Adult female mixed breed 4-year-old canine (Canis lupus familiars).This dog presented to the Center for Zoonoses Control in Natal, Brazil with anorexia, cachexia, exudative dermatitis, facial edema, and keratoconjunctivitis.
Necropsy was performed immediately after humane euthanasia.Â The body condition of this dog was thin with minimal subcutaneous and abdominal adipose tissue.Â Externally, the skin had multifocal to coalescing regions of crusting with seborrheic exudate, the muzzle of the face was markedly edematous, and the eyes had amucopurulent palpebritis and keratoconjunctivitis.Â There was a significant burden of ticks within the ears of the dog.Â The spleen was enlarged to 1.5 times normal size with a mottled irregular appearance.Â The liver was mildly enlarged and mottled in appearance.Â The kidneys were bilaterally pale and mildly enlarged with a mottled appearance and an undulating cortical surface.Â The bladder contained cloudy urine with numerous protein casts.
Section of kidney with marked multifocal infiltrates of inflammatory cells including large numbers of plasma cells, macrophages, and lymphocytes.Â These cellular infiltrates were primarily located in perivascular and periglomerular areas of the cortical and medullary interstitium.Â Large foamy macrophages containing 1-3 small 1.5-3 micron amastigotes with an occasionally visible kinetoplast perpendicular to the protozoal nucleus were commonly found within areas of inflammation.Â Glomeruli were diffusely altered, with 10-15% being shrunken and hypocellular with increased collagen both within the glomerular tuft and Bowman's capsule (sclerosis), and others with the glomerular mesangium diffusely expanded by streaks of eosinophilic collagen with marked mesangial and endocapillary hypercellularity (membranoproliferative glomerulonephritis).Â Synechiae were numerous, often with the formation of glomerular crescents.Â Bowman's capsule was similarly expanded to 3-6 times its normal thickness by eosinophilic material in most affected nephrons.Â The tubular interstitium was prominently expanded by the inflammatory cell infiltrates as well as the deposition of fibrillar eosinophilic material (collagen).Â Distal medullary tubules were ectatic and contained hyper-eosinophilic proteinaceous concretions.
Kidney: Glomerulonephritis, membranoproliferative, chronic, diffuse/global, severe, with prominent glomerulosclerosis and multifocal to coalescing lymphoplasmacytic and histiocytic interstitial nephritis with intra-histiocytic protozoal amastigotes; morphology consistent with Leishmania species (Leishmania infantum (synonym chagasi)).
Canine leishmaniasis, primarily caused by Leishmania infantum, is a progressive and fatal disease with public health significance in endemic areas.(6) These endemic regions include the Mediterranean basin, northern and sub-Saharan Africa, Central and South America, and northern and northwestern China.(6) Additionally, within the United States, canine leishmaniasis is endemic with the American Foxhound breed, with sporadic occurrence in the Neapolitan Mastiff, Italian Spinone, other European origin breeds, and military service animals from the Middle East.Â Transmission is via one of numerous phlebotomine sandflies in endemic regions and vertical transmission independent of vector species has been documented.Â Dogs are also susceptible to cutaneous leishmaniasis caused by a variety of species including L.Â braziliensis and L.Â panamensis.(6)
Leishmania species have a unique pathogenesis and means of persistence within host cells enabling the establishment of long-term chronic infection.Â After a sandfly bite, an influx of both neutrophils and macrophages occurs, even in the absence of parasites.Â Parasites are able to survive within neutrophils due to the ability to inhibit the acidification of the phagosome, but have not been shown to transform into amastigotes or proliferate within in the neutrophil.(9) At the time of neutrophil apoptosis, surviving parasites are phagocytosed by resident and infiltrating macrophages, where the parasites will transform into amastigotes, replicate, and establish long-term infection.Â Dermal dendritic cells also become infected at the site of inoculation, becoming mature and migrating to the lymph node.Â Leishmania are resistant to acidification as amastigotes, and persist in these compartments which are late endosome associated LAMP1, Rab7 positive vacuoles.(13)
The immune response to all Leishmania species as an intracellular pathogen is dependent upon a timely and appropriate Th1 response including IL-12 production by dendritic cells and macrophages, efficient MHC II presentation, and subsequent IFNy production from T cell populations.Â Parasite killing is dependent primarily upon intracellular killing via superoxide and nitric oxide within phagolysosomes of infected macrophages.Â Leishmania utilize a number of immune evasion strategies to inhibit the immune response including the interruption of DC maturation, the stimulation of anti-inflammatory cytokines such as TGF-p and IL-10, the interruption of cellular signaling of the STAT pathways necessary for IFNy production, and through the induction of CD25+, FoxP3+ T regulatory cells.
Clinical presentation varies and includes dermal lesions, splenomegaly, generalized lymphadenopathy, cachexia, anorexia, muscle wasting, polyuria and polydipsia, proteinuria, keratoconjunctivitis, nail overgrowth, and hematologic abnormalities.(2,8,14) Splenic and hepatic lesions typically consist of granulomatous splenitis characterized by variable numbers of amastigote-infected macrophages, and lymphoplasmacytic and granulomatous portal and periportal hepatitis.(14) Skin lesions are one of the most common presenting signs in endemic regions and can include nonpruritic dermatitis, ulcerative dermatitis, focal or multifocal nodular dermatitis, proliferative dermatitis, or mucocutaneous ulcerative or proliferative dermatitis.(14) With these lesions, secondary bacterial pyoderma is the most common complicating co- morbidity.(8) Histologically, these lesions are granulomatous or pyogranulomatous with acanthosis, orthokeratotic and hyperkeratotic hyperkeratosis, and ulceration with serocellular crust formation.(8) Lymphoplasmacytic vasculitis and perivasculitis may also be present.Â Ocular lesions may also occur in approximately 16% of patients, depending on disease severity.(11) Common manifestations are conjunctivitis, blepharitis, and anterior uveitis.(11)
Renal disease due to glomerulonephritis and interstitial nephritis is a common clinical sign of canine leishmaniasis due to Leishmania infantum, occurring in greater than 96% of symptomatic dogs.Â Alterations in renal function during active VL are generally reversible with anti-Leishmania therapy with antimonials or amphotericin B.(1,7) However, VL-associated kidney disease is progressive and without therapy can result in end stage renal disease (>25% of canine cases).(7,12) Renal lesions due to visceral leishmaniasis have been previously characterized as progressive glomerulonephritis including mesangial proliferative, membranoproliferative (MPGN), focal segmental glomerulosclerosis, and minimal change glomerulonephritis, and a smaller percentage with crescentic glomerulonephritis.(4,5) Multiple studies have evaluated the morphology and ultrastructural characteristics of renal lesions due to canine leishmaniasis.(4,5) Previous characterizations described a wide array of morphologic changes, primarily of a membranoproliferative and mesangial proliferative type.(4,5)
Dogs with symptomatic VL typically have a hypergammaglobulinemia and a high degree of circulating parasite antigen.(3) It is logical that immune complexes comprise glomerular deposits responsible for VL-associated MPGN.Â However, studies evaluating the proteins associated with these glomerular deposits have had conflicting results, with either presence or absence of lgG, lgM, or C3b in glomerular deposits.(5,10) All studies found a significant increase in the amount of L.Â infantum antigen and inflammatory cells within the glomerular basement membrane and mesangium.(4,5) Increased numbers of CD4+ T cells within the glomerulus of affected animals as well as increased expression of adhesion molecules ICAM-1 and P-Selectin have been characterized.(5)
Kidney: Glomerulonephritis, membranoproliferative, diffuse, severe, chronic, with multifocal to coalescing lymphoplasmacytic and histiocytic interstitial nephritis and intra-histiocytic protozoal amastigotes.
The contributor does an excellent job of summarizing the epidemiology, pathogenesis, clinical appearance and gross/histologic features of canine leishmaniasis.Â Leishmania sp.Â produces three general types of disease in veterinary medicine: cutaneous, mucocutaneous and visceral.Â VL has both anthroponotic (L.Â donovani) and zoonotic (L.Â infantum) forms- dogs are the primary reservoir of zoonotic leishmaniasis.(6) VL has received a significant amount of media attention in recent years, owing to hundreds of reported cases of Old World cutaneous and (less frequently) visceral leishmaniasis in US soldiers and military working dogs deployed to Iraq or Afghanistan.(15)
While there are numerous potential clinical presentations of canine leishmaniasis, diffuse mesangioproliferative or membranoproliferative glomerulonephritis and interstitial nephritis are the most common renal manifestations.(1,4) As noted by the contributor, although a type III hypersensitivity mechanism has historically been accepted as the primary mechanism of VL glomerulopathy, there is new evidence to suggest that migration of CD4+ T-cells and increased expression of adhesion molecules such as ICAM-1 and P-Selectin are also involved, while decreased apoptosis may play a role in the proliferative pattern of MPGN.(5) The basic pathogenesis of type III hypersensitivity and immune mediated glomerulonephritis involves persistent antigenemia with a slight antigen excess, which results in circulating soluble immune complexes that deposit in glomerular capillaries.Â These antigen-antibody complexes activate the complement cascade via the classical pathway, which induces production of C3a, C5a and C5-9 (the membrane attack complex or MAC).Â C5a is chemotactic for neutrophils, which release toxic proteinases, arachidonic acid metabolites and oxygen free radicals, while both C3a and C5a are potent anaphylatoxins.Â Additionally, the MAC is capable of directly damaging the glomerular capillaries and mesangium.(16)
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