the protein content of the diet is indicated these signs. Decreasing the protein content of the diet prior to the onset of clinical signs does not affect the progression of kidney failure. The pathogenesis of kidney failure is not clear and the rate of progression is variable.
* We know that increasing the protein in the diet results in increased blood flow to the kidneys - this occurs in both healthy dogs and those with decreased kidney function.

* Increased levels of dietary protein do not seem to change the rate of progression of kidney failure. Protein levels in the diet do not seem to affect mortality, rate of progression of uremia or the development of kidney lesions.

* Decreased protein levels in the diet may impair immune responses, decrease hemo-globin levels, cause anemia, decrease total protein levels and result in muscle wasting.

* Phosphorus restriction is an important factor in management of dogs with kidney failure.

* 3/4 to 15/16 of the kidney mass must be lost before progression of kidney failure occurs.

* When protein restriction is initiated fat and carbohydrate levels must be increased to provide alternate energy sources.

Much of the research in kidney failure and diet have been done in rats, dogs who have had surgically induced kidney failure and geriatric dogs with progressive kidney failure due to age-related changes. Does this information pertain to dogs with amyloidosis, immune-mediated kidney diseases or inflammatory kidney diseases? Studies need to be done to address these scenarios. The information available can be used to formulate the following general guidelines:

* Feed a diet with a protein level which fits the dog's activity level. Couch potatoes on a high protein diet become obese leading to other problems.
* Dietary protein levels do not appear to be involved in the progression of renal disease or play a role in the prevention of kidney failure. However, I prefer to err on the conservative side. I think protein levels in the 20-24 % range are probably safe. Of course other factors enter in such as the protein source, the bioavailability of the protein, fat content, carbohydrate levels, etc. must be considered as well.
* When the BUN is greater than 75mg/dl and/or signs of uremia develop, moderate protein restriction is indicated to decrease the BUN and the clinical signs. Phosphorus restriction is also indicated at this time. This is most easily done with the available commercial kidney diets on the market.
* What this also means is that these dogs must be monitored closely to follow changes in the BUN and creatinine levels. My experience in Shar-Pei indicates that they show clinical signs of kidney failure very late in the course of the condition when their BUN and creatinine levels are extremely elevated. Often, Shar-Pei owners miss the very subtle early changes and present their dogs when it's too late.

Diet does not appear to play a major role in prevention of kidney disease in Shar-Pei at this time. I think avoiding substances and situations which result in kidney damage are preventative steps that can be taken. Certain drugs such as aminoglycoside antibiotics can cause kidney damage and should be avoided, when possible. Decreased kidney blood flow can lead to kidney damage emphasizing the importance of IV fluids administered during anesthetic procedures and use of monitoring equipment. Situations, which result in low blood flow to the kidneys such as heat stroke, bloat, and shock must also be avoided. Infectious diseases can also result in kidney damage. These include bacterial kidney disease, heartworm, leptospirosis, Lymes disease, etc. Toxins such as ethylene glycol (antifreeze) and arsenic can cause kidney damage as well. To a large extent we can prevent some of these things. The major emphasis has to be monitoring the dogs so the onset of kidney failure is uncovered early in the course of the disease when dietary manipulations may be useful.

Amyloidosis is the deposition of an abnormal substance called amyloid in the tissues of the body. These amyloid deposits are composed of protein fibrils formed by the polymerization of protein subunits forming a specific pattern called the beta-pleated sheet. The specific biophysical arrangement of this sheet gives the amyloid deposits their unique staining and optical properties. Due to this structure amyloid is insoluble and can be thought of as "wax". It is also important to realize that amyloidosis is not a single disease, but can be the end point of many diseases. The structure of amyloid also is responsible for the characteristic green color after staining with Congo red.

In Shar-Pei amyloidosis is a reactive amyloidosis. This form of systemic amyloidosis usually occurs with chronic inflammatory diseases and is characterized by the presence of amyloid protein AA. Amyloid protein AA is derived from an acute phase protein called serum amyloid A protein (SAA) produced by the liver. There are many other acute phase proteins produced by the liver which have important roles in the inflammatory process and in tissue repair after injury. It is important to understand that amyloid protein AA is a normal protein and that it's production is a normal response to tissue injury and inflammation. It is also important to realize that many diseases, traumatic injuries, cancer disorders, stresses, etc. can stimulate the production of the acute phase proteins. There appears to be a balance between the production of SAA and the degradation and excretion of SAA from the body. It is not known whether the development of amyloidosis in the Shar-Pei is due to prolonged excessive SAA production by the liver which overwhelms the degradation mechanisms or a defect in the degradation process itself, or a combination of both. We do know that Familial Shar-Pei Fever is an inflammatory process which does stimulate the synthesis and release of acute phase proteins from the liver. That this occurs can be surmised from the changes seen on the hemogram and biochemical profiles of Shar-Pei during, or shortly after, an FSF episode. It certainly appears that the cause of amyloidosis in Shar-Pei has a genetic basis.

Reactive amyloidosis results in extracellular deposition of amyloid protein in tissues. This means the "waxy" amyloid is surrounding the cells and slowly crushes them as well as interfering with nutrition of the cells. These cells die and the structures they make up are replaced by fibrous, nonfunctional scar tissue. There are species differences as to which tissues amyloid will accumulate in. In dogs, the kidney is the primary organ involved with the spleen and liver affected less often. The kidney is especially vulnerable due to its decreased ability to replace damaged cells and ultimately, when a certain number of cells have been irreparably damaged, kidney failure with its accompanying clinical signs develops. Once amyloid is deposited in the tissues it appears that nothing can remove it.

Why does amyloidosis have so many different clinical presentations? Why does it occur in some Shar-Pei at 2 years of age and in others at 10 years of age? Why do some Shar-Pei develop amyloidosis and others don't? Why is it a genetic disease in Shar-Pei? There are many questions which have no answers at this time. I think several theories are plausible to explain the variations we see:

1. The underlying basis of amyloidosis in Shar-Pei is Familial Shar-Pei Fever (FSF). It is quite possible that FSF has variable age of onset and variable degrees of severity in terms of the inflammatory disease it causes. This may result in a variable rate of progression in the development of amyloidosis in different individuals. For example, the response of the liver to FSF and the synthesis and release of the acute phase proteins, especially SAA, may be more acute in some dogs resulting in a more rapid deposition of amyloid. In other individuals, the response to FSF may be more chromic and result in slower deposition of amyloid. In effect, there may be milder forms and more severe forms of the same disease.
2. The exact mechanism of amyloid deposition may be different in different individuals.
3. There may be other effects of FSF on the body which are additive with the amyloidosis. As an example, we know Shar-Pei are more susceptible to disseminated intravascular coagulation (internal blood clotting) during an episode of FSF and blood clots in the kidneys may cause more kidney damage than just amyloid deposition itself.
4. Some dogs may have other disease processes going on which can be additive with the effects of amyloidosis.

These are just some ideas on why we see different presentations of the same disease. One fact remains - any amyloid deposits found in a Shar-Pei have to be regarded as related to FSF and genetic until proven otherwise. It really doesn't matter whether a little or a large amount of amyloid is found. Another point to keep in mind is that the mechanisms initiating amyloid deposition are normal protective responses seen in any breed of dog. It appears in our breed that the mechanisms, which regulate the inflammatory response, don't work properly allowing this normal response to go out of control and cause disease.

Inflammatory bowel disease is not so much a disease as it is a group of clinical signs related to a large number of underlying causes. The clinical signs primarily involve the gastrointestinal tract and can vary somewhat based on what part of the GI tract is affected. Vomiting is the primary sign if the stomach is affected. If the small bowel is affected the signs are related to a protein-losing enteropathy-diarrhea or loose stools, weight loss, loss of appetite, etc. If the large bowel (colon) is affected signs are related to colitis such as loose stools (cow-pie type), mucous and/or bloody stools, straining to defecate and increased frequency of defecation. The underlying pathology in IBD is infiltration of the gut wall by various types of inflammatory cells such as eosinophils, macrophages, lymphocytes and plasma cells. This infiltration causes thickening of the bowel wall which interferes with digestion of food and absorption of nutrients - malabsorption/maldigestion syndrome. ANY SHAR-PEI WITH A NONSPECIFIC ILLNESS SHOULD BE WORKED UP FOR IBD! Laboratory findings are nonspecific, but may include a low albumin and globulin due to intestinal loss of these proteins, mild anemia due to GI hemorrhage and electrolyte abnormalities due to chronic vomiting and diarrhea. Special testing such as B12/Folate levels may be useful. Fecal alpha-1 protease inhibitor is a new test which may prove useful in the diagnosis of IBD. The primary mode of diagnosis is intestinal biopsy which may be done via gastrointestinal endoscopy which is non-invasive or via exploratory laparotomy abdominal surgery. These procedures should be considered early in the course of the disease when the dog is the best anesthetic candidate. Waiting too long increases the risk. Bear in mind also that there is a 5-7 day delay in getting the biopsy results back. Therapy and prognosis does vary somewhat based on the type of IBD seen on the biopsy. Exploratory surgery also allows the veterinarian to rule-out other causes of GI disease and chronic illness such as cancer, bacterial or fungal disease, liver disease and intestinal foreign objects.

The cause of IBD in Shar-Pei is probably related to two breed predispositions - food allergy and IgA deficiency. Anywhere from 70 - 90% of Shar-Pei are deficient in IgA which is an immunoglobulin found in secretions in the GI tract, reproductive tract and the respiratory system. IgA has an important immune system function in these areas. It helps prevent infectious agents and antigens in the diet from crossing the lining of the gut. When antigens in the diet gain access to the gut wall an immune response is stimulated which eventually results in inflammation and damage to the gut wall. Allergic responses to substances in the diet can also elicit a severe inflammatory reaction. Other causes have yet to be elucidated.

Therapy of IBD involves the use of specific drugs and dietary management. Drug therapy consists of immunosuppressive therapy with prednisolone or other corticosteroid. These are used to decrease inflammation and suppress the immune response so healing can occur. Other drugs are often combined with corticosteroids because of a synergistic effect. Metronidazole is an antibiotic with immunostimulant properties. Sulfasalazine is often used for immune-mediated colitis as an anti-inflammatory medication. It is converted to aspirin in the colon. Sometimes other more potent chemotherapeutic agents are needed such as azathioprine. Dietary therapy is also extremely important. The use of novel protein sources is paramount as is the use of simple diets available through your veterinarian specifically formulated for use in IBD. They often use lamb, chicken, rabbit, duck, turkey or venison as their protein source. All natural diets are sometimes used as well. IBD should be one of the major considerations in any Shar-Pei with weight loss and normal laboratory findings.

The special GI functions tests described in this article are done at the Gastrointestinal Function Test Lab. The address is:

GI Lab
TAMU 4474
College Station, TX 77843-4474
Telephone: (979) 862-2861
e-mail: gilab@cvm.tamu.edu

MAST CELL CANCER seems to be a particularly aggressive and troublesome problem in the Shar-Pei breed. The following discussion hopefully will provide you with some useful information.

1. CAUSE: Mast cells are a number component of the body. These cells contain granules in their cytoplasm which contain heparin (an anticoagulant), serotonin (an inflammatory mediator), histamine, and a number of other substances. The release of these cytokines cause inflammation, itching, edema, and attract other cells to the area. This response is usually helpful in responding to allergic reactions, foreign objects, infection, etc. This also explains why mast cell tumors tend to be swollen, inflamed and itchy. Shar-Pei have a higher than normal population of mast cells in their subcutaneous tissue which may partially explain the frequency and aggressiveness of these tumors in our breed. Due to the increased mucin in the subcutaneous tissues of Shar-Pei spread of mast cells may occur more easily as well -- the mucin may also hinder the identification of the tumor margins and thus the complete surgical removal of mast cell tumors. There appears to be an inherited or genetic aspect to mast cell cancer as well as it appears more often in some lines of Shar-Pei. The ultimate cause of this type of cancer is unknown.

2. DIAGNOSIS: Any lump or bump on a Shar-Pei is suspicious. Mast cell tumors are often confused with histiocytoma, a benign tumor of the skin which also has a high incidence in the Shar-Pei. If the mass is large enough a fine-needle aspirate may be done to identify the mast cells. Often the tumor must be identified after it is removed. A particularly troublesome variation of mast cell tumor known as AGRANULAR SPINDELOID MAST CELL is seen in the Shar-Pei and is characterized by mast cells without granules. This is a very aggressive form of mast cell and can be confused with other tumor types. The most commonly used grading system for mast cell has a Grade 1 which indicates a well-differentiated mast cell type and is considered least malignant, Grade 2 which is an intermediate type and which I consider malignant in the Shar-Pei and a Grade 3 which is an undifferentiated type of mast cell and definitely considered malignant.

3. TREATMENT: Surgical removal of the tumor with wide normal margins is the current recommended treatment. Obviously the smaller the tumor the more easily this is accomplished. Location of the mass also determines how successful surgery will be. I often recommend referral to a veterinary oncologist (cancer specialist) or a veterinary cancer center. At the cancer center there is usually a group consisting of a veterinary surgeon, veterinary oncologist and often, radiation treatment facilities. The chemotherapeutic approach for mast cell cancer is not well worked out at this time and is an area of active research. Mast cells are radiation-sensitive and radiation therapy is often used as an adjunct to surgery. The Shar-Pei owner must decide early on how aggressive an approach they will seek. Local recurrence and spread of mast cell cancer often occurs within 4-6 months after surgery alone. The prognosis in the Shar-Pei is guarded to poor. I have seen mast cell cancer in Shar-Pei as young as 10 months. Chemotherapy often includes prednisolone in combination with other agents.

4. MASTOCYTOSIS: This is a form of mast cell cancer which is systemic and involves internal organs such as the liver, spleen , lymph nodes and GI tract. This can have a much poorer prognosis.

5. PARANEOPLASTIC SYNDROME: This term denotes systemic signs which accompany certain types of cancer. The inflammatory response which often accompanies mast cell cancer can result in GI tract ulceration with vomiting and diarrhea, often with blood, as a consequence. Sometimes excessive manipulation of a mast cell tumor can result in massive degranulation of the tumor cells which can lead to a life-threatening systemic shock reaction. Most common is the localized swelling, draining and itching at the tumor site.

Streptococcal Toxic Shock Syndrome

While the vast majority of the episodes of Familial Shar-Pei Fever (FSF) seen in Shar-Pei run a fairly benign course there are occasional exceptions which can have live-threatening consequences. Over the last few years Streptococcal Toxic Shock Syndrome (STSS) has been seen more frequently as a complication of FSF in the Chinese Shar-Pei. STSS involves infection with a group G streptococcus called Streptococcus canis. In the Shar-Pei cases I've seen this streptococcal infection is a rapidly progressing, highly invasive process which results in a necrotizing faciitis and/or STSS leading to a shock-like syndrome and multiorgan failure. If not recognized early STSS can lead to death in 24 hours or less. A similar syndrome has been seen in human medicine, the so-called "flesh-eating bacteria".

Necrotizing Faciitis

I consider this a localized form of streptococcal infection. Dogs with NF tend to develop extensive soft tissue sloughing along facial planes. Fascia is dense connective tissue which covers the muscles. Usually this syndrome presents as large areas of skin and the underlying fatty tissue dying and peeling away, hence it has been called "flesh eating bacteria". Many of these dogs will survive with debridement or clearing away of the dead tissue, but healing is prolonged and skin grafts are often necessary. Long-term management is intense with frequent bandage changes, cleaning of the wounds, antibiotic therapy and the need for multiple anesthetic procedures to repair and reconstruct the damaged areas. The areas I've seen involved are often the hock joints, the flanks and the abdominal skin.

Streptococcal Toxic Shock Syndrome

STSS seems to be a generalized or systemic form of streptococcal infection. Streptococcus canis in a potent exotoxin producer and it is thought that in cases of STSS the toxin may be responsible for the rapid progression of sepsis, shock and multiorgan failure (MODS). On necropsy these dogs show severe edema of the gastrointestinal tract, congestion of multiple organs, severe pulmonary (lung) congestion and evidence of thromboembolism (blood clots) all pointing to shock due to sepsis or toxemia. These dogs typically die within 24-48 hours in spite of aggressive fluid therapy, antibiotic treatment and intensive supportive care.
Clinical signs in the localized form of STSS, necrotizing fasciitis, consist of areas of skin bruising, dead skin and/or areas of sloughing where the skin is falling away. Usually there is a pus discharge from these areas. The dogs are very painful, running a high temperature, depressed and, in general, sick dogs. Often there is a history of an FSF episode, dog fight wounds, or other traumatic event. In the generalized or systemic form of STSS symptoms have a much more rapid onset and are more shock-like such as severe weakness, rapid heart rate, pale mucous membranes, extreme pain, collapse, coma and acute death. Many of these dogs develop DIC (disseminated intravascular coagulation) which rapidly leads to multiple organ dysfunction syndrome (MODS) and death despite heroic efforts at treatment.
The cause of this condition is unknown. It is known that Streptococcus canis can be part of the normal bacterial flora of the dog and that NF and STSS have occurred in other breed. Predisposing factors in the Shar-Pei may be related to:
1. The increased amounts of mucin in the subcutaneous tissues.
2. The prevalence of FSF in the breed.
3. The prevalence of dog fights and bite wounds in the breed.
4. An increase in skin laxity resulting in more trauma.
5. Immune system insufficiencies.
6. Perhaps an increased virulence of some strain of Streptococcus canis.
Diagnosis is based on the history of previous trauma or FSF episode, bacterial culture and sensitivity of discharges or tissue samples, and clinical signs. One important point is that the organism is often resistant to enrofloxicin (Baytrilâ) and the aminoglycosides such as Amikacinâ and Gentocinâ. Consider the use of multiple antibiotic therapy with agents such as Clavamoxâ, cephalexin, clindamycin, lincomycin, erythromycin, penicillin and the potentiated sulfas. Of course, the best approach is based on sensitivity information from a culture, but that takes some time to generate.
Treatment of the necrotizing fasciitis involves appropriate antibiotic selection and administration, and basic wound care of the affected areas. I have seen dogs have recurrence of necrotizing fasciitis with repeat FSF episodes. Usually they seem to slough out the same area every time. Treatment of the STSS involves intensive care with intravenous fluid therapy, shock treatment with IV antibiotics, pain management, steroids (?), and intensive monitoring for the development of DIC, etc. At this time the prognosis for systemic STSS must be considered very poor.
Increased owner awareness of NF and STSS, rapid initiation of appropriate antibiotic therapy and intensive supportive care are the keys to survival in this condition. An excellent article on STSS appeared in the October 15, 1996 issue of the Journal of the American Veterinary Medical Association, Volume 209, Number 8, pages 1421-1426 by C. Miller, J. Prescott, K. Mathews et al. entitled "Streptococcal Toxic Shock Syndrome in Dogs".