Newsletter: Volume 10, Issue 1 April 2006

GAG Mimetics

Amyloid deposits are complex structures where the amyloid fibrils are intertwined with other amyloid proteins called proteoglycans that are always present in the deposits regardless of the type of amyloid fibril present. Proteoglycans, especially the sulfated glycosaminoglycan (PSGAG) molecule portion of specific proteoglycans, have been shown to interact with the amyloidogenic amyloid proteins. These GAGs promote fibril formation. Glycosaminoglycans may affect precursor processing, folding of the amyloidogenic proteins to form a beta-pleated sheet conformation or polymerization and deposition of amyloid fibrils. An increase in the rate of synthesis of glycosaminoglycans in tissues in which amyloidosis developed would argue for a local response and against nonspecific binding of GAGs.

Small, organic molecules known as GAG mimetics have a similar structure to the sulfated GAG molecules but inhibit the fibrillogenesis process. These GAG mimetics compete with the natural GAGs for the same binding sites on the amyloid proteins preventing the association of the natural GAGs with the protein. By preventing the natural GAGs from binding to the amyloid proteins, the GAG mimetics can prevent fibril formation. The first GAG mimetic tobe commercially available for the treatment of amyloidosis is a drug called Fibrillex™. Unfortunately these drugs are very expensive and not readily available so I don’t foresee their wide application in the very near future.

Thromboemboliism and Splenic Infarction

Thromboembolism is the process of blood clots forming in the cardiovascular system. These can remain stationary or can break loose and travel throughout the blood vessels eventually lodging in smaller capillary beds located in the lungs, liver, spleen, and kidneys. Worse case scenarios involve clots ending up in the brain and heart which can rapidly lead to life threatening consequences. I have seen a syndrome of thromboembolism in Chinese Shar-Pei especially leading to splenic infarction or thromboembolism. In fact, the only breed I’ve seen this in during the last 26 years have been in Shar-Pei and only those suffering with Familial Shar-Pei Fever. Predisposing factors for splenic infarction can be categorized:

1. Coagulopathies
2. Splenic enlargement
3. Cardiac disease
4. Liver disease
5. Renal disease
6. Neoplasia
7. Hyperadrenocorticism (Cushing’s disease)
8. Sepsis
9. Splenic hematoma
10. Vasculitis

I believe there are several reasons that splenic infarction is often associated with Familial Shar-Pei Fever. It is well known that protein-losing kidney disease often accompanies FSF. Renal amyloidosis can result in protein- losing kidney disease as well as immune-mediated glomerulonephritis. This results in urinary loss of antithrombin III and other coagulation proteins leading to a hypercoagulable state which can result in thromboembolism. It is also known that FSF results in vasculitis or inflammation of blood vessels. This leads to damage of the lining of the blood vessels and potential activation of the coagulation cascade as well as platelet activation. FSF also causes release of acute phase proteins from the liver such as tumor necrosis factor, C-reactive protein, cytokines and other products which can activate the platelets and the coagulation system. Systemic Inflammatory Response Syndrome (SIRS) leading to disseminated intravascular coagulation (DIC) often leads to thromboembolism. Hepatic amyloidosis involving the liver can result in deficiencies of coagulation factors as well. Clinical signs include acute collapse, anorexia, lethargy, vomiting, polyuria/polydipsia, pale mucous membranes, abdominal pain and sometimes a palpable abdominal mass. I would include this syndrome in my “ain’t doing right” (ADR) dog category. Laboratory findings may include anemia, higher white cell count, increased platelet counts, increased liver and kidney enzymes, low serum albumin levels and abnormal coagulation tests. Radiology may reveal a lack of definition in the anterior abdomen where the spleen is usually seen in the lateral view as a distinct triangular shadow. Ultrasound is a very useful diagnostic tool as well. Treatment involves exploratory surgery and removal of the spleen. Mortality is high due to the underlying causes, coagulation problems such as DIC and other organ involvement.

What is the spleen and what does it do?

The spleen is important in the primary immune response – probably as important as the lymph nodes in that regard. It has several functions including acting as a blood filter removing old red blood cells and filtering out antigenic particles (such as bacteria, viruses, protozoa, rickettsial organisms, etc.), acting as a storage organ for red blood cells and platelets and serving as a primary organ participating in immune responses.

Histologically the spleen consists of two components: the red pulp and the white pulp. The red pulp functions in red blood cell storage and antigen trapping due to its large population of macrophages or antigen presenting cells. The white pulp contains lymphocytes and here is where the immune response occurs. Antigens trapped in the spleen are taken up by macrophages in the white pulp which eventually results in a proliferation of antibody-producing cells known as B-lymphocytes. The antigens processed in the spleen also result in “lymphocyte trapping” phenomena which causes the lymphocytes to stay in the spleen increasing the efficacy of the immune response.

(1/31/06)

Hardie EM, Vaden SL, Spaulding K, Malarkey DE. Splenic Infarction in 16 Dogs: A Retrospective Study. J Vet Intern Med 1995; 9: 141-148

Homemade Kidney Diets

1. Restricted Protein/Phosphorus Diet for Dogs
   1/4 lb. ground beef (regular) – not lean ground beef or chuck. Braise the meat, retaining fat.
   1 large egg, hard-cooked
   2 cups cooked white rice without salt
   3 slices white bread, crumbled
   1 tsp. calcium carbonate

   Combine all ingredients and mix well. This mixture is somewhat dry and the palatability can be improved by adding some water (not milk). Yield: 1 1/4 lb.

   Analysis:
   Moisture % …………………………………..65.5
   Protein % ………………………………………6.9
   Fat % …………………………………………….5.5
   Carbohydrate …………………………………21.0
   Ash % …………………………………………….1.0
   Phosphorus %…………………………………..0.1
   Sodium %………………………………………..0.1
   ME (kcal) ……………………………………..750/lb

   This diet supplies 17% protein calories, 30% fat calories and 53% carbohydrate calories.

2. Restricted Protein/Phosphorus Ultra Low Protein Diet for Dogs
   2 1/2 cups cooked rice
   1 oz. (2 T.) vegetable oil
   1 large hard-cooked egg
   1/4 tsp. calcium carbonate
   1/4 tsp. salt

   Cook rice as per package instructions except use only 1/4 tsp. salt. Add other ingredients and mix well. Refrigerate between feedings. Yield: 1.1 lbs.

   Analysis:
   Moisture % …………………………………69.2
   Protein % ……………………………………..3.0
   Fat % ……………………………………………6.7
   Carbohydrate % ……………………………20.5
   Ash % ………………………………………….. 0.6
   Calcium % ……………………………………..0.12
   Phosphorus % …………………………………0.07