Exam 2 Flashcards
Diseases of Immunity, Chapter 5
Adaptive Immunity: is a group of specific second-line defense responses that occur days to weeks after exposure to microbial agents during the innate immune response. It is highly specific to a particular genera or species of antigens.
-Mature B-lymphocytes are activated by a specific antigen-binding molecule on its membrane, the antigen receptor is membrane-bound immunoglobulin. Mature T-lymphocytes express TCR which can recognize only antigens associated with MHC molecules resulting in self or non-self recognition.
-MHC I (CD8+) in all nucleated cells
-MHC II (CD4+) primarily in antigen presenting cells.
-ILCs (innate lymphocytic cells) are a heterogenous population of non-B and non-T lymphocytes that are not antigen specific. They can be polarized toward restricted cytokines (similar to T-helper CD4), but can be polarized to undesirable responses (dysregulated) also.
-Cytotoxic and non-cytotoxic types.
-Cytotoxic: resistance to viruses and neoplastic transformation, Induce chronic inflammation.
-Non-cytotoxic: resistance to bacteria, protozoan, allergic diseases, induce chronic inflammation, facilitate metabolic homeostasis.
Innate immunity: firs-line defense that occurs immediately or within a very short time (minutes or hours).
-Barrier systems: mucosal layer, pH, and body temperature, inflammatory and phagocytic responses.
-Key components: intact epithelial cells, neutrophils, monocytes, and tissue macrophages, innate lymphoid cells (ILCs), plasma proteins in the complimentary system
-Endothelial cells, phagocytic cells, and ILCs have PRRs, TLRs, that respond to PAMPs. These ligand-receptor interactions initiate the acute inflammation and recruitment of phagocytic cells from vasculature
-Recognition of intracellular and extracellular microbes leads to different types of responses, cell-intrinsic and cell extrinsic recognition mechanisms.
-ILCs located within the skin or mucosal of barrier systems act through PRR-PAMP
Hypercellular Lymph Node
Primary Lymphoid tissue: bone marrow, Peyers patches
Secondary lymphoid tissue: thymus, spleen, lymph nodes
Paracortical area: T-lymphocytes
Marginal and germinal zones: B-lymphocytes
Type I reaction
Most sensitive to anaphylaxis: Guinea Pig
Shock organs:
Dogs: liver
Rabbit: pulmonary vasculature
Sheep/cattle:lungs
Horses/cat/pig: lung and intestines
parenteral: IV, IM
Mast cells are easily identified by their abundant metachromatic cytoplasm granules (purple, usually).
-Acute inflammation and late-phase response
-Vasoactive amines
-Increased blood flow initially, vascular permeability, edema, smooth muscle spasms.
-Hypotension
-Tachycardia
-Hyperemia
-Pruritus
-Severe bronchospasm can lead to hypoxemia, edema of the respiratory airway.
Atopy: is the genetic predisposition to develop localized type I hypersensitivity called anaphylaxis to innocuous antigens. Ex: food allergies, asthma, allergic dermatitis and rhinitis.
Allergic Rhinitis of ruminants: can progress to type IV. Antigen inhalation, ingestion, or percutaneous absorption.
Type II
“Cytotoxic Reaction” Cell surface antigens.
-Minute to hours
a. Cell damage by complement: C3b opsonization, C5b MAC. Cell lysis
b. Antibody dependent cell mediated cytotoxicity opsonization
c. Antibody directed at cell surface resulting in cell dysfunction (either agonistic or antagonistic).
The biochemical properties of RBCs, platelets, and leukocytes make them susceptible to cytotoxic reactions. Commonly the case of transfusion reactions.
-Immune mediated hemolytic anemia disease of the newborn.
-Autoimmune forms of hemolytic anemia, agranulocytosis, and thrombocytopenia.
Clinicopathologic manifestation
-Hemolysis anemia
-Bleeding
-Vesiculobullous (disease of the skin)
-Vasculitis
-Muscle weakness, paralysis
-Abnormal erythropoiesis, anemia
-Subepidermal characterized by basement membrane clefts.
Type III Immune complex
When antigen is slight excess over antibody complex deposition, activation of complement vs a lot of antigen
Arthus reaction (localized) in the dermis
Formation of antibody-antigen complex that activate complement and result in tissue damage.
-“innocent bystander” the complexes become stuck to the cell or tissue.
-Involve IgM and IgG and occur within hours after exposure in a sensitized host.
- Immune complex formation
- Immune complex deposition
- Immune complex-mediated inflammation
A. Localized: Cutaneous Arthus. Acute inflammation, thrombosis, ischemia.
Blue eye (CAV-1) some forms of glomerulonephritis
Inhalation of fungus: emphysema, fibrosis, chronic obstrubtive pulmonary disease (COPD).
B. Generalized
-Systemic Lupus Erythematous
Vasculitis, glomerulonephritis, and arthritis = formation of micro thrombi by activation of coagulation cascade. Tissue Schemia, infraction, tissue necrosis.
Type IV (Delayed-type)
It is not dependent on antibody
-48-72 hours
Mediated by CD8+ cytotoxicity or CD4+ mediators (macrophages) to produce chronic inflammation.
-It is dependent on sensitized T-lymphocyte
Tuberculin: after an intradermal exposure a purified protein derivative of the tubercle bacillus would produce a localized type IV reaction on a previously sensitized host within 24-72 hours = Swollen and firm nodule.
-CD4+ & Th1 to MHCII: IFN-gamma, macrophage response
-CD4+ & Th2 to MHCII: IL-4, IL-5, Eosinophilic response
-CD8+ & cells to MHCI: Cytotoxic response
Example: Atopy, mites, pollen, organ transplant rejection. tuberculin response, intracellular organisms.
Clinopatholigic manifestations
-Granuloma formation
-Perivascular dermatitis
-Chronic arthritis with inflammation destruction of articular cartilage and bone
-Granulomatous enteritis
-Inflammation of graft tissue
-Uveitis
- Describe the features, pathogenesis and lesions of the four types of hypersensitivities and provide examples for each.
Immunity: defensive system recognition and protection from infectious pathogens and cancer. However, sometimes response illicit an inflammatory response that is not appropriate to the inciting antigen, these fall into three categories.
1. Hypersensitivity reactions
2. Autoimmune diseases
3. Immunodeficiencies
Immunity = beneficial
Hypersensitivity = harmful
Hypersensitivity reactions have two phases:
1. Sensitization phase: previous or prolonged exposure to the antigen
2. Effector phase: pathologic response, commonly inflammation or cell lysis.
Type I (15-30 minutes): immediate-type most often a result of IgE response directed against environmental or exogenous antigens (allergens).
-Release of vasoactive mediators from mast cells, resulting in edema of interstitial tissue.
-Can have systemic (anaphylaxis) or local (allergic dermatitis). Extrinsic asthma is another example. Urticaria, angioedema, flea bites, atopy.
Pathologic lesions:
-Vascular dilation, edema, smooth muscle contraction, mucus production, inflammation
Type II: cytotoxic hypersensitivity, most often occurs when IgG or IgM is directed against either al altered self-protein or a foreign antigen bound to a tissue cell.
1. Destruction of tissue or cell by antibody-dependent cellular cytotoxicity or complement-mediated lysis or
2. Altered cellular function without evidence of tissue damage
Ex: Pamphygus vulgaris, transplant rejection.
Pathologic lesions:
-Cell lysis, inflammation
Type III: Immune complex hypersensitivity caused by the formation of insoluble antibody-antigen complexes resulting in activation of the complement systems.
-Inflammatory reaction at the site of immune complex deposition.
-It can have generalized (rheumatoid arthritis and systemic lupus erythematosus) and localized (cutaneous Arthus reaction = Blue eye anterior uveitis in dogs) forms.
Pathologic lesions:
-Necrotizing vasculitis (fibrinoid necrosis), inflammation
Type IV: delayed-type hypersensitivity, results from activation of sensitized T lymphocytes to a specific antigen. The resulting response is either cytotoxicity or cytokines mediated macrophages produced chronic inflammation. It is the underlying mechanism for tuberculin testing in cattle for Bovine tuberculosis (Mycobacterium bovis) and allergic contact hypersensitivity, and granulomatous inflammatory responses.
Pathologic lesions:
-Perivascular cellular infiltrates, edema, cell destruction, granuloma formation.
Cytokines
Granulocytes in tissues
Cytokine-Related Disease
-Excessive elaboration of cytokines during bacterial septicemia and shock.
-Gram-negative endotoxin = IL-1 and TNF-alpha, fever, disseminated intravascular coagulation and shock.
-MHC II-TRC complex: severe damage to tissues and organ systems
Natural Killer cells
-Viral infections
-Activated by IFN-alpha, IFN-beta, released by virus infected cells, IL-12 released by macrophages, then they produce IFN-gamma = Th1 response.
- Describe the features of transplant rejections.
The MHC complex is essential component in humoral and cell-mediated immunity. Histocompatibility designation determines transplant tissue compatibility.
-The repertoire of MHC molecules is genetically controlled and determines an individual’s ability to respond to a specific antigen.
-Three different kinds of genes that encode for MHC grouped according to their structure, tissue distribution, and function.
-Class I and II genes: encode cell surface molecules
-Class III genes: encode components of the complement system, enzymes 21-hydroxylase A and B, cytochrome p450, TNF-alpha and Beta, and heat shock protein 70.
-MHC I: all nucleated cells, major function present CTL (CD8+) antigen fragments.
-Antigen uptake by antigen-presenting cells by phagocytosis or endocytosis = peptide fragment presented.
-MCH II molecules: induction of Th-lymphocytes (CD4+).
The most common in VetMed is Kidney transplant grafts
- Direct pathway: CD8+ CTL recognizes allogenic MHC molecules expressed by antigen presenting cells within the graft (donor).
- Indirect pathway: CD4+, the CTLs do not directly kill graft cells bc they are only recognizing graft antigens, but facilitate the development of an antibody (humoral) response.
Rejections can be hyper acute, acute, or chronic.
- Describe the features of and diagnose these autoimmune diseases:
Systemic lupus erythematosus: systemic, undetermined cause
Discoid Lupus erythematosus: localized to skin
Rheumatoid arthritis
Sjögren-like syndrome
Inflammatory bowel disease
Vogt Koyanagi Harada Like syndrome
Systemic Lupus Erythematous: multi-systemic including the skin
-Type III: forms immune complexes
-Glomerulonephritis, vasculitis, dermatitis.
-Production of antibodies directed against a wide array of normal tissue and cellular components.
-ANA predominant (Antinuclear Antibody) is directed against nuclear antigens, and cytoplasmic components which are neither organ specific nor species specific.
-RBCs cell surface antigens
-Affects: mice, horses, dogs, cats, snakes, iguanas.
-Average age of diagnosis is approximately 5 years
-40% fatal within 1 year
-Supportive care
-Exacerbated by sunlight
Breeds
-Beagle, Shetland sheepdog, German Shepherd, Old English sheepdog, Irish setter, Poodle.
-Siamese, Himalayan and Persian Cats predisposed.
Lesions
-Fever, non erosive poly arthritis, glomerulonephritis, mucocutaneous lesions, lymph node and spleen enlargement, hematologic abnormalities (anemia, thrombocytopenia, leukopenia).
Discoid Lupus Erythematous: localized to the skin
-Tx: sunscreen, glucocorticoids, VitE, Niacinamide, tetracycline.
-Low morbidity (good prognosis)
-Mostly dogs
-Depigmentation, rythma, scaling, erosion, ulceration, crusting.
-Skin of the nasal plant, nose, less commonly oral mucosa.
Rheumatoid arthritis
-Erosive lesion
-IgG antibodies
-Most species
-Rare
-C/S: lameness, joint laxity, Rheumatoid Factor (RF) anti-IgG antibody
-Chronic, sterile, erosive poly arthritis PANNUS (is an abnormal layer of fibrovascular tissue or granulation tissue, joints and cornea) formation.
-Fibroblast in the pannus enzymatically degrade cartilage.
-The pannus may act as a physical barrier between synovial fluid and the cartilage, prevent deliver of nutrients to the chondrocytes.
Sjogren-Like Syndrome
-Viruses are suspected as causes
-Systemic autoimmune disease characterized by keratoconjunctivitis sicca, xerostomia, and lymphoblasmacytic adenitis.
-Dry eyes, dry mouth, gingivitis and stomatitis.
-Inflammation of the salivary gland.
Clinical pathology
-Hypergammaglobulinemic
-Might have an ANA titer
-Might have a positive RF
Inflammatory Bowel Disease
-Cats, dogs
-Basenji, GSD
-Microscopic: lymphoplasmacytic enteritis
-Can lead to malabsorption and chronic PLE
-Cats may be caused by dietary antigens, may progress into lymphoma.
Vogt-Koyanagi
-Targets uveal and dermal melanocytes
-Akitas, Huskies, Alaskan Malamutes, Samoyeds, other breeds
-Breakdown of blood-retinal barrier, exposure of retina to specific antigen production of anti-retinal antibodies = blindness.
-Skin lesions mediated by T cells, macrophages (Th1), Ocular Th2 with B cell
-Clinical syndrome of dermal depigmentation and severe generally bilaterally symmetric uveitis is distinctive.
- Describe tolerance in regards to autoimmune diseases
Immune response to self-antigens
Loss of immunologic tolerance to self-tissue pr cellular antigens and it is characterized by abnormal or excessive activity of self-reactive immune effector cells.
Autoimmunity can be organ specific, localized, or systemic. Autoantibodies or self-reactive T-lymphocytes can cause the problem.
Alternating clinical disease and convalescence
-Immunologic tolerance is described as the failure of the immune system to respond to a specific antigen after previous exposure to that antigen. It is an absence of a functional response rather than a lack pf any response at all. The development of autoimmunity can be simply described as an scape from the mechanism by which self-tolerance is maintained.
-Deletion, energy, and suppression mechanisms.
Deletion: eliminating self-reactive T-lymphocytes in the thymus = CENTRAL TOLERANCE.
PERIPHERAL TOLERANCE: mature cells exposed to antigens in the peripheral tissues. The most likely to influence autoimmunity
-Anergy: Functional activation of lymphocytes that encounter antigen. Requires co-stimulation protein from APC; no co-stimulatory protein = anergia T cell.
-Suppression: Cross regulation of CD4+ Th1 responses by T-reg lymphocytes. Inhibition of lymphocyte activation
-Antigen Sequestration: (Testis, eyes, and brain = immunological privilege sites). BBB, absence of lymphatic drainage, or limited MHC expression. If antigens released as a result of trauma or infection, then severe immune response occurs.
- Describe the features of and diagnose these immunodeficiency syndromes:
a. SCID
b. Agammaglobulinemia
c. Chédiak-Higashi Syndrome
d. LeukocyteAdhesionDeficiencies
Immunodeficiency Syndromes
*Failure of the immune system to protect the host from infectious organisms or the development of cancer.
Primary = genetic or congenital
Secondary = loss of immune function due to infections, malnutrition, irradiation, chemotherapy.
SCID
-Severe combined immunodeficiency disease
-Primary immunodeficiency
-Deficiency in humoral and cell mediated immunity
-Defects in T-l ymphocytes or T & B. If severe Lymphoid Stem Cell defect.
-Common sequelae: fungal or viral infections. Bacterial if nor reliant on passive humoral immunity
SCID in Horses
-Autosomal recessive in Arabian (or cross) breed.
-Severe Lymphopenia
-At birth deficient in IgM
-Microscopically profound lymphoid hypoplasia of primary and secondary lymphoid tissue.
-Lymph nodes lack lymphoid follicles, plasma cells, and corticomedullary differentiation.
-Spontaneous mutation in gene encoding catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is required for the recombination of immunoglobulin heavy chain and TCR genes.
-Jack Russell Terries have similar mutation SCID
SCID dogs
-Basset hounds X-linked defect (XSCID)
-Lymphopenia with increased number of B-lymphocytes and few to no T-lym
-Not as profound as in horses
-At 6-8 weeks they develop recurrent infections of the skin
-Hypogammaglobulinemic with normal IgM and decreased IgA, IgG.
-Mutation on common gamma subunit of IL-2, IL-4, IL-7, IL-9 and IL-15. They can’t class switch to IgA.
SCID Mice
-Autosomal recessive
-Absence of mature B and T lymp
-Susceptible to infection but can be housed in ‘sterile’ facilities to keep alive longer (lab animal)
Agammaglobulinemia
-Primary (congenital)
-Inability to produce immunoglobulins and absence of mature B lymphocytes and plasma cells
-Thoroughbreds, quarter horses, standardbred breeds of horses.
-X-linked trait
-Microscopically and absence of plasma cells, primary follicles, and germinal centers in LNs.
Lesions
-Extracellular bacterial infections of the joints and respiratory system
-Chronic bacterial disease
-Pneumonia
-Arthritis
-Enteritis
-Dermatitis
-Laminitis
Chediak-Higashi Syndrome
-Cats, cattle, killer whales, beige mice, rats, Aleutian minks.
-Inherited autosomal recessive
-Defective lysosomes, melanosomes, platelet-dense granules, and cytolytic granules.
-Mutation of Last gene
Manifestation/lesions
-Hypopigmentation
-Bleeding tendency, platelet count normal, but defective.
-Ocular abnormalities
-Recurrent infections
-Hallmark: presence of enlarged granules within melanocytes or cytoplasmic granules
LAD
-Primary immunodeficiency disease
-Inability of leukocytes to migrate from circulation to sites of inflammation
-Recurrent bacterial infections
-Autosomal recessive trait
-Irish setter, Holstein cattle most affected.
-Leukocytosis with marked neutrophilic
-Defective expression of Beta-2 integrins
-Death at 6-7 its or both
-Pictures of inflamed gums, with bacterial infection
- Describe the characteristics of the different types of amyloidosis in domestic species.
Amyloid Light Chain (AL) derived from immunoglobulin light chains of plasma cells.
-Neoplasm of plasma cells present, myeloma, extra medullary plasmacytoma or multiple myeloma.
-Broad spectrum of clinical and pathological conditions with the deposition of amyloid material
-Amyloid is a pathologic proteinaceous substance of different chemical properties with an identical conformational property of forming a B-pleated sheets of non-branching fibrils.
-Improper folding deposition in blood vessels, basement membranes, spaces of dissent, spleen. Kidney = glomerulonephropathy = protein loss.
Amorphous, eosinophilic, hyaline, extracellular substance. Progressive accumulation causes pressure atrophy of adjacent cells and tissue.
Congo Red Stain = Red-orange color viewed by polarized light (apple green perfringence)
-AL amyloid: secreted in B cell proliferative disorders
-AA amyloid: liver secrets SAA during inflammation. AA synthesized from SAA.
Hereditary Amyloidosis: Shar Pei, Abyssinian cats.
Reactive Systemic Amyloidosis
-Most common form in animals
-Often secondary to chronic inflammation
-No underlying disease found, prolonged increased serum concentration of SAA protein. Siberian tigers, captive Cheetahs.
- Summarized the ways to diagnose amyloidosis.
Amorphous, eosinophilic, hyaline, extracellular substance. Progressive accumulation causes pressure atrophy of adjacent cells and tissue.
Congo Red Stain = Red-orange color viewed by polarized light (apple green perfringence)
Neoplasia
1.Define:neoplasm,benign,malignant,metastatic,anaplasia,hyperplasia,metaplasia,dysplasia, hypertrophy
2. Name a neoplasm based on its location and morphologic features. Outline the location and morphologic features when given the name of a neoplasm.
3. Describeandgiveexamplesoftransmissibletumors.
4. Classify a neoplasm as being benign or malignant based on gross and histopathologic features.
5. State the role of tumor suppressor genes (p53, RB) in neoplasia. Describe characteristics of labile/stable/permanent cells in relation to the cell cycle
6. DescribehowtocountmitoticfiguresinanH&Emicroscopicfield.
7. Identify and describe the steps of tumor development (Multistage Carcinogenesis)
8. Summarize lymphatic, hematogenous, and transcoelomic (carcinomatosis) metastasis.
9. Describe methods in which tumor cells manipulate the immune response
10.Define: cancer stem cells, tumor-initiating cells, stroma, angiogenesis, paraneoplastic effects, cachexia, functional endocrine tumors, humoral hypercalcemia of malignancy, hypertrophic osteopathy. Give examples of paraneoplastic effects.
11.Describe the differences and causes of Dystrophic and metastatic mineralization
12.List the types of oncogenic viruses and the tumor(s) they cause in the domestic species.
13.Describe the steps in diagnosing cancer and recommend the best diagnostic tests depending on the patient’s circumstances.
14.In your own words, explain: ancillary diagnostic tests: including differences between cytology, histopathology, special staining, clonality assays, molecular diagnostic techniques, grading, staging, surgical margins.
1.Define:neoplasm,benign,malignant,metastatic,anaplasia,hyperplasia,metaplasia,dysplasia, hypertrophy
2. Name a neoplasm based on its location and morphologic features. Outline the location and morphologic features when given the name of a neoplasm.
Neoplasia is the process of “new growth” “new” “plasma” in which normal cells undergo irreversible genetic changes, which renders them unresponsive to ordinary controls on growth exerted from within the transformed cell or by surrounding ‘normal’ cells.
- It can be malignant or benign.
-The cells expand beyond their anatomical boundary, creating microscopically and macroscopically lesions detectable = Neoplasms.
-Hyperplasia: increase in the number of cells in a tissue through mitotic division of cells, cellular proliferation
-Hypertrophy: increase in size through the addition of cytoplasm and associated organelles.
-Metaplasia: transformation of one differentiated cell type into another of the same lineage
-Dysplasia: is an abnormal pattern of tissue growth and usually refers to disorderly arrangement of cells within the tissue.
-Anaplasia: describes loss of cellular differentiation and reversion to more primitive cellular morphology, often irreversible progression to neoplasia.
Neoplastic cell lineage, Tumor Types
Mesenchymal (Round cells):
Bening tumors suffix -oma to the name of the cell of origin. Thus a fibroma is a benign tumor of fibroblast origin. Malignant suffix-sarcoma (fleshly growth). Fibrosarcoma is a tumor composed of malignant fibroblasts.
The cells of the hematopoietic system are also mesenchymal; thus tumors arising from these cells are sarcomas. Ex: malignant tumor of lymphocytes = lymphosarcoma, short is lymphoma.
a. Fat/adipocytes
b. Fibroblasts
c. Smooth/striated muscle
d. Astrocytes (nervous)
e. Monocytes (muscle)
f. Osteocytes
g. Chondrocytes
Round Cell Tumors
-T and B lymphocytes
-Mast cells
-Histiocytes
-Transmissible venereal tumors
-Plasma cells
Nomenclature
-Plasma cells: Plasmacytoma (benign) Multiple Myeloma (malignant).
-Histiocyte: Histiocytoma (benign) Histiosarcoma (malignant)
-Mast cell: Grade 1-2, or 1-3. >3 bad.
-Transmisible Venereal Tumors: a. Spontaneous regression (within 6mts), indolent growth; or very rarely progressive growth with metastasis.
-Tasmanian Devil Facial Tumor: similar to TVTs. Spread by biting (males especially)
Epithelial
Benign
-Adenoma: arising from glandular epithelium like mammary epithelium or tissue that exhibits a tubular pattern microscopically, such as renal tubular adenoma.
-Papilloma: usually exophytic (growing outward) from a cutaneous or mucocutaneous surface.
-Polyp: is a grossly visible benign epithelial tumor projecting from a mucosal surface, used interchangeably with papilloma.
Malignant
-Carcinomas: may contain nests, cords, islands of neoplastic epithelial cells. Invasive and can metastasize.
Examples: hepatocellular carcinoma, hepatocellular adenoma.
Scirrhous
-Others: nervous, undifferentiated (anapestic) and Mixed tumors.
Mixed Tumors
Mixed Tumors
-Tumor containing multiple cell types.
-Believe to arise from a single pluripotent or totipotent stem cell capable of differentiating into a variety of more mature cell types
-Example: mammary gland tumor of dogs typically contains a variable mixture of neoplastic epithelial or glandular elements. -Variable mixture of neoplastic epithelial or glandular elements (luminal epithelium and myoepithelium, mesenchymal elements: fibrous connective tissue, fat, cartilage, and bone)
Teratomas and Teratocarcinomas
-Arise from titopotential germ cells, three embryonic cell layers and thus composed of a bizarre mixture of adult and embryonic tissue types.
Bening Tumors, Malignant Tumors & Tumor-like lesions
Bening tumors
-Do not invade surrounding tissue (well demarcated, +/- capsulated)
-Do not become metastatic (usually)
-Can become malignant
-Composed of well differentiated cells
-Expansile, compress adjacent tissues
-Slow growing
One criteria does NOT indicate benign, more is better!
Malignant Tumors
-Poorly demarcated, unencapsulated
-Invade surrounding tissues, +/- hemorrhage and necrosis
-Often stimulate angiogenesis
-More likely to become metastatic
-Cells become poorly differentiated, +/- anapestic
-Rapid growth
Always use multiple criteria to come up with a more accurate diagnosis of whether benign or malignant*
-Example criteria under the scope: anisocystosis (cell size), anisokaryosis, cytomegaly, cellular pleomorphism (shape), well/poorly differentiated, anisokaryosis, karyomegaly, mitotic figures (rare, frequent, bizarre), multiple nuclei.
40x + 10x = 400x. 7-10 fields of view average! The more you look at the better the average you get! more representative sample!
Tumor-like lesions
-Nonneoplastic growths when examined microscopically.
-Example:
Hamartomas are disorganized but mature mesenchymal or epithelial tissues found in their normal anatomic location
-Many of Hamartomas consist of abnormal proliferation of blood vessels, may be the result of aberrant differentiation in development rather than true neoplasia
Choriostoma: “normal” tissue in an abnormal location. AKA “Ectopic”.
-Dermoid, a mass consisting of mature skin cell and adnexa, found in an unusual sites including the cornea.
Tumor-like Lesions
Harmatomas
Odontomas
Neoplasm Nomenclature examples
Neoplasm Nomenclature examples
Lymphoma (lymphosarcome)
Squamous cell carcinoma
Cell division, Rb, p53
Liable/Stable and Permanent Tissues
a. Liable: repeated dividing
b. Stable: “quiet” but can divide
c. Permanent: non dividing
Normal cell division is largely controlled by soluble or contact-dependent signals from the microenvironment that either stimulates or inhibit cell division. An excess of stimulators or deficiency of inhibitors leads to net growth.
Neoplastic Transformation
- Initiation: first step in carcinogenesis is introduction of irreversible genetic change into normal cells by action of mutagenic initiating agent or initiator, which can be chemical or physical carcinogens that damage DNA.
- Promotion: the outgrowth of initiated cells in response to selective stimuli, mostly promoting agents or promoters driving proliferation. Tumor progression is initially benign. Papillomas can regress.
- Progression: benign tumor evolves into increasingly malignant tumor during malignant transformation and can become metastatic. Benign-malignant-metastatic
Latency: time before a tumor is clinically detectable. Smallest size considered is 1cm. May have already divided 30 times!. Growth appears rapid after that bc only 10 subsequent cycles are required to convert a 1g tumor into a 1kg tumor!
Mitosis: Prophase, Metaphase, Anaphase, Telophase.
Stages
G1: presynthetic
S: DNA synthetic
G2: premitotic
M: mitotic
Quiescent cells are in physiological state G0
-In response to DNA damage even actively dividing cells undergo cell cycle arrest, usually at one of several cycle checkpoints.
-Cell cycle arrest is initiated by p53 (multifunctional tumor suppressor gene product 53). It gives the cell time to repair DNA damage.
-Many neoplastic cells do not respond to extrinsic or intrinsic signals directing them into G0 and no longer express functional p53. Thus, they continually move through the cycle and progressively accumulate mutagenic DNA.
-Because DNA replication machinery is unable to duplicate the extreme ends of DNA templates, the telomeres that form the ends of chromosomes are shortened at each cell division. Very short telomeres trigger cellular senescence in normal cells. Neoplastic cells regain the ability to produce telomerase and replicate their telomeres, escaping senescence = immortality.
Apoptosis: DNA damage induces apoptosis triggered by p53. Neoplastic cells lack expression or inactivate p53. Occurs from withdrawal of growth factors. Binding of death receptors (Fas ligand and TNF-alpha). Hypoxia or DNA damage trigger. T lymphocytes and NK cells stimulation
Checkpoints
-G1/S
-G2/M
Tumor Suppressor Genes
-p53: if unable to repair, it activates BCL2 associated X protein (BAX). Pro-apoptotic molecule following DNA damage. Target gene p21. G1-S, G2-M
-Retinoblastoma gene (RB): inactive gene allows for cell to proceed through G1/S phase
Tumor Angiogenesis and Mechanisms of Metastases
Continued growth of solid tumors depends absolutely on an adequate blood supply to provide oxygen and nutrients to tumor cells. Development of blood vessels (1-2 mm diameter). Recruitment of endothelial cells through ECM, and maturation of differentiation of the capillary sprout. The endothelial cells of tumor blood vessels produce growth factors, such as PDGF and IL-1 that stimulate tumor proliferation.
It is the tumor production of
-Pro-angiogenic: VEGF (Vascular endothelial growth factor)
-Anti-angiogenic: Thrombospondin down regulated by tumor
Mechanisms of Metastases
Primary tumors are not usually the cause of death, but the metastasis that interferes with critical body functions. Fortunately, metastasis is rather an inefficient process. Only a few cells from the original tumor can enter the lymphatic or blood circulation.
-Adhesion: Detach, breach BM, enter ECM.
Detach from the main tumor mass, penetrate the basement membrane, and enter the ECM. Loss of catherins or catenins, elements of intracellular junctions.
-Invasion: MMPs (ECM breakdown)
Degradation of basement membranes, cleavage of basement membrane, migration through BM.
Tumor emboli: once inside the lymphatic or blood vessel, tumor cells tend to clump together to form a small emboli held together by shared adhesion molecules. While in the vessels they may be recognized and attacked by host lymphocytes or may be surrounded by platelets, which may protect the emboli from immune-mediated destruction, thus increasing potential for metastasis.
-Migrations: growth factors, formation of emboli.
Mediated by cytoskeleton and cellular adhesion structures. Tumor cell migration is stimulated by autocrine growth factors, such as hepatocyte growth factor (HGF) “scatter factor” and by cleavage of ECM components including fragments of collagen.
Pathways for Metastasis pic 1 hematogenous, pic 2 “carcinomatosis” transcoelomic.
Lymphatic Spread
Regional LN (mostly carcinomas)
-Closest to tumor affected first and develop the largest metastatic tumor masses. Example: adenocarcinomas of the intestines to mesenteric lymph nodes and later to other LNs in the abdominal cavity.
Hematogenous Spread
-Sarcomas do tend to use hematogenous route more frequently than carcinomas. Tumors generally invade veins rather than arteries bc the vessel walls are thinner and easier to penetrate.
Transcoelomic
When cancers arise on the surface of an abdominal or thoracic structure, they encounter few anatomic barriers to spread. Thus mesotheliomas may be confined to the peritoneal, pericardial, or pleural cavities, but the tumor cells within these cavities readily spread to cover visceral and parietal surfaces.
-Ovarian, pancreatic, adenocarcinomas spread transcoelomically, resulting in multiple tumor masses throughout the abdomen = carcinomatosis. Generally fatal.
Metastatic Suppression, Invasion of the Immune Response
Altered major histocompatibility complex expression
-CTLs recognize tumor antigens only on tumors that display antigens in the context of MHC class I molecules. Those that fail to express class I antigens are also more susceptible to NK cell killing.
-Tumors may also downregulate expression of class II MHC required for activation of Th-lymphocytes.
-No MHCII no Th CD4 cell response.
Antigen Masking
-Tumors become invisible to the immune system by losing or masking their tumor antigens. Clonal tumor variants that do not express tumor antigens is favored during tumor evolution.
Tolerance
-“self antigens” (normally found on cells) identified as self and do not attack. T-reg cells in tumors can actively promote tolerance to tumor tissue.
Immunosuppression
-TGF-alpha production by tumor cells: inhibits growth and function of macs and lymphocytes.
-Administration of monoclonal antibodies raised against tumor antigens generates a rapid but short-lived passive tumor immunity.
-Multiple approaches to stimulate the active immunity have been attempted.
-Blocking the activity of tumor-associated macrophages and T-reg cells is a new and promising approach.
Paraneoplastic effects
Effects due to products of neoplastic cells, not due to tumor size or invasion.
-Hypercalcemia of malignancy: due to anal gland adenocarcinomas (AGASACA), lymphomas, multiple myeloma
-Hypoglycemia is associated with hepatocellular carcinomas
-Polycythemia vera associated with pheochromocytoma
-Hypertrophic osteopathy: associated with thoracic tumors
Systemic: Cachexia
-Loss of muscle and fat
-Different from starvation
-Hormones and cytokines
-TNF-alpha, IL-1, IL-6, and prostaglandins
-Leading to anorexia and debilitation
Endocrine
-Hypercalcemia
-Hypercalcemia of malignancy
Vascular
-Anemia (hemangiosarcoma)
-Hyperviscosity syndrome
-Hypergammaglobulinemia in plasma
-Multiple myelomas
Non-endocrine tumors
A variety of non endocrine neoplasms may also produce hormonally active substance nor normally found in the tissue where the tumor originates =Ectopic hormone production.
-The most common in vetmed is parathyroid hormone-related peptide (PTHrP), resulting in humoral hypercalcemia of malignancy.
-Humoral hypercalcemia of malignancy: muscle weakness, cardiac arrhythmias, anorexia, vomiting, and renal failure. May be a result of excessive parathyroid hormone production by parathyroid neoplasm or tumor metastasis to bone and result in bone resorption, which would be direct effect of the tumor.
a. Anal gland adenocarcinoma
b. Lymphoma
c. Multiple myeloma
HARD IONS = Hypercalcemia
-Hyperparathyroidism
-Addison’s disease
-Renal disease (especially in horses)
-D: Vitamin D toxicity
-Idiopathic/Iatrogenic/Infectious (granulomatous disease, fungal disease)
-Osteolytic disease
-Neoplasia
-Spurious
Oncogenic viruses (cause cancer)
-FIV
-FeLV
-BLV
-Mutations in DNA nor an etiologic agent
Sampling tumors (Or suspected Tumors)
Critical thinking is vital
-What is your goal? diagnose? Complete removal?
-Do I aspirate, smear? biopsy? excise?
-Location matters: CSF vs. brain biopsy
General Rule of Thumb for Biopsies
-Interface!
-Want to see the tumor cells, but also what they are doing to the surrounding tissue.
Incisional vs. Excisional Biopsies
Grading Vs. Staging Neoplasia
A tumor grade is assigned by a pathologic to provide some indication of how similar or dissimilar the neoplastic cells are to their normal counterparts.
-Underlying assumption is that this grade provides some indication about biologic behavior, but it is not universally true.
-Classification: well differentiated (very similar to normal cells), moderately differentiated (somewhat similar to normal cells), poorly differentiated, (anapestic) cells. Translate into low, medium, and high grade or grades I, II, III respectively.
-Other criteria: features of malignancy, mitotic index (number of mitotic figures per 400x field), the extend of tumor necrosis, H&E tumor sections, invasiveness, mitoses, hemorrhage.
Tumor Staging
-Indication of the extent of tumor growth and spread in the animal. TNM System: based on the size of the primary tumor (T), degree of lymph node involvement (N), and extent of metastasis (M).
-Within each category a number is assigned based on clinical, diagnostic, and histopathological evaluations.
-Overall TNM provides a standard measurement by which the natural course of disease and impact of treatment modalities can be compared.
-CT, MRI, are more sensitive techniques
Tumor Diagnosis (Ancillary Diagnostics)
-There is no way to diagnose all “cancers”
-Cytology
-Histopathology: features malignancy
-Special Staining (H&E, IHC, other stains)
-IHC: Vimentin: mesenchymal
Cytokeratin: epithelial
Some cells can stain positive for both
-Clonality assay: difficult to distinguish benign hyperplasia from neoplasia.
-Most neoplasms are clonal (derived from a single transformed cell as in lymphoma).
-Inflammatory cells (lymphocytes) are polyclonal.
Cytogenic analysis: evaluating chromosomes
-Pedigree analysis: those Boxers sure love mast cells.
-Molecular diagnostic techniques: microarrays (measures thousands of mRNAs). High-throughput sequencing (sequence entire genome, look for mutations.
Tumor Stroma
A tumor consists of the tumor cells proper, termed the parenchyma and a non-neoplastic supporting structure called Stroma.
Tumor Stroma
A tumor consists of the tumor cells proper, termed the parenchyma and a non-neoplastic supporting structure called Stroma.
Describing the Lesion
- Write a gross description for a lesion.
- Choose the degree, duration, distribution, and tissue reaction for lesions (morphologic diagnosis).
- Properly use the suffixes,-itis, -osis, and –opathy, to label the tissue reaction
- Be able to visualize and identify an example what a lesion looks like based on a gross description
- Identify the fundamental changes in a tissue that would result in raised and depressed lesions and determine which is most likely based on a visual representation.
- Determine a likely etiology (or differentials) based on lesion pattern.
- Be able to determine size, volume, weight or extent of lesion without instrumental aid.
Important observations
Anatomic Location
Distribution
Color
Size
Shape
Contour
ACCDSS
- Anatomic location, location, location!
-Size: approximate, mm, cm, or extent 25% of the organ, etc.
-Distribution: Focal, multifocal, military, unilateral, bilateral, symmetrical, segmental, etc.
-Shape: Circular, rhomboidal, linear, etc.
-Color: Red, green, yellow, black, white (cream, tan), clear
-Contour: raised, depressed, flat.
-Texture: soft, firm, hard
-Smell
-Weight, volumen (g, kg, mL, L, etc)
-Taste
Estimating size
-Measuring devices may not be available
-Index finger/hand rule (1 cm)
-Index finger to knucle (7.5 cm)
-Palm width (7.5 cm)
Anatomy
Liver: Left lateral lobe, Left medial lobe, quadrate lobe (by gallbladder), Right medial lobe, Right lateral lobe, Caudal process of the caudal lobe. Hepatic veins, Caudal vena cava, Falciform ligament, lesser momentum.
Focal/Focus
-Foci: many
Example:
-Diaphragmatic (capsular) surface of the liver, centrally located within the left medial lobe.
-Focally distributed
-Approximately 1-2 cm in diameter
-Circular, well demarcated.
-Cream to grey, flattened
-Hardened
Multifocal
-Embolic showering: Ex; sepsis, neoplasia.
-Multifocal, coalescing: indicates chronic embolic shower
Example:
Anatomy: diaphragmatic surface (capsular) of liver
Distribution: Multifocal, coalescing, randomly involving all the liver lobes.
Size: varying in size from 0.5 cm to 3 cm approximately
Color: Cream
Contour: well demarcated, flattened.
Shape: Round to oval
Miliary Distribution
-Miliary indicates embolic shower
-Multiple little spots, circular diffused
Anatomic Location: Diaphragmatic surface of liver (capsular).
Distribution: Military, randomly scattered among all liver lobes
Color: Cream
Contour: Well demarcated
Shape: Circular
Size: 1-2mm
Diffused Distribution
Diffused yellow pigment involving all liver lobes Diaphragmatic surface or parenchyma, smooth.
Poorly demarcated
-Blurry dot example.
Example: Diaphragmatic capsular surface of liver, focal circular and poorly demarcated and flattened lesion of approximately 4cm in diameter centrally located in right medial lobe.
Symmetrical Distribution
-Think about paired organs
-Example: Bilateral adrenal hyperplasia secondary to pituitary tumor.
-Example: Lamb brain, hemorrhagic symmetrical encephalomalacia (C. per fringes type D).
Raised Contours
-Something is added, cells, fluid, gas, cellular byproducts (stroma), parasites.
-Example:Ventral border of right medial lobe of liver. Focal, raised, red, approximately 2-3 cm, firm.
-Example: bovine papular stomatitis, oral mucosa, periodontal.
Depressed Contours
-Something is removed
-Ex: necrosis, atrophy, atelectasis (lungs), scar tissue.
-Mottled: means patchy
-Example: The object is white, multilobulated, with yellow to brown innersurface coating in area of cavitation at one end of the object proximately 1 cm in diameter and 1 cm in depth. The caveated region is speckled or mottled yellow-tan-golden and flaky. The object emits a pleasant buttery and salty odor.
Real lesions
Cat kidney: extra capsular depressions, cream color neoplasia lymphocytes, focal cortex 1x1 cm circular to wedge shaped located within the cortex expanding into the medulla and bulging out of cortex, well demarcated.
Microbial Infections
- List the various portals of entry of microbes throughout the body.
- Describe where mucosa-associated lymphoid tissues are located and what
lymph nodes they drain to during a bacterial infection. - Tell how microbes exploit the body’s natural processes for their benefit.
- Diagnose genetic disorders that result in increased susceptibility to infectious
diseases. Paraphrase the pathogenesis. o Epitheliogenesis imperfecta
o Ciliary dyskinesia
o Leukocyte adhesion deficiencies o Agammaglobulinemia
o Severe combined immunodeficiency - Paraphrase the key features of virulence factors. Give examples of adhesion,
colonization, and toxigenesis of microbes.
Generalities of Target Cells
Target cells at portal of entry tend to be epithelial cells, mucosa-associated macrophages (monocytes), lymphocytes, dendritic cells and nerve endings.
-Microbes can use nerve endings and fibers (CNS, PNS) to spread neurologically (Microglial, Astrocytes) or systematically
-Leukocyte trafficking: thoracic duct and circulatory system - other organ systems in which specific target cells are infected, including lymphoid organs (spleen, lymph nodes, BM).
-Sometimes leukocyte trafficking ultimately returns microbe back to mucosal, M/C junction, or skin initially encountered at portal of entry.
Epithelial target cells
-Covering epithelium: serosa (mesothelium, meninges), epidermis (Mucocutaneous junction, cornea)
-Lining epithelium: mucosal, endothelium
-Glandular epithelium: Endocrine, salivary, gonads
Alimentary system Mechanisms overview
-Portals of entry
a. Tonsilar epithelium
b. Villus epithelium
c. Crypt epithelium
d. M cells (Peyer’s patches)
Respiratory System Mechanism Review
Portals of entry
-inhalation
-Hematogenous
-Direct penetration
-Metabolic (from club cells)
Urogenital System Mechanisms Overview
Portals of entry
-Ascending infection most common route
-Hematogenous
-Metabolic (Kidney PCT)
-Coitus
Integumentary System
Components
-Epidermis
-Dermis
-Subcutis
-Adnexa
Portals of entry
-Direct contact
-Abrasions
-Bites
Non-cell Microbial Targets
Pathways to Cross Barriers
Mechanisms of Adhesion, Colonization, Invasion, Replication
Mucous
Example
-Brachyspira hyzdysenteriae (spirochete bacteria)
-Pigs
-Cecum, colon are targets
-Able to actively move through the mucus layer to gain access to mucosal epithelial and goblet cells.
-Prefers to initially replicate in mucigen droplets within goblet cells (Large intestine has more epithelial and goblet cells)
-Stimulate goblet cells to increase production of mucus
-Mucohemorrhagic necrofibrinuous and typhilis with diphtheritic membranes
Specific Parts of the Cell
-Cilia
-Microvilli
Pathways Used to Cross Barriers and Enter MALT
M cell entry
-Postweaning multi systemic wasting syndrome (porcine circovirus type 2) is an example of a viral disease in which the virus uses the alimentary system as its portal of entry to subsequently be physiologically transported through the system to reach the small intestine and encounter, enter, and cross the mucosa using M cells that overlie Peyer’s patches (GALT)
-Via M cells the virus gains access to and infects mucosa-associated lymphocytes and lymphocytes in GALT.
-Leukocyte trafficking spreads the virus systemically via lymphatic vessels to regional lymph nodes and then post capillary venues and the thoracic duct to the circulatory system, spleen, lymph nodes, and other lymphoid tissues.
1. Trancytosis - M cells: (GALT).
2. Intercellular junctions:
3. Transcytosis: Erysipelothrix rhusiopathiae is an example of bacterial disease that enters a vesicle formed by an invagination of the membrane, crosses the interior of the cell in the vesicle, fuses with the basolateral membranes and it is ejected from the vesicle into the surrounding tissues. Inhalation or ingestion. MALT.
4. Process of dendritic cells: Poxviruses are examples in which each virus uses dendritic cells within mucosae of the respiratory and alimentary systems as portals of entry via inhalation or ingestion, transfers across the mucosa into MALT and leukocytes. Via leukocyte trafficking it spreads. (MALT)
5. Leukocyte trafficking- lymphocyte: (BALT).
6. Leukocyte trafficking, macrophage, monocyte
7. Nerve endings: Bovine meningoencephalitis
Mechanisms of Adhesion, Colonization, Invasion, Replication
Cell polarity
-The surface of an epithelial cell exposed to the lumen is called the apical domain, the surface below junctional complexes on the sides of the lumen and base makeup the basolateral domain.
-Parvoviruses use receptors expressed only on the basolateral surfaces to infect small intestinal crypt cells by spreading from cells located in Peyer’s patches, whereas influenza viruses use receptors expressed only on apical surfaces to infect respiratory endothelial cells via airway.
Transcytosis/Endocytosis/Exocytosis:a normal function of epithelial cells, endothelial cells, and many other types of cells, is used to move macromolecules across cells in micro vesicles (endosomes). Microbes enter via receptor mediated actions. Exit cell from basolateral surface via exocytosis into lamina proper and/or dermis and encounter mucosa or dermis associated lymphoid tissue (MALT) or other ECM tissues.
Microbes that Inhibit Phagosome Lysosome Fusion
-APC phagocytoses antigen forms phagosome
-Phagosome Lysosome fusion is disrupted, microbe lives, proliferates and spread (lymphatics).
-Or fusion does occur, microbe can neutralize enzymes in lysosomes = failure to degrade microbe
Examples
-Mycobacterium avid subs. paratuberculosis
-Rhodococcus equi
-Corynebacterium paratuberculosis
Virulence factors
-Factors expressed genetically by microbes with enable them to cause disease.
-Virulence factors allow for the following:
Adhesion, Colonization, Invasion, Replication, Growth, Evasion, suppression of immune system, Systemic spread.
ADHESINS: attach to receptor (s) on cell membranes or on substances as mucus, mucins, or ECM proteins; facilitate entry into cell by endocytosis/phagocytosis. Example: Fimbriae, Pili.
TOXINS: bacteria such as live Gram-positive, Lipoteichoicacid
Dead Gram-negative: endotoxins
End result: cell dysfunction and death
Leukotoxins: Mannheimoisis
Neurotoxins: Botulism and botulinum toxin (Clostridium botulinum) tetanus and tetanospasmin (Clostridium tetani)
Infectious Causes of Ciliary Dysfunction
-Paralyze, destroy, cilia or kill ciliated cells
Bordatella bronchiseptica, Mycoplasma spp, Mannheim hemolytica (also has leukotoxins)
Genetic diseases that disrupt innate immunity leading to infections
-Autosomal recessive trait
-Irish setter and Holstein cattle breeds most affected
-Hallmark: leukocytosis with marked neutrophilia
-Defective expression of Beta-2 interns
-Death at 6-7 its for both.
LAD Irish setters, Holstein cattle
Portal of entry Alimentary, Respiratory, Integumentary Systems
Urinary System
Describe the normal gross and microscopic anatomy of the kidney and the relationship to portals of entry and defense mechanisms.
Identify the renal responses to injury and common gross/ microscopic lesions of the urinary system
- Renal infarcts
- Renal fibrosis/ Glomerulosclerosis Hemorrhage
- Thrombosis
- Hyperemia/congestion
- Glomerulonephritis
The microscopic big 4 (GITV)
-Glomerulus
-Tubule
-Interstitium
-Vasculature
-Capsule, medulla (composed or renal pyramids), pelvis/calyx, bladder ureters, urethra
-Cortica/Medullary ratio: 1:2 or 1:3 in domestic animals. Desert animals = 1:10 or 1:15
CATS kidney
-Single renal papilla (sub capsular veins, lipid accumulation). Cortex is gray to tan and has a single renal papilla
-Dogs, sheep, horses: renal crest
-Carnivores, horses: unipolar kidneys
-Porcine, bovine: multi lobar
Functional unit: Lobules
-Collection of nephrons separated by medullary rays.
-Renal lobes (not to be confused with lobule): represented by a renal pyramid
-Renal parenchyma is divided into cortex and medulla
Because of the limited ways the renal tissue can respond to injury and the limited patterns of injury, in severe and prolonged disease, the endpoint will be similar - chronic renal disease and failure.
Urinary System
Describe the normal gross and microscopic anatomy of the kidney and the relationship to portals of entry and defense mechanisms.
Identify the renal responses to injury and common gross/ microscopic lesions of the urinary system
- Renal infarcts
- Renal fibrosis/ Glomerulosclerosis Hemorrhage
- Thrombosis
- Hyperemia/congestion
- Glomerulonephritis
The Nephron
-Corpuscle: Bowman’s capsule, glomerulus
-Renal tubules (cuboidal epithelium): PCT, LOH, DCT
-Distal convoluted tubule
-Glomerulus: complex, convoluted tuft of fenestrated endothelial-lined capillaries held together by a supporting structure of cells in a glycoprotein matrix = the mesangium. Mesangial matrix: mesangial cells are pluripotential contractile and phagocytic capable of secreting inflammatory mediators.
-Bowman’s space
-Proximal convoluted tubule
-Macula densa, Juxtaglomerular complex
-Loop of henley (Medulla)
-Collecting duct
Urinary System
Describe the normal gross and microscopic anatomy of the kidney and the relationship to portals of entry and defense mechanisms.
Identify the renal responses to injury and common gross/ microscopic lesions of the urinary system
- Renal infarcts
- Renal fibrosis
*Glomerulosclerosis Hemorrhage - Thrombosis
- Hyperemia/congestion
- Glomerulonephritis
Vasculature
- Renal infarcts: focal ischemic necrosis
-Renal artery: kidney receives blood through renal artery
-Interlobar artery: extends along the boundary of each renal lobe (renal column) and then branches at right angles to form an arcuate artery that runs along the corticomedullary junction. They branch from arcuate artery and have no anastomoses, making them susceptible to focal ischemic necrosis (infarct) as in any organ with end arteries.
-Interlobar eventually form afferent arterioles that enter and exit as efferent arterioles.
Flow: renal artery-inter lobar artery-arcuate-interlobar-afferent-glomerulus-efferent-peritubular network & vasa recta-interlobular vein-arcuate vein-inter lobar vein-renal vein.
Urinary System
Describe the normal gross and microscopic anatomy of the kidney and the relationship to portals of entry and defense mechanisms.
Identify the renal responses to injury and common gross/ microscopic lesions of the urinary system
- Renal infarcts
- Renal fibrosis/ Glomerulosclerosis Hemorrhage
- Thrombosis
- Hyperemia/congestion
- Glomerulonephritis
Renal fibrosis
-Chronic renal failure from progressive disease with loss of nephrons and severe scarring.
-Uremia, soft tissue calcification, tubular basement membrane calcification.
-Hallmark = alterations in calcium/phosphorous metabolism in the uremic animal.
-Decreased EPO
-Inability to convert VitD to active form.
*pale, tan to white, shrunken, pitted, and firm consistency, along with excessive adhesions of the capsule to the underlying cortex. Diffuse and finely stippled with pinpoint and granularity of the capsular surface. Coarse, deep and irregular depressions, multifocal or patchy distribution.
C/S: polyuria, polydipsia, anorexia, weight loss, uremia signs, vomiting, seizures. Nonregenerative anemia. Hyperphosphatemia, low to normal calcium, these alterations are the hallmark of chronic renal failure. Decreased intestinal absorption of calcium. Parathyroid is not suppressed anymore by vitamin D, so hyperparathyroidism, fibrous osteodystrophy and soft tissue calcification.
-Fibrosis with a fine granular pattern can occur subsequent to widespread necrosis of renal epithelium (acute tubular necrosis). Ex: Oak poisoning in cattle.
a. The toxins are not removed
b. The basement membrane does not remain intact
c. Adequate tubular epithelium does not survive destruction by microbes or the toxic dose of a nephrotoxin to allow for complete repair.
-It is the replacement of renal parenchyma, including tubules, glomeruli, and interstitial with mature fibrous connective tissue.
-Manifestation of a healing phase of a preexisting lesion.
-IL-6 T-lymphocytes
-Follows infraction, glomerulonephritis, tubulointerstitial disease/chronic pelvic disease.
Glomerulosclerosis
-Chronic change-end stage of glomerulonephritis
-Glomeruli shrink, are hyalinized and have increased fibrous CT
-Sequelae: Tubular hypoxia (no blood flow)
Injuries
Glomeruli: deposition of immune complexes type III, thromboembolism, bacterial emboli, viral infection.
-Necrosis, thickening of membranes, infiltration of leukocytes, reduced vascular perfusion.
-Atrophy
-Fibrosis
-Mesangial cell proliferation
-Increased vascular permeability
-Pallor of parenchyma, accentuation of the glomerular tufts as fine red dots, petechial hemorrhages, later = shrunken kidney, fine granularity to the cortical cut section, capsule may be adherent.
Tubules: undergo degeneration, necrosis, apoptosis, atrophy, basement membrane rapture or thickening.
-Ascending infections, blood-borne infections, damage from toxins, ischemia, infarction.
-When nephrons are lost, tubules can undergo compensatory hypertrophy in an attempt to maintain overall renal function, but no regeneration of nephrons occur.
-Tubulointerstitial nephritis: from bacterial or viral septicemias, Leptospirosis.
Interstitium: Hyperemia, congestion, hemorrhage, fibrosis, inflammation.
-Interstitial nephritis: lymphoplasmacytic infiltrate, leukocytes present (equine infectious anemia, canine ehrlichiosis)
-Cortical necrosis: gram-negative septicemias or endotoxins (pyometrias that have gone septic).
Vasculature: thrombosis, sclerosis, basement membrane thickening, endothelial cell hypertrophy.
Renal Function
- Plasma filtration: formation of urine elimination of metabolic waste
- Acid base regulation: bicarbonate K+ under influence of aldosterone
- Conservation of water through reabsorption, ADH
- Maintenance of potassium ion concentration passive reabsorption. Blood pressure control
- Control of endocrine function: EPO, vitamin D conversion to calcitriol, which facilitates absorption of calcium by the intestine
Renal failure (loss of function)
-Alteration in tubular structure or function influence glomerular structure and function and vice versa. For example: necrosis or atrophy of renal tubules results in loss of function of the affected nephron and secondary atrophy of the glomerulus, and reduction of blood flow.
Acute renal failure
-It occurs when kidney fails to excrete waste products and to maintain fluid electrolyte homeostasis
-Animals die of acute renal failure often because of cardiotoxicity of elevated potassium, metabolic acidosis, and/or pulmonary edema.
-Hyperkalemia results from decreased filtration, decreased tubular secretion, and decreased tubular sodium transport.
-Cell lysis and increased serum potassium
C/S: vomiting, oliguria, anuria, diarrhea, ammoniacal-smelling breath, azotemia and uremia.
Azotemia and Uremia: intravascular increased of these nitrogenous waste products = urea, creatine, and waste products of protein catabolism.
a. Prerenal: compromised renal percussion (shock, severe hypovolemia, circulatory collapse, thrombus)
b. Intrarenal: compromised kidney function (oliguria = decrease in urine production or anuria = absence of urine production). Ascending disease (pyelonephritis), intraluminal toxic metabolites, ischemia.
c. Postrenal: obstruction of urinary tract.
Tubular necrosis is the single most important cause of acute renal failure
1. Tubular necrosis from infectious microbes (Escherichia coli, Streptococcus spp, etc.) or viruses (infectious canine hepatitis virus, canine herpes virus)
2. Obstructive nephropathy from urolithiasis, cell neoplasms, or trauma.
3. Renal ischemia with tubular necrosis from occlusive vasculitis/vasculopathy caused by bacteria, bacterial toxins, or tumor emboli.
RTE of proximal tubules most severely affected due to high metabolic demands. Stimulate vasoconstriction - ischemia (nephrotoxin - associated ischemia)
4. Tubular necrosis from nephrotoxic drugs (NSAIDs cause perfusion problems)
5. Tubular necrosis from chemicals
Chronic Renal Failure, Uremia
UREMIA: TOXICOSIS
Non-renal lesions of uremia
-Chronic renal failure from progressive disease with loss of nephrons and severe scarring.
-Uremia, soft tissue calcification, tubular basement membrane calcification.
-Hallmark = alterations in calcium/phosphorous metabolism in the uremic animal.
-Decreased EPO
-Inability to convert VitD to active form.
-Intravascular accumulation of other metabolic wastes
-Reduced blood pH (metabolic acidosis)
-Alterations in plasma ion concentrations (K+, Ca++, Na+, Phosphate)
-Hyoertension
-Endothelial dmg = vasculitis and thrombosis
-Increased erythrocyte fragility
-Mineralization
-Uremic pneumonitis
Severity of lesions will vary
UREMIA: TOXICOSIS. NEPHROCALCINOSIS
-Pulmonary edema
-Fibrinous pericarditis: fine granular deposits of calcium in the epicardium (visceral pericardium)
-Ulcerative hemorrhagic gastritis
-Ulcerative hemorrhagic colitis in horses and cattle: colic mucosa edematous and dark red, bloody intestinal contents and ammonia smell.
-Ulcerative and necrotic stomatitis
-Atrial and aortic thrombosis
-Hypoplastic anemia
-Soft tissue mineralization: example; mineral intercostal connective tissue deposits. Cranial intercostal spaces calcification of sub pleural CT, white-gray granular pleural thickenings with a horizontal ladder-like arrangement. Firmness and crunchiness on muscles can occur.
-Fibrous ostedystrophy
-Parathyroid heperplasia
Acute Tubular Necrosis
Nephrotoxins: pigments
Hemoglobinuric Nephrosis
Acute Tubular Necrosis
-Response to injury following exposure to nephrotoxins such as:
Pigments
-Hemoglobin
-Myoglobin
-Bile/bilirubin
Hemogobinuria: as a result of in vivo hemolysis gives red plasma
Myoglobin: is rapidly cleared from plasma, so it will not be red.
Hemoglobinuric nephrosis: not in itself nephrotoxic, but events lead to ischemic tubular necrosis. Frequently occurs in hypo perfused kidneys complicated by hemoglobinuria. Hemoglobonemia results in hemoglobinuria when the renal threshold for resorption is exceeded. Example:
-Copper toxicity or Molybdenum deficiency in sheep: they are more susceptible bc accumulate it faster (in liver) than other species. Damage to liver = massive release of copper = hemolysis
-Leptospirosis or Babesiosis in cattle,
-Red Maple toxicity in horses,
-Babesiosis or Autoimmune hemolytic anemia in dogs.
Heavy Metals
-Lead: Old paint, car batteries, car parts.
-Mercury
-Thallium
-Arsenic
Pharmaceutical agents
-Cisplatin
-Aminoglycosides: (gentamicin, neomycin) ototoxic, nephrotoxic.
-Oxytetracycline: cattle, dogs.
-Cisplatin: (chemotherapeutic)
-Monensin: primary target is skeletal/cardiac muscle
-NSAIDs: Papillary necrosis; Dogs and horses. Especially during dehydration, chronic renal disease, CHF.
Primary renal papillary necrosis: response of inner medulla to ischemia, decrease PGs, decrease renal perfusion.
Prostaglandins are responsible for maintaining normal renal blood flow. NSAIDs result in afferent arteriolar constriction that decreases renal perfusion = acute renal tubular degeneration and medullary papilla necrosis and acute renal failure.
-Fungal toxins: Aspergillus spp, Penicillium spp. Ochratoxin is nephrotoxic for mono gastric animals = tubular necrosis, renal fibrosis.
-Nephrotoxins: plants and fungus
Blacken Fern: Enzootic Hematuria
Pigweed: Amaranthus retroflexus: perirenal edema
Hairy Vetch: systemic toxin, granulomatous nephritis Weeks after ingestion, skin lesions.
Oak tannis (oak toxicosis-acorns/leaves) ruminants
Lilies: cats, acute tubular necrosis
Oxalate-containing plants: similar to Ethylene Glycol toxins
-Ethylene Glycol:
-Vitamin D
-Hypercalcemia
Heavy metals and Pet Food Contaminants
Heavy Metals
**Damage to membranes of proximal convoluted tubules epithelial cells.
Mitochondrial damage produced by these toxins, mitochondrial swelling and cellular death.
-Lead: Old paint, car batteries, car parts.
-Mercury
-Thallium
-Arsenic
**Eosinophilic intracellular renal inclusions
Pet food Nephrotoxins
-Melamine/Cyanuric acid
-Both compounds are considered relatively nontoxic when administered separately, but when they are combined they form insoluble crystals.
Raising/grapes: contain tannins (like Oak) = Acute Renal Failure
Nephrotoxins: Vitamin/Minerals
Vitamin D toxicity
-Calciferol-containing rodenticides can cause nephrosis in dogs and cats.
-In livestock: plants such as Cestrum, Solanum sp. can also cause it.
-Ingestion of excessive VitD can cause hypercalcemia resulting in decrease cAMP formation, which impairs sodium reabsorption and interferes with ADH receptors.
Kidneys have a smooth capsular surface, necrotic and atrophic calcified deposits in the tubules scattered randomly throughout the cortex. In chronic cases, the surface of the kidney is finely granular as a result of fibrosis.
White, chalky deposits can be seen within the cortex. Interstitial fibrosis, tubular dilation, glomerular atrophy, and extensive calcification of tubular BM microscopically seen
Acute Tubular necrosis, Oak toxicity cow kidney
White-spotted kidney in cattle = Chronic interstitial nephritis, glomeruli usually spared. Can be incidental
Renal Leptospirosis in cattle
E. coli
Salmonella spp.
Brucella spp.
Pulpy Kidney, sheep
Bacterial toxins such as epsilon exotoxin, enteric proliferation by Clostridium per fringes type D in small ruminants
-Bilateral renal lesions termed pulpy kidney
-Acute tubular epithelial degeneration and/or necrosis and interstitial edema and hemorrhage
Glomerulonephritis types in dogs, microscopically
Renal Parasites & Kidney worms, Horse and Pig
Klossiela equi: sporozoan parasite (horse)
Pretty!
Oral infection to kidney
Clinical signs: variable- subclinical
Histologically: various stages of schizogony in PTC (and glomeruli)
Kidney worms
-Stephanurus dentatus: porcine, Southern USA, other countries
-Perirenal fat or inside the kidney
-Microscopically: granulation tissue, fibrosis.
Stephanurus edentates kidney worm pigs, perirenal fat picture
Dioctophyma renale, kidney worm dogs
-Giant kidney worm
-Granulomatous nephritis, +/- nematodes
-Lesions heal by fibrosis
-DDX Migratory Toxocara canis larvae
-CApillaria plica and Capillaria feliscati in dogs and cats
-Ethylene Glycol: antifreeze
Oxalate nephrosis
-Calcium Oxalate precipitation similar to oxalate accumulation in plants (Halogen, Sarcobatus, Rheum, and Rumex): Cattle and sheep.
Illness due to
-renal disease, neuromuscular dysfunction from hypocalcemia produced by chelation of serum calcium oxalates.
Macroscopic morphology
-The kidney is diffusely pale beige and swollen, the cortex is beige finely mottled due to deposition of multiple small foci of oxalate crystals in the renal tubules. Tubular dilation, necrosis and early regeneration.
-NSAIDs: Dogs and horses.
-NSAIDs: Dogs and horses. Especially during dehydration, chronic renal disease, CHF.
Primary renal papillary necrosis: response of inner medulla to ischemia, decrease PGs, decrease renal perfusion.
Prostaglandins are responsible for maintaining normal renal blood flow. NSAIDs result in afferent arteriolar constriction that decreases renal perfusion = acute renal tubular degeneration and medullary papilla necrosis and acute renal failure.
Morphological appearance
-Crystallin depositions
-Infarcts
-Greenish areas, necrosis, hyperemic rim.
Myoglobinuric Nephrosis
Myoglobinuric Nephrosis
*Hemoglobin and myoglobin are not in themselves nephrotoxic but combined with ischemia (from hypovolemic shock +/- anemia) it IS.
A set of events resulting from acute and extensive muscle necrosis lead to ischemic tubular necrosis in hypoperfused kidneys. Serum concentrations of myoglobin are increased, myoglobin more freely passes through glomerular filtration barrier and is excreted in the urine.
At necropsy the renal cortices are diffusely stained red-brown to blue-black and have intratubular myoglobin casts.
Equine: Exertional rhabdomyolysis (“tying up” “Monday morning disease”)
Greyhounds
Wild animals: capture myopathy
Cassia spp and karwinskia spp tox
Any: severe trauma to muscle.
Severe myoglobin staining of the cortex and medulla (reddish to brown).
Pyelonephritis
Bacterial infection of the pelvis with extension into the renal tubules causing concomitant tubulointerstitial inflammation
Results from ascending bacterial infection
-Agents: E. coli, proteus, Staph, Strep, Pseudomonas (all species)
-Cattle/pigs: Corynebacterium renale, C. suis.
Chronic Pyelonephritis
Lumpy, bumpy, loss of architecture
Bacterial infection of the pelvis with extension into the renal tubules causing concomitant tubulointerstitial inflammation is referred to as pyeolenephritis, and considered a form of tubulointerstitial nephritis.
-Inflammation of both renal pelvis and renal parenchyma
-Suppurative tubulointerstitial disease
-Usually originates as an extension of bacterial infection from lower urinary tract that ascends the ureters to the kidneys and establishes an infection in the pelvis and inner medulla.
Ascending/descending renal bacterial infections
Hematogenous (ascending) infections of the kidney can result from bacteremia, E. coli and Staphylococcus spp. The outcome is bacterial emboli in the renal cortex. Embolic glomerulonephritis
Ascending infections result from a combination of urinary bladder infection and vesicoureteral reflux leading to pyelitis and concurrent intrarenal reflux leading to pyelonephritis.
Patent Urachus
Most common urinary bladder malformation. Foals!
-Failure of uranus to close, persistent opening to umbilicus, dribbling of urine from their umbilicus.
-GETAWAY for infection!
-Urachus rupture causes uroperitoneum (not bladder rupture)
Urinary calculi, Urolithiasis (obstructive disease)
Supersaturation of urine with the component of stone-forming salts is the essential precursor to initiation of urolith formation.
Consequences
-Bladder rapture, uroperitoneum, trauma HBC can cause this too!
-Stranguria, hematuria, dysuria.
-Bladder diffusively thickened
-Site of obstruction in males penile urethra and the urethral process.
-Ventral aspect, dog, calculi lodged in the urethra proximal to caudal end of os penis.
-Cattle: sigmoid flexure
-Goats: urethral process (vermiform appendage)
-Dogs: base of the os penis
Microscopically: crystals are more common than grossly visible aggregates of mineral(calculi).
Macroscopically: calculi are grossly visible, typically hard spheres or ovoids, with central nidus, surrounded by concentric laminae.
Large renal pelvic calculi (nephroliths) have the shape of renal calyces in animals that have tru calyces. Variable sizes (2-10cm)
Calculi formation
-Familial, congenital, and/or pathophysiological factor occur together and cause the precipitation of excretory metabolites in urine into grossly visible stones.
-Reduced water intake
-Bacterial infections
-Foreign bodies
-Drugs: sulfonamides and tetracyclines
-Unusual metabolism of certain substances, such as uric acid in Dalmatian dogs.
-Diet: increased Silicic acid in native pastures (Silica calculi)
-Phosphorous grain-based rations (Struvite calculi)
-Estrogen in subterranean clover
-Oxalate
-Hereditary defects leading to abnormal processing of substances by the kidney, such as Cystine, Xanthine.
Struvite calculi
-Magnesium ammonium phosphate hexahydrate
-Most common in female dogs
-Associated with lower UT disease
-White-to-grey, chalky, easily broken
-“Blocked male cats”
Feline Lower Urinary Tract disease
-Feline idiopathic cystitis
-Complex interaction between urinary bladder, nervous system, adrenal glands, and environmental factors.
-C/S: stranguria, dysuria, hematuria
-A diagnosis of exclusion
-Lesions are nonspecific
Oxalate
Calcium oxalate
* Hard, heavy, white or yellow,
jagged spines or smooth, solitary
can also geti t
– Associated with primary hyperparathyroidism, hypercalcemia, cushing’s, steroid administration
Uric Acid and Urates
- Metabolite of purine
- Ammonium urate with uric acid and
phosphate or sodium urate - **male dalmations: high uric acid in urine
- PSS!!!: ammonium biurate
- Multiple, hard, laminated, brown-green
Xanthine
-Dalmations
-Usually degraded to uric acid
Cystine
-Dogs more than cats
-Predispose breeds: Newfoundlands, Dachshunds, Mastiffs, Bassets.
-Small, irregular, soft, friable, light yellow to red-brown that turns green in sunlight
Chronic, Acute cystitis
Acute cystitis
Inflammation of the urinary bladder is common in domestic animals, may be acute or chronic. UTI predisposition.
-Bacterial: are able to overcome normal defense mechanisms and adhere or invade (colonize) the urinary bladder mucosa. E. coli, Corynebacterium renale.
-Chemical/toxic: Blacken Fern, Cantharadin (Blister beetle)
Features
-Hemorrhagic
-Catarrhal
-Fibrinopurulent
-Necrotizing
-Ulcerative
Chronic
-Diffuse
-Follicular (dogs)
-Polypoid variants
-Cystitis common with concurrent chronic urolithiasis
-Small raised nodules present on the mucosal surface. **Hyperplastic lymphoid cells surrounded by hyperemia and hemorrhage.*
Renal Neoplasia
-Occur most frequently in dogs, and less common in cats. Rarely in other species.
-Braken-fern induced bladder neoplasm in cattle is the exception
Scottish terrier, Shetland sheepdog, Beagle, and Collie at increased risk.
Factors:
-Topical insecticides
-Exposure to marshes sprayed with chemicals for mosquitoes
-Environments with high industrial activity
-Female gender
-Obesity
-Breed
Epithelial Tumors
-80% of the neoplasm of lower urinary tract
-Transitional cell papillomas, transitional cell carcinomas, squamous cell carcinomas, adenocarcinomas, and undifferentiated carcinomas.
-Adenoma: Rare, solitary (dogs, cats, horses)
-Carcinoma/adenoma: most common primary renal neoplasia. Large, +/- hemorrhage and necrosis. Carcinoma associated with paraneoplastic conditions (polycythemia)
-Excessive EPO produced: poor prognosis
The neoplasm is pale, white, lobulated, and has infiltrated and replaced one pole of the kidney (renal carcinoma).
Mysenchymal tumors:
-Include fibromas, fibrosarcomas, leiomyomas, leiomyosarcomas, rhabdomyosarcomas (<18 its of age dogs), lymphomas, hemangiomas, hemangiosarcomas, hemagiomas and huemanfiosarcomas are rare.
-Usually metastasis from other organ.
Transitional cell carcinomas:
invasive, poor prognosis, Trigone area.
Raised nodules or diffuse thickening of the urinary bladder wall. They are composed of pleomorphic to anapestic transitional epithelium.
Round Tumors
-Lymphoma (lymphosarcoma) metastasis from another organ.
-Mast cell tumor
Embryologic tumors
-Pigs, chickens mostly
-Arise from metanephric blastemal (primitive pluripotent) tissue
-Solitary or multiple; lobulated
-Incidental
-Neoplasm results from malignant transformation during normal nephrogenesis or from neoplastic transformation of nests of embryonic tissue that persists in the postnatal kidney.
Histologically: primitive glomeruli, tubules and mesenchymal (cartilage, bone, skeletal, muscle adipose) tissue.
Mast cell tumors, Round tumors
Miscellaneous Responses to injury of Renal Tubules
Portals of entry Pathways of Spread
Lipofuscinosis: Fine golden granules of brown iron-free pigment with staining characteristics of lipofuscin (wear and tear pigment).
-Renal cortex streaks of brown discoloration
-No renal function affects
Hydronic degeneration: cloudy swelling from acute cellular swelling.
-Potentially reversible
Glycogenic degeneration: abundant cytoplasmic vacuoles of tubular epithelium of outer medulla
Fat: in cats usually pale, golden color of kidneys. Dogs fat is restricted to inner cortex. No renal function alteration.
Hemosiderin and ferritin: pigment can be present in the renal tubules. Likely from degradation of Hb reabsorbed from glomerular filtrate by proximal tubular epithelium. Lesions of hemolytic crisis are not present, just incidental findings. Cortex diffusely black but the medulla is unaffected.
Portals of entry Pathways of Spread
-Hematogenous
-Ascending from ureter
-Glomerular filtrate
-Direct penetration (cystocentesis)
Defense mechanisms
-Barrier system: glomerular basement membrane
-Monocyte-macrophage system: glomerular mesangium
-Immune system: innate, humoral and cellular response.
Hyperemia and Congestion
Hemorrhage and Thrombosis
Hyperemia: increase in arterial blood flow. It is an active process usually secondary to acute renal inflammation
-Kidneys are darker than normal, perceptibly swollen, and ooze blood from the cut surface.
Congestion: increase in venous blood flow pooling within the vasculature of the kidney.
-Physiologic, passive, secondary to hypovolemic shock, secondary to cardiac insufficiency, hypostatic.
-Dark red and ooze blood from the cut surface unoxygenated blood in the renal venous system.
Hemorrhage: when red blood cells extend beyond vessels walls. Factor VIII deficiency, trauma, bleeding disorders related.
-Subcapsular and renal cortical hemorrhages occur in association with septicemic diseases, vasculitis, vascular necrosis, thromboembolism, and DIC.
-Perirenal hemorrhage noted with ovine herpes virus arteritis (MCF) and blunt trauma.
-Petechial hemorrhages seen throughout the surface and cortex of pigs with hog cholera, bacterial infections.
-Ecchymotic hemorrhages associated with multifocal tubular and vascular necrosis are client, neonatal puppies herpesvirus. Thrombus that break free can lodge in the glomeruli.
-DIC causes widespread thrombosis, widespread cortical infraction results and is designated renal cortical necrosis.
Infraction
- Acute initially is swollen and hemorrhagic, coagulative necrosis (red-dark red) focal wedge-shape area. Bulging out of cortex.
*Rabbits: acute to subacute = pale infarcts, wedge-shape. bulging out of renal cortex - Surrounded by a zone of hyperemia (red/blood border) and hemorrhage
- Chronic infants are pale, shrunken and fabric resulting in distortion and depression of the renal contour
They are areas of coagulative necrosis that result from local ischemia of vascular occlusion and usually are due to thromboembolism. Commonly interlobular arteries get obstructed leading to cortex infraction. Less commonly occlusion of interloper and arcuate arteries = WEDGE SHAPE
Renal emboli are derived from
-Thromboemboli: from valvular endocarditis
-Parasitic: canine dirofilarisis and equine strongylosis
-Arteriosclerosis in cattle (rare)
-Neoplastic cell emboli
-Endotoxemia
-Bacterial emboli: Trueperella pyogenes in cattle, Erysipelothrix in pigs, and Staphylococcus aureus in small animals
Septic infarcts: initially hemorrhagic, but bc of pyogenic bacteria, the necrotic tissue undergoes liquefactive necrosis, abscess and substantial scars.
Describe the types of congenital urinary diseases
Describe acute renal failure / Acute tubular nephrosis
Diagnose and describe the effects of the urinary diseases in multiple species
* Acute tubular necrosis
* Toxic nephropathies / nephritis
* Aminoglycosides / Antimicrobials
* Heavy metal toxicity
* Hemoglobinuric nephrosis
* Myoglobinuric Nephrosis (Rhabdomyolysis)
* Papillary Necrosis
* Oak T oxicity
* Hairy Vetch Toxicosis
* Ethylene Glycol Intoxication
* Grape /raisin T oxicity
* Melamine and Cyanuric Acid Contamination
* Lily Toxicity
* Amyloidosis
Developmental Disorders
-Aplasia (agenesis): failure of development of kidney. The ureter may be present or absent.
-Dobermans, Beagles
-Unilateral: can live, Bilateral = death.
-Hypoplasia: incomplete development in a variety of species, fewer than normal number of nephrons are present. Large White pigs in New Zeland. Dogs, cats, clinically silent. The shrunken, pitted kidneys in young animals, particularly dogs, are often diagnosed as hypoplastic. However, the small kidneys are due to
a. Renal fibrosis
b. Dysplasia
c. Progressive juvenile nephropathy
-Dysplasia: Abnormality of altered structural organization (abnormal differentiation during nephrogenesis) Autosomal dominant in sheep. Dysplastic changed can be unilateral or bilateral and con involve much of an affected kidney or occur as focal lesions.
Kidneys can be small, misshapen or both.
Microscopically: 1. Small Hypercellular glomeruli 2. Persistence of primitive mesenchyme 3. Persistent metanephric ducts 4. Atypical (adenomatoid) tubular epithelium 5. The presence of cartilaginous and/or osseous tissue.
-Fused Kidneys: Horseshoe kidneys result from the fusion of the left and right cranial or left and right caudal poles of the kidneys during nephrogenesis. Function is normal.
-Cysts/PKD: spherical, think-walled, variable sized distentions principally in the cortical or medullary renal tubules and are filled with clear, watery fluid. Congenital or primary entity in cases of renal dysplasia. Obstruction of nephrons can cause increased luminal pressure and secondary dilation (cystic dilation). Weakened tubular basement membranes, tubular epithelial hyperplasia with production of new BM, increased tubular secretions and increased intratubular pressure = enlarged dilated tubules.
-Polyscystic kidneys: have many cysts that involve numerous nephrons. Occur Sporadically in many species. Inherited autosomal dominant lesion in pigs and lambs, West Highland white terriers. Persian cats and Bull terriers. PKD1/2 gene defect (transmembrane proteins for cell-to-cell matrix interaction and calcium channeling, they are also important for renal tubular transduction, control cell cycle, and migration. Cilia is modified, resulting in increased fluid secretion. The gross appearance of kidney is “swiss cheese”
Airy Vetch Toxicosis (Vicia spp)
Hairy vetch is a legume used throughout regions with extensive farming and can be fed as pasture, hay, or silage. It is uncommon and it is unique manifestation results in
-Lesions of eosinophilic and granulomatous inflammation within the kidney, skin, and other viscera. Similar to type IV hypersensitivity reaction.
Lesions
-Multifocal to radiating cortical infiltrates, often around the vasculature. Histologically infiltrates are mixed with monocytes, lymphocytes, multinucleate giant cells, and eosinophils. Clinical disease develops several weeks later after ingestion and dermal manifestations of pruritus are seen. Death 10-20 days later.
-Holstein and Angus most susceptible.
Metabolic Diseases: Pathophysiology
Fibrous Osteodystrophy (end result)
Chronic Renal Disease: secondary hyperparathyroidism, activation of endosteal and subperiosteal osteoclast, bone resorption and replacement by fibrous connective tissue.
Fibrous Osteodystrophy (end result)
a. Primary
-Hyperthyroidism: functional parathyroid edemas, parathyroid carcinomas, idiopathic bilateral parathyroid hyperplasia.
b. Secondary
-Renal: reduction in functional nephrons, decreased GFR, chronic renal failure, metabolic acidosis, elevated serum phosphorous, ionized calcium fraction increases, decreased intestinal calcium transport, decreased serum calcium concentration and increased retention of phosphate by kidney, secondary increase in PTH secretion, increased calcium and phosphate release from bone.
Nutritional
-Decreased dietary intake of calcium, excess diatary phosphorous, and or vitamin D or malabsorption. Parathyroid gland chief cell hyperplasia, increased PTH, renal retention of calcium, renal excretion of phosphate, bone resorption = RUBBER JAW, low to normal serum calcium and phosphate.
Bran’s Disease: Nutritional Secondary Hyperparathyroidism
Bilateral or symmetrical maxillary fibrous osetodystrophy
-Decreased calcium or increase phosphorous in diet, decreased serum calcium, parathyroid hyperplasia and increased PTH, osteoclast stimulation, bone resorption with fibrous replacement.
Iguana Metabolic Bone Disease
Osteodystrophy, fibrous
Low diet in Vit D2 or D3
Can also be renal disease but nutritional is more common
Glomerular Amyloisosis
Secondary Papillary necrosis
Familial/hereditary = medullary deposits (AA) Shar Pei dogs, Abyssinian cats this first picture.
Tan, Waxy, Swollen.
AL amyloid
-Patients with plasma cell myelomas or other B lymphocyte dyscrasias
-Composed of fragments of light chains of immunoglobulins.
AA amyloidosis
-Reactive, spontaneously occurring.
-Liver secretes acute phase reactant protein called Serum Amyloid-A (SAA) protein.
-Chronic inflammatory disease or neoplastic disease
-Hereditary: Shar Pei dog, (medullary deposition)
-Hereditary: Abyssinian cats (medullary deposition)
Beta-amyloid
-Alzheimer’s patients, also found in dogs.
The problem
-Beta-pleated sheet deposition in blood vessels, basement membrane, spaces of dissent, spleen.
-Material can not be broken down, compression, occlusion of spaces, organs affected
**Kidney: glomerulonephropathy = protein loss
-Liver: birds
-Spleen, and many others
Glomeruli amyloidosis
Iodine stain
Formalin Special stain: Congo red, apple green perfringence under polarized light.
Different than AA hereditary
Viral Glomerulitis
Canine hepatitis this picture, HALO
-Caused by a direct viral insult to the glomerulus
-Occurs in acute systemic viral diseases
Viral diseases
-Canine Hepatitis (CHV-1)/ (CAV-1)
-Equine arteritis virus infection (EHV-1)
-Hog cholera (CSF)/ ASF/ Circovirus/Porcine cytomegalovirus
-Avian new castle disease
-Neonatal porcine cytomegalovirus infection.
Lesions
-Mild, usually transient, and result from viral replication in capillary endothelium
-Petecheal hemorrhages common in viremia, septicemia
-Microscopically: viral inclusions are present in glomeruli capillary endothelium. The inclusions are similar in all viremia and are usually large, basophilic to magenta, HALO.
-Endothelial hypertrophy, hemorrhages, necrosis of endothelium, thickened and edematous mesangium.
Acute viral GN gross lesions
-Kidney are often slightly swollen
-Renal capsular surface is smooth
-Kidneys are normal or pale color
-Glomeruli are visible as pinpoint red dots on the cut surface of the cortex.
Adenovirus Pathophysiology
Picture example in lungs, slightly enlarged, multiple small grey foci
The multiple dark foci scattered throughout the lung is unlike most other lung diseases, so think of one not seen or talked about much. It is Adenovirus Pneumonia and is quite specific
– During viremic phase, virus localized in glomeruli
* transient immune-complex GN
– Recovery from acute phase of disease
– Onset of systemic immune response
– Virus in glomeruli disappear- then reappear in tubular
epithelial cells in nephron
– basophilic INIBs → intranuclear inclusion
– Tubular epithelial persistence of virus (weeks-months) * Viral induced cytolysis of tubular epithelium
– Chronic lymphocytic, plasmacytic, and, less commonly, histiocytic interstitial nephritis
Feline FIP Mutated enteric Coronavirus
Vasculitis
Microscopic: granulomatous vasculitis (phlebitis)
Careful!! It can look like lymphoma (often ddx)
Pale irregular white areas, mostly in cortex.
Remarks: FIP lesions tend to follow the blood vessels
Embolic Bacterial Nephritis
Kidney Horse
Result of Bacteremia
Embolic nephritis or acute suppurative glomerulitis is the result of bacteria lodge in random glomerular capillaries and in interstitial capillaries, arterioles, causing multiple foci of inflammation
-Microabscesses through the renal cortex.
-Manifestation of renal vascular disease
-Microscopically: glomerular capillaries contain numerous bacterial colonies intermixed with necrotic debris and extensive infiltrates of neutrophils
-Glomerular or interstitial hemorrhage can occur as well
-If survival, coalescing scars from lymphocytes, plasma cells, macrophages, and fibroblast.
-Foals: Actinobacillus equiuli. Die within days of birth and have small abscesses (1 mm diameter) in many visceral organs.
-Pigs: Erysipelothrix rhusiopathiae, Salmonella, Strep sp.
-Sheeo/goats: Corynebacterium pseudotuberculosis, Trueperella pyogenes.
-Cattle: Arcanobacterium pyogenes, Staphylococcus aureus, Mannheim hemolytic, Strep bovis.
Embolic Bacterial Nephritis
-Pigs: Erysipelothrix rhusiopathiae, Salmonella, Strep sp.
Embolic Bacterial Nephritis
-Cattle: Arcanobacterium pyogenes, Staphylococcus aureus, Mannheim hemolytic, Strep bovis.
Diseases of the Tubules
Urinary Bladder Emphysema
Inherited abnormalities in tubular metabolism, in transport, or in reabsorption of glucose, amino acids, ions and proteins have been described in dogs.
-Secondary to splitting of glucose molecules (by bacteria) with subsequent release of CO2
-Primary renal Glucosuria an inherited disorder in Norwegian elkhounds dogs, sporadically in other breeds.
-Glucosuria from diabetes mellitus predisposes dogs to:
-Bacterial infections of the lower urinary tract
-Urinary bladder emphysema
-Escherichia coli, Clostridium perfringes, rarely Candida yeasts with subsequent carbon dioxide release into the bladder lumen and absorption of gas into the lymphatic vessels.
Diagnose the urinary diseases on the disease list
* Pyelonephritis
* Hydronephrosis
* Obstructive Nephritis / Cystitis
*Urinary bladder rupture * Patent Urachus *Urolithiasis
*Enzootic hematuria
Diagnose the urinary diseases * Acute / Chronic Cystitis
* Feline Idiopathic Cystitis
Differentiate the types of neoplasia of the urinary system Describe the lesions associated with Bracken fern toxicosis
Enzootic Hematuria
Bracken fern ingestion cattle
-Acute: hemorrhage, anemia, hematuria
-Chronic: chronic cystitis, neoplasia, carcinogenic
-TCC, SCC, Papilloma, adenoma, hemangioma, hemangiosarrcoma, leiomyoma/sarcoma, fibroma/sarcoma.
Leptospira interrogans, Ramona. Cattle and pigs.
Cortical tubular necrosis, and acute interstitial inflammatory infiltrates.
Cattle, calves, = Multifocal Lymphoplasmacytic Interstitial Nephritis. Embolic nephritis, White-Spotted Kidney
-Initially manifested as a multiple suppurative foci (white-spotted kidney). E. coli septicemia, Salmonella, Brucella.
Lesions can be
-Small to larger, patchy, coalescing, areas of pale cortex. TuboInterstitial inflammation or embolic nephritis are Acute lesions rarely seen in cattle. Chronic are lymphocytes, macrophages, etc in the interstitial. Capsular adhesions may be present.
Acute Tubular Necrosis (Aminoglycosides)
Leptospirosis dogs (interrogates servers canicola, icterohaemorrhagiae)
Cortical tubular necrosis, and acute interstitial inflammatory infiltrates.
Aminoglycoside antimicrobials, such as gentamicin, neomycin, kanamycin, tobramycin, amikacin, and streptomycin, are nephrotoxic.
-Neomycin is highly nephrotoxic
-Susceptibility of animal varies
-Amynoglycosides become concentrated in lysosomes and their toxic effect occur after release of large concentrations of the drugs from these organelles.
Lesions
-Acute swelling of proximal tubular epithelial cells, mitochondria swelling, rupture lysosomes, dilation of ER, shedding of tubular brush border, and cellular death.
-Swollen-bulges on cut surface
-Mottled tan-gray cortical surface and inner cortex
-Diffuse (dogs)
-Multifocal: bovine, pigs.
Leptospirosis = Interstitial nephritis, Acute tubular necrosis.
Leptospires enter the body through breaches in the mucous membranes, multiply and spread to the kidneys, where they persist in renal tubular cells.
C/S: anorexia, fever, vomiting, dehydration, icterus, muscle pain, and evidence of coagulopathy.
Lesions
-Grossly multifocal, coalescing inflammatory infiltrates that extend from the cortical medullary junction to the capsular surface are present.
-Neutrophilic infiltrates in highly acute stage, but later changes to lymphocytes and plasma cells.
-Chronic cases, various forms of fibrosis and sub scapular scarring occur.
-Silver stain = Leptospires in cytoplasm and the lumen of affected tubules
-The hilarious fat and medulla are yellow from jaundice
-Coagulation necrosis and hemorrhage
Ascending/descending renal bacterial infections
Hematogenous (ascending) infections of the kidney can result from bacteremia, E. coli and Staphylococcus spp. The outcome is bacterial emboli in the renal cortex. Embolic glomerulonephritis
Ascending infections result from a combination of urinary bladder infection and vesicoureteral reflux leading to pyelitis and concurrent intrarenal reflux leading to pyelonephritis.
