Performance Assessment of New Urinary Translational Safety Biomarkers of Drug-induced Renal Tubular Injury in Tenofovir-treated Cynomolgus Monkeys and Beagle Dogs.

Newer urinary protein kidney safety biomarkers can outperform the conventional kidney functional biomarkers blood urea nitrogen (BUN) and serum creatinine (SCr) in rats. However, there is far less experience with the relative performance of these biomarkers in dogs and nonhuman primates. Here, we report urine protein biomarker performance in tenofovir-treated cynomolgus monkeys and beagle dogs. Tenofovir intravenous daily dosing in monkeys for 2 or 4 weeks at 30 mg/kg/day resulted in minimal to moderate tubular degeneration and regeneration, and tenofovir disoproxil fumarate oral dosing in dogs for 10 days at 45 mg/kg/day resulted in mild to marked tubular degeneration, necrosis, and regeneration. Among biomarkers tested, kidney injury molecule 1 (Kim-1) and clusterin (CLU) clearly outperformed BUN and SCr and were the most reliable in detecting the onset and progression of tenofovir-induced tubular injury. Cystatin C, retinol binding protein 4, ß2-microglobulin, neutrophil gelatinase-associated lipocalin, albumin, and total protein also performed better than BUN and SCr and added value when considered together with Kim-1 and CLU. These findings demonstrate the promising utility of these urinary safety biomarkers in monkeys and dogs and support their further evaluation in human to improve early detection of renal tubular injury.

Use of bovine pericardium (Tutopatch®) graft for surgical repair of deep melting corneal ulcers in dogs and corneal sequestra in cats.

OBJECTIVE: To evaluate the efficacy of bovine pericardium (BP) graft in the treatment of deep melting corneal ulcers in three dogs and corneal sequestra in three cats. PROCEDURE: Three dogs with keratomalacia affecting the deep third of the stroma and three cats with corneal sequestrum were evaluated and underwent surgery. Following keratectomy, BP material was placed into the keratectomy bed and sutured to the recipient cornea with 9/0 polyglactin suture material. Postoperative treatment with topical and systemic antibiotics, systemic nonsteroidal anti-inflammatory agents, and topical atropine was prescribed. Follow-up examinations were carried out 1, 2 weeks, 1 and 2 months after the surgery and consisted of a complete ophthalmic examination. Optical coherence tomography (OCT) was performed 1 and 2 months after the surgery in one dog and in one cat. RESULTS: At 1 week, corneal neovascularization was present around the BP graft in all cases. Four weeks after the BP graft, in two dogs and in all cats, the vascularization was regressing and the graft was integrated into the cornea, which was regaining transparency. Topical treatment with anti-inflammatory agents was then prescribed for 2 weeks. Two months after the surgery, 5 of 6 corneas in two dogs and three cats had healed with focal corneal scarring. The remaining dog had progression of the keratomalacia involving the deep BP graft that required additional surgery, but became blind. CONCLUSION: Bovine pericardium graft offers a promising option for surgical reconstruction of the cornea following keratectomy for the management of corneal ulcers and sequestra.

Intravitreal cidofovir injection for the management of chronic glaucoma in dogs.

OBJECTIVE: The objective of this retrospective study was to determine whether an intravitreal injection of 562.5 ug of cidofovir was effective in lowering the intraocular pressure (IOP) in chronically glaucomatous avisual canine eyes. PATIENTS: This study reviews the medical records of 167 canine patients diagnosed with chronic glaucoma between 2006 and 2011. The criteria for study inclusion were patients with irreversibly avisual eyes that were refractory to medical management, without evidence of endophthalmitis or intraocular neoplasia as determined by historical, clinical, and/or ultrasonographic examination, who were treated with an intravitreal injection of cidofovir. PROCEDURE: Using only topical anesthesia for most patients, aqueouscentesis was followed by an intravitreal injection of 562.5 ug of cidofovir and 1 mg of subconjunctival triamcinolone. An initial recheck was performed 14 days following the injection. RESULTS: The mean IOP immediately prior to injection was 46 ± 13 mm Hg with a median of 47 mm Hg. At the initial recheck, the mean IOP was 10 ± 11 mm Hg with a median of 6 mm Hg. A common postinjection finding was mild intraocular inflammation, which was controlled in all cases with topical neopolydex solution. Post injection complications included corneal ulceration (2.4%) and endophthalmitis (2.4%). Phthisis bulbi was a common sequalae (70%). One injection of cidofovir was successful in lowering the IOP in 85% of cases (P < 0.0001); multiple injections raised the success rate to 97%. CONCLUSIONS: An intravitreal injection of cidofovir was found to be an effective method of lowering intraocular pressure to <20 mm Hg. While the common side effect of phthisis bulbi resulted in a less than optimal cosmetic result, patients subjectively benefited from enhanced comfort warranting consideration of this approach in the management of chronically glaucomatous avisual canine eyes.

Intracranial meningioma causing partial amaurosis in a cat.

OBJECTIVE: To describe a case of intracranial meningioma causing visual impairment in a cat, successfully treated by surgery. PROCEDURES: An adult neutered male domestic cat was referred with a 10-month history of progressive visual impairment and altered behavior. Investigations included physical, ophthalmologic and neurological examinations as well as hematology, serum biochemistry and CT scan of the head. RESULTS: The menace response was absent in the left eye and decreased in the right eye. Electroretinograms were normal on both eyes, as was ophthalmic examination, ruling out an ocular cause and allowing a presumptive diagnosis of partial amaurosis due to a post-retinal lesion. CT scan demonstrated a large sessile extra axial mass along the right parietal bone and thickening of the adjacent bone. Cerebrospinal fluid was not collected because high intracranial pressure represented a risk for brain herniation. A right rostrotentorial craniectomy was performed to remove the tumor. Ten days after surgery, vision was improved, neurological examination was normal and normal behavior was restored. Ten months after surgery, ophthalmological examination showed no visual deficit and CT scan did not reveal any sign of recurrence. CONCLUSION: Advanced imaging techniques allow veterinarians to detect early cerebral diseases and to provide specific treatment when it is possible. In cases of feline amaurosis due to intracranial meningioma, the vital prognosis is good while the visual prognosis is more uncertain, but recovery of normal vision and normal behavior is possible as demonstrated in the present case.

Congenital orbital cysts of neural tissue in two dogs.

A 3-month-old English Cocker Spaniel and a 6-month-old miniature poodle presented with clinical signs related to an abnormal right eye since birth. In both dogs, the right globe could not be identified and was replaced by a fluctuant intraorbital mass covered by a vascularized mucous membrane. Ultrasonography demonstrated that both masses were cystic structures markedly larger in size than the normal contralateral globes. In both cases, surgical excision revealed a multilobular cyst filling the whole orbital cavity. Histopathologic examination and immunostaining for glial fibrillary acid protein and S100 protein supported a diagnosis of neural cysts associated with ocular dysplasia. The definitive diagnosis was congenital cystic eye and microphthalmos with cyst for the Cocker Spaniel and miniature poodle, respectively. Karyotype was normal in both dogs. Congenital cystic eye and microphthalmos with cyst result from defects in early embryonic life that arise following formation of the optic vesicle and prior to closure of the optic fissure. To the authors' knowledge neither has been reported in the canine species. They should be considered in the differential diagnosis of orbital cysts in dogs.

Goniodysgenesis associated with primary glaucoma in an adult European Short-haired cat.

A 9.5-year-old, male castrated European Short-haired (ESH) cat was presented with bilateral glaucoma associated with pectinate ligament dysplasia and an open iridocorneal angle (ICA) upon gonioscopy. The right eye (OD) was avisual and slightly enlarged; the left eye (OS) was still visual. Intraocular pressure (IOP) had been controlled with medical therapy over a 1.5 year-period in both eyes (OU). Eventually IOP could not be adequately controlled medically and the painful and blind right eye was enucleated and transscleral diode laser cyclophotocoagulation was performed twice in the left eye with less than optimal results and progressive loss of vision. Histopathology of the right eye showed goniodysgenesis characterized by failure of differentiation of the pectinate ligament, which existed as a solid sheet of uveal tissue at the entrance of a hypoplastic ciliary cleft, which contained loose mucoid mesenchymal tissue. The trabecular meshwork was hypoplastic and the scleral venous plexus could not be identified. Other findings of chronic glaucoma were inner retinal atrophy, optic nerve atrophy with disc cupping, scleral thinning, peripheral corneal vascularization and pigmentation, and mild focal iridal mononuclear inflammatory cell infiltrate.

Classification of feline intraocular neoplasms based on morphology, histochemical staining, and immunohistochemical labeling.

The objectives of this study were to evaluate morphologic, histochemical, and immunohistochemical characteristics of well-differentiated and anaplastic intraocular neoplasms of cats, and to develop a diagnostic algorithm for, and investigate the association of ruptured lenses with these neoplasms. Seventy-five feline globes with intraocular neoplasms were stained with hematoxylin and eosin and examined by light microscopy. Morphologic diagnoses included 33 intraocular sarcomas, 17 diffuse iris melanomas, 15 lymphosarcomas, three ciliary adenomas, one metastatic carcinoma, and six undifferentiated intraocular neoplasms. Sections of these globes were then stained with periodic acid Schiff (PAS), and immunohistochemical (IHC) labels for various cellular markers. Histochemical staining and IHC labeling confirmed cellular differentiation in 73/75 neoplasms but was discordant with morphologic diagnoses in 8/75. These included four neoplasms morphologically diagnosed as lymphosarcomas but which expressed differentiation antigens consistent with melanoma (n = 3) or ciliary adenocarcinoma (n = 1), and four tumors morphologically diagnosed as intraocular sarcomas that expressed differentiation antigens for melanoma (n = 2), metastatic carcinoma (n = 1), or remained undifferentiated (n = 1). Immunohistochemical labeling suggested a diagnosis in 5/6 morphologically undifferentiated neoplasms including one intraocular sarcoma, two diffuse iridal melanomas, and two ciliary adenocarcinomas. Based upon morphologic, histochemical, and IHC characterization, ruptured lens capsules were detected in 28/30 intraocular sarcomas, 3/24 diffuse iris melanomas and 1/11 lymphosarcomas, but not in ciliary epithelial neoplasms, metastatic carcinomas, or undifferentiated intraocular neoplasms. An algorithm is provided that facilitates stain and IHC label selection for differentiating anaplastic intraocular feline neoplasms.

Ocular histopathologic observations in Norwegian Elkhounds with primary open-angle, closed-cleft glaucoma.

A retrospective histopathologic study of primary glaucoma in the Norwegian Elkhound was undertaken with the study of 9 clinically normal eyes and 22 glaucomatous eyes. All glaucomatous eyes showed goniodysgenesis as manifested by pectinate ligament dysplasia and/or trabecular meshwork dysplasia. Cystic degeneration of the iridociliary epithelial and/or peripheral retina was present in a high percentage of both normotensive and glaucomatous eyes. Utilizing the scheme proposed by Smith et al. (Veterinary and Comparative Ophthalmology 1993; 3: 16-28) the morphology of this disease in the Norwegian Elkhound would be classified as an open-angle, closed-cleft glaucoma, with histopathologic alterations of the outflow pathway similar to that described in other breeds with primary glaucoma.

Bilateral neuroepithelial choristomas of the optic disc in a cynomolgus monkey (Macaca fascicularis): a case report.

A 6-year-old intact male cynomolgus monkey of Chinese origin was received at the Sierra Biomedical Facility. While physical examination revealed good body condition with no abnormalities, routine ophthalmic examination revealed bilateral proliferative optic neuropathy involving the dorsal aspect of the optic disc. No changes were noted in the appearance of the lesions over 8 months, and fluoroescein angiography revealed no abnormalities other than obstruction of the view of the retinal vessels by the lesions. Histopathologic studies revealed characteristics consistent with a diagnosis of bilateral neuroepithelial choristoma.