Meryl P. Littman

Guidelines for the Identification, Evaluation, and Management of Systemic Hypertension in Dogs and Cats

Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM) provide veterinarians with guidelines regarding the pathophysiology, diagnosis, or treatment of animal diseases. The foundation of the Consensus Statement is evidence-based medicine, but if such evidence is conflicting or lacking, the panel provides interpretive recommendations on the basis of their collective expertise. The Consensus Statement is intended to be a guide for veterinarians, but it is not a statement of standard of care or a substitute for clinical judgment. Topics of statements and panel members to draft the statements are selected by the Board of Regents with input from the general membership. A draft prepared and input from Diplomates is solicited at the ACVIM Forum and via the ACVIM Web site and incorporated in a final version. This Consensus Statement was approved by the Board of Regents of the ACVIM before publication.

Familial Protein‐Losing Enteropathy and Protein‐Losing Nephropathy in Soft Coated Wheaten Terriers: 222 Cases (1983–1997)

Records and pedigrees of Soft Coated Wheaten Terriers (SCWT) with protein-losing enteropathy (PLE) or protein-losing nephropathy (PLN) were studied retrospectively. Criteria for inclusion were defined based on analysis of blood (panhypoproteinemia for PLE, hypoalbuminemia for PLN) and urine (proteinuria for PLN) and histopathologic examination of tissue. Two hundred twenty-two affected dogs (female:male ratio = 1.6, P < .001) were clinically identified. Dogs were diagnosed with PLE earlier (P < .005; mean +/- SD age: 4.7+/-2.6 years, n = 76) than with PLN (6.3+/-2.0 years, n = 84) or with both diseases (5.9+/-2.2 years, n = 62). Clinical signs included vomiting, diarrhea, weight loss, pleural and peritoneal effusions, and less commonly thromboembolic disease. Dogs with PLE generally had panhypoproteinemia and hypocholesterolemia; intestinal lesions included inflammatory bowel disease, dilated lymphatics, and lipogranulomatous lymphangitis. Dogs with PLN generally had hypoalbuminemia, proteinuria, hypercholesterolemia, and azotemia; renal lesions typically showed chronic glomerulonephritis/glomerulosclerosis, and less commonly endstage renal disease. Dogs with combined PLE/PLN had intermediate mean values (P < .001) for serum total protein, albumin, globulin, and cholesterol but had a higher mean urine protein:creatinine ratio than did PLN dogs (P < .05); intestinal and renal lesions in these dogs were similar to those in the other groups. Two dogs had incidental mild renal dysplasia. Pedigree analysis from 188 dogs demonstrated a common male ancestor, although the mode of inheritance is unknown. Both PLE and PLN are common diseases in this small breed population. The prognosis is poor. Compared with previously reported intestinal and renal diseases in dogs, a new, distinctive familial predisposition for both PLE and PLN has been recognized in the SCWT breed.

Consensus Recommendations for the Diagnostic Investigation of Dogs with Suspected Glomerular Disease

BACKGROUND The International Renal Interest Society (IRIS) offers guidelines for chronic kidney disease and acute kidney injury. As dogs with glomerular disease may present differently and require different treatment than those with whole nephron or tubular disease, the IRIS Canine Glomerulonephritis (GN) Study Group was convened to formulate guidelines for these cases. The Diagnosis Subgroup was asked to make recommendations for diagnostic evaluation of such cases. OBJECTIVE To seek consensus among renal specialists for the evaluation of dogs with proteinuria because of suspected glomerular disease. METHODS After reviewing the literature, subgroup members discussed and wrote the draft paper and recommendations, which members of the IRIS Canine GN Study Group voted upon by electronic secret ballot, with comments noted. Consensus was declared if votes showed strong or general agreement from 85% of the respondents. RESULTS Diagnostic tests were categorized as essential, recommended, or potentially helpful, with prioritization dependent on case characteristics, eg, for cases with uncomplicated proteinuria versus complicated with hypoalbuminemia, azotemia, or both. Consensus was reached with 86-100% agreement on all questions posed. All cases should have basic examinations including blood pressure measurement, blood, and urine testing, and a search for infectious diseases relevant to their environs. The majority ranked imaging (chest radiographs, abdominal ultrasonogram) and renal biopsy procured and interpreted by experienced personnel as essential evaluations in complicated cases, but a few respondents deemed these to be essential in uncomplicated cases as well. CONCLUSIONS AND CLINICAL IMPORTANCE Strong consensus about recommendations for diagnostic evaluation of dogs with suspected glomerular protein loss was attained. These guidelines help clinicians characterize disease processes for more informed therapeutic decision-making.

MHC class II association study in eight breeds of dog with hypoadrenocorticism.

Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison’s disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.

Consensus recommendations for treatment for dogs with serology positive glomerular disease

The finding of glomerular proteinuria concurrent with a positive titer for an infectious agent with recognized potential to incite glomerular disease is often interpreted to support a cause–effect relationship between these two findings. Such a conclusion is risky and may erroneously influence clinical decisions including the diagnostic approach, diagnosis, therapeutic strategies and risks, and outcomes of the disease. Although any infection can be causally associated with glomerular diseases, infections with Borrelia burgdorferi and Leishmania in dogs are especially problematic because of the seemingly common association of these infections with proteinuric conditions (Tables 1, 2). However, in some areas of the United States, common exposures to heartworm, Borrelia burgdorferi, Ehrlichia, Anaplasma, or Babesia spp. lead to seroconversion without development of proteinuria; and in Mediterranean countries exposure to Leishmania promotes a positive IFAT result that indicates exposure to the infection but not necessarily active infection. Thus, serology alone is not conclusive evidence that an infectious agent is the cause of a coexisting glomerular disease (Tables 1, 2). If a patient has clinical evidence of an active infectious disease associated with proteinuria, it is compelling to presume the linkage between the serology and glomerular disease may be real. This is clearly evident for Leishmaniasis in which serology has a 98% predictive sensitivity, but is less compelling for dogs with Borrelia-associated glomerular disease in which less than 30% of dogs with concurrent seropositivity and glomerular disease have nonrenal signs consistent with active Lyme disease. Proteinuria is an uncommon finding in dogs with Lyme-seropositivy, and may be recognized in less than 2% of seropositive dogs. Furthermore, clinical signs ascribed to an infectious agent like Borrelia may be the result of a coinfection with another organism (ie, Rickettsia rickettsii, Ehrlichia spp., etc) that also can cause proteinuria and similar clinical signs (Table 2). Lyme seropositivity, at a minimum, is a marker for tick and wildlife exposure, and co-infections which cause proteinuria should be considered. Similarly depending on the phase of disease and magnitude of the titer, up to 55% of seropositive dogs with titers for Leishmaniasis do not manifest evident clinical signs of the disease. The response to anti-infective treatment also is not reliable proof of causation because other infectious agents may be sensitive to the treatment, and therapies like doxycycline may have anti-inflammatory and antiarthritic properties sufficient to resolve clinical signs unassociated with an infectious cause. Renal histopathology can be helpful to support an association between the seropositivity and the glomerulopathy if lesions characteristic for the disease are identified in the biopsy, but this too cannot prove a cause–effect relationship unless agent-specific antigens associated with active immune deposits in glomerular lesions are proven to be from the infectious agent. However, currently this testing is not available clinically. In a study of Lyme-positive dogs with glomerular disease, 84% had Lyme-specific immune deposits in their glomeruli. Agent-specific immune deposits, however, may have been deposited nonspecifically in abnormal glomeruli. Nonetheless, a properly processed and evaluated renal biopsy provides a basis for guiding decisions to intervene with immunotherapy. (See “Consensus Recommendations for Immunosuppressive Treatment of Dogs with Glomerular Disease Based on Established Pathology” and “Pathologic Evaluation of From the Animal Medical Center, New York, NY (Goldstein); the ANUBI Ospedale per Animali da Compagnia, Moncalieri, Italy (Brovida); the Departamento de Medicina y Cirug ıa Animal, Universidad de Murcia, Spain (Fern andez-del Palacio); the University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA (Littman); the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN (Polzin); the Medical Consultancy Services, Ta’ Xabiex, Malta (Zatelli); and the Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA (Cowgill). All subgroup members of the IRIS Canine GN Study Group contributed equally in the preparation of this manuscript. Corresponding author: R.E. Goldstein (Chair), Chief Medical Officer, The Animal Medical Center, 510 East 62nd Street, New York, NY 10065-8314; e-mail: richard.goldstein@amcny.org. Submitted September 16, 2013; Revised September 16, 2013; Accepted September 16, 2013. Copyright

Putative candidate genes for canine hypoadrenocorticism (Addison's disease) in multiple dog breeds

CANINE hypoadrenocorticism results from structural damage/functional defects of the adrenal cortex. In human beings, 21 hydroxylase autoantibodies are an early marker for a clinically similar condition (Addisons disease) in 80–90 per cent of patients (Betterle and others 1999, Falorni and others 1995, 1997, Laureti and others 1998), but these antibodies have not been identified in dogs. There are currently no genetic or other biomarkers for the condition in dogs, and diagnosis is based on high adrenocorticotropin (ACTH) and low cortisol levels or impaired cortisol secretory response to synthetic ACTH; however, diagnosis is complicated and often delayed because of the multifaceted clinical presentation. With a timely diagnosis, affected animals can be treated and they can live a relatively normal life, but many dogs are treated incorrectly for more common conditions, reaching ‘Addisonian crisis’ before a diagnosis has been made. Understanding the genetic involvement in canine hypoadrenocorticism could facilitate the development of a genetic test for disease risk that could be used to identify dogs at increased risk for hypoadrenocorticism and enrol them into a screening programme. Furthermore, it could be used to inform breeding strategies and reduce the incidence of hypoadrenocorticism in susceptible dog breeds. Currently, there is limited understanding of the genetic aetiology in dogs or human beings, although the human leucocyte antigen DRB1 is widely accepted as a functional susceptibility locus in the latter with further risk given by the major histocompatibility complex (MHC) class l region (Gombos and others 2007, Erichsen and others …

Familial renal disease in soft-coated wheaten terriers.

Objective To review what is known about the familial renal diseases in soft-coated wheaten terriers (SCWT), provide an update in developments in this field including the relationship with protein-losing nephropathy (PLN) and the potential association with protein-losing enteropathy (PLE). Data Sources Information was derived from studies of dogs maintained in the North Carolina State University colony, information contained within an open registry of affected dogs, and data gathered from the general population of wheaten terriers at risk as well as studies performed on banked DNA samples from affected SCWT in the general population and normal geriatric dogs seen at the University of Pennsylvania (PennVet). Human Data Synthesis A two-hit pathogenesis has been proposed in some types of human focal segmental glomerulosclerosis, specifically the subset of cases that are associated with a podocytopathy. At risk podocytes may be predisposed to injury by disease processes that would be reversible in other patients. Veterinary Data Synthesis Mutations were found in association with PLN in SCWT, indicating a podocytopathy that causes a change in glomerular permselectivity. This podocytopathy leads to the development of lesions resembling focal segmental glomerulosclerosis. There is also strong evidence supporting a high prevalence of food hypersensitivity reactions in SCWT, although it is unclear if these reactions have a primary or secondary role in the development of PLE. There are also suggestions of immunodysregulation in affected SCWT. Conclusions PLN in SCWT is due to a podocytopathy. The cause of PLE has not been identified; however, it is possible that PLE develops from a functional-structural abnormality in the intestines and food allergies develop as secondary phenomena. It is also possible that inflammatory events that are the result of either immunodysregulation or food allergies might lead to the development of PLE. In either case, PLE most likely exacerbates PLN in affected SCWT.OBJECTIVE To review what is known about the familial renal diseases in soft-coated wheaten terriers (SCWT), provide an update in developments in this field including the relationship with protein-losing nephropathy (PLN) and the potential association with protein-losing enteropathy (PLE). DATA SOURCES Information was derived from studies of dogs maintained in the North Carolina State University colony, information contained within an open registry of affected dogs, and data gathered from the general population of wheaten terriers at risk as well as studies performed on banked DNA samples from affected SCWT in the general population and normal geriatric dogs seen at the University of Pennsylvania (PennVet). HUMAN DATA SYNTHESIS A two-hit pathogenesis has been proposed in some types of human focal segmental glomerulosclerosis, specifically the subset of cases that are associated with a podocytopathy. At risk podocytes may be predisposed to injury by disease processes that would be reversible in other patients. VETERINARY DATA SYNTHESIS Mutations were found in association with PLN in SCWT, indicating a podocytopathy that causes a change in glomerular permselectivity. This podocytopathy leads to the development of lesions resembling focal segmental glomerulosclerosis. There is also strong evidence supporting a high prevalence of food hypersensitivity reactions in SCWT, although it is unclear if these reactions have a primary or secondary role in the development of PLE. There are also suggestions of immunodysregulation in affected SCWT. CONCLUSIONS PLN in SCWT is due to a podocytopathy. The cause of PLE has not been identified; however, it is possible that PLE develops from a functional-structural abnormality in the intestines and food allergies develop as secondary phenomena. It is also possible that inflammatory events that are the result of either immunodysregulation or food allergies might lead to the development of PLE. In either case, PLE most likely exacerbates PLN in affected SCWT.

Resolution of a proteinuric nephropathy associated with Babesia gibsoni infection in a dog.

A 4 yr old male castrated Labrador retriever was evaluated for a short history of inappetance, lethargy, small-bowel diarrhea, polyuria, and polydipsia. Clinicopathologic abnormalities were consistent with protein-losing nephropathy and renal azotemia. Expansive infectious disease testing implicated Babesia gibsoni via whole blood polymerase chain reaction. Renal histopathology results were consistent with membranoproliferative glomerulonephritis and immune complex deposition. The dog was treated with azithromycin, atovaquone, and one dose of corticosteroids/cyclophosphamide. Three months after therapy was completed, the dog was clinically healthy, and all clinicopathologic abnormalities (including Babesia species polymerase chain reaction) had resolved. Atypical presentations of Babesia gibsoni should be considered with proteinuric nephropathy.

Presumptive hepatotoxicity and rhabdomyolysis secondary to phenazopyridine toxicity in a dog.

OBJECTIVE To describe a rare, but potential clinical manifestation of phenazopyridine (PAP) toxicity in a dog. CASE SUMMARY A 6-year-old spayed female Chihuahua was evaluated for ataxia and dysphagia after ingestion of 200 mg (66 mg/kg) of PAP hydrochloride. The dog was presented to the hospital with shifting leg lameness involving all 4 limbs, which progressed to reluctance to walk and severe diffuse muscle hyperesthesia. Clinical laboratory abnormalities included marked increases in serum alanine aminotransferase, aspartate aminotransferase, creatine kinase, mild increases in alkaline phosphatase, and increased c-Tnl-troponin concentration. Treatment included administration of intravenous fluids, muscle relaxants, pain medications, and hepatoprotectants for 5 days in the hospital, and medical management at home for an additional 5 days. Follow-up examinations performed 1 and 6 months after initial presentation revealed the dog to be clinically healthy with serum biochemical profiles within reference intervals. NEW OR UNIQUE INFORMATION PROVIDED The purpose of this report is to describe an unusual manifestation of PAP toxicosis in a dog, which has not been previously reported in the literature. A review of the ASPCA Animal Poison Control Center database revealed 347 cases of PAP exposure in dogs during 2000-2009 underscoring the importance of being aware of this toxicity in the dog.

ACVIM consensus update on Lyme borreliosis in dogs and cats

An update of the 2006 American College of Veterinary Internal Medicine (ACVIM) Small Animal Consensus Statement on Lyme Disease in Dogs: Diagnosis, Treatment, and Prevention was presented at the 2016 ACVIM Forum in Denver, CO, followed by panel and audience discussion and a drafted consensus statement distributed online to diplomates for comment. The updated consensus statement is presented below. The consensus statement aims to provide guidance on the diagnosis, treatment, and prevention of Lyme borreliosis in dogs and cats.