@article{hill_blikslager_2012, title={Effect of a zincl-carnosine compound on acid-induced injury in canine gastric mucosa ex vivo}, volume={73}, ISSN={0002-9645}, url={http://dx.doi.org/10.2460/ajvr.73.5.659}, DOI={10.2460/ajvr.73.5.659}, abstractNote={Abstract
Objective—To examine whether a zinc l-carnosine compound used for treatment of suspected gastric ulcers in dogs ameliorates acid-induced injury in canine gastric mucosa.
Sample—Gastric mucosa from 6 healthy dogs.
Procedures—Mucosa from the gastric antrum was harvested from 6 unadoptable shelter dogs immediately after euthanasia and mounted on Ussing chambers. The tissues were equilibrated for 30 minutes in neutral Ringer's solution prior to incubation with acidic Ringer's solution (HCl plus Ringer's solution [final pH, 1.5 to 2.5]), acidic Ringer's solution plus zinc l-carnosine compound, or zinc l-carnosine compound alone. Tissues were maintained for 180 minutes in Ussing chambers, during which permeability was assessed by measurement of transepithelial electrical resistance. After the 180-minute treatment period, tissues were removed from Ussing chambers and labeled with immunofluorescent anti–active caspase-3 antibody as an indicator of apoptosis.
Results—Permeability of the gastric mucosa was significantly increased in a time-dependent manner by addition of HCl, whereas control tissues maintained viability for the study period. Change in permeability was detected within the first 15 minutes after acid application and progressed over the subsequent 150 minutes. The zinc l-carnosine compound had no significant effect on this increase in permeability. Apoptosis was evident in acid-treated tissues but not in control tissues. The zinc l-carnosine compound did not protect against development of apoptosis.
Conclusions and Clinical Relevance—Addition of HCl caused a dose-dependent increase in gastric permeability over time and apparent induction of apoptosis as determined on the basis of immunofluorescence. However, there was no significant protective effect of a zinc l-carnosine compound. Nonetheless, results suggested the utility of this method for further studies of canine gastric injury.}, number={5}, journal={American Journal of Veterinary Research}, publisher={American Veterinary Medical Association (AVMA)}, author={Hill, Tracy L. and Blikslager, Anthony T.}, year={2012}, month={May}, pages={659–663} }
 @article{minter_wood_hill_lewbart_2010, title={CYSTOSCOPIC GUIDED REMOVAL OF ECTOPIC EGGS FROM THE URINARY BLADDER OF THE FLORIDA COOTER TURTLE (PSEUDEMYS FLORIDANA FLORIDANA)}, volume={41}, ISSN={["1042-7260"]}, DOI={10.1638/2009-0196.1}, abstractNote={Abstract Three gravid, female, wild Florida cooter turtles (Pseudemys floridana floridana) were evaluated and treated by the North Carolina State University College of Veterinary Medicine Turtle Rescue Team as a result of traumatic injuries or infection. As part of medical management, oviposition was induced using oxytocin, which was only partially effective. In all three cases, ectopic eggs were subsequently identified in the urinary bladder by ultrasound and were successfully removed via a minimally invasive cystoscopic-guided technique. One of the three turtles died within several days of the procedure, and necropsy revealed granulomatous bacterial cystitis. It is hypothesized that these complications were likely due to the length of time between induction with oxytocin and the identification and removal of the ectopic egg.}, number={3}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Minter, Larry J. and Wood, Michael W. and Hill, Tracy L. and Lewbart, Gregory A.}, year={2010}, month={Sep}, pages={503–509} }
 @article{cruse_vaden_mathews_hill_robertson_2009, title={Use of Computed Tomography (CT) Scanning and Colorectal New Methylene Blue Infusion in Evaluation of an English Bulldog with a Rectourethral Fistula}, volume={23}, ISSN={["1939-1676"]}, DOI={10.1111/j.1939-1676.2009.0320.x}, abstractNote={Journal of Veterinary Internal MedicineVolume 23, Issue 4 p. 931-934 Open Access Use of Computed Tomography (CT) Scanning and Colorectal New Methylene Blue Infusion in Evaluation of an English Bulldog with a Rectourethral Fistula A.M. Cruse, A.M. Cruse Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorS.L. Vaden, S.L. Vaden Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorK.G. Mathews, K.G. Mathews Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorT.L. Hill, T.L. Hill Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorI.D. Robertson, I.D. Robertson Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NCSearch for more papers by this author A.M. Cruse, A.M. Cruse Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorS.L. Vaden, S.L. Vaden Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorK.G. Mathews, K.G. Mathews Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorT.L. Hill, T.L. Hill Department of Clinical Sciences, North Carolina State University, Raleigh, NCSearch for more papers by this authorI.D. Robertson, I.D. Robertson Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NCSearch for more papers by this author First published: 26 June 2009 https://doi.org/10.1111/j.1939-1676.2009.0320.xCitations: 3 Corresponding author: Shelly L. Vaden, DVM, PhD, DACVIM, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606; e-mail: shelly_vaden@ncsu.edu. This work was performed at North Carolina State University, College of Veterinary Medicine. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abbreviations CT computed tomography NCSU-VTH North Carolina State University Veterinary Teaching Hospital Rectourethral fistulas are uncommonly reported in veterinary medicine having only been reported in 13 dogs.1-11 Seven were English Bulldogs and 3 were Miniature Poodles. The diagnosis of a rectourethral fistula is challenging. Survey radiography, double contrast cystography, pneumocystography, and colonoscopy are unreliable modalities for the diagnosis of a fistula.6-9 Four of the 13 previously reported dogs required more than 1 contrast imaging study to confirm the presence of a rectourethral fistula.2, 4, 7, 9 In 1 affected dog, 4 contrast cystourethrograms were performed over a 7-year period before identifying the fistula.4 To date, no case report in the veterinary literature has described use of computed tomography (CT) scanning or new methylene bluea as alternate methods for the diagnosis of rectourethral fistulas. Most rectourethral fistulas in people are acquired secondary to trauma, pelvic surgery, inflammatory bowel disease, or malignancy.12 The diagnosis can be made by witnessing fecaluria or by using advanced diagnostic procedures. Some physicians prefer the aid of contrast cystourethrography13, 14 whereas others have reported the usefulness of CT scanning for both establishing the diagnosis and for surgical planning.15 CT scanning for the detection of anorectal anomalies was first described in infants and has since become a valuable diagnostic tool.16, 17 To date, the most commonly utilized diagnostic techniques in people include cystourethroscopy, advanced imaging such as CT scanning or magnetic resonance imaging, and radiographic contrast imaging.13-19 This report describes the successful use of CT and cystourethrography to diagnose a rectourethral fistula in an English Bulldog. Whereas cystourethrography was used to determine that a fistula was present, the exact anatomic location could not be verified. In contrast, the CT scan was very useful in establishing an accurate anatomic localization of the fistula and surgical planning for repair. In addition, this report describes a technique of colorectal infusion of new methylene blue during cystourethroscopy, which may be a useful adjunctive procedure to verify the presence of an abnormal communication between the urinary and gastrointestinal tracts. A 1-year-old 26.1 kg male castrated English Bulldog was presented to the North Carolina State University Veterinary Teaching Hospital (NCSU-VTH) with a 4-month history of recurrent urinary tract infections. The owner reported pollakiuria, stranguria, and hematuria. Upon initial presentation to the referring veterinarian, gross hematuria, bacteriuria, and pyuria were detected in a voided urine sample. Clinical signs transiently abated after treatment with amoxicillin-clavulanic acidb (15 mg/kg PO q12h for 14 days). Approximately 21 days after initial presentation, a urine sample collected by cystocentesis grew Escherichia coli and Proteus mirabilis that were susceptible to amoxicillin-clavulanic acid. Although abdominal radiographs were unremarkable, small cystoliths, bilateral renal mineralization, and a thickened bladder wall were detected on abdominal ultrasonography. Urinary crystalline material analyzed by the Minnesota Urolith Centerc was identified as magnesium ammonium phosphate. Ninety days after initial presentation, urinalysis of a catheterized sample indicated hematuria and bacteriuria. Microbial culture of the same sample resulted in growth of Klebsiella pneumoniae and E. coli. Based on susceptibility test results, the dog was treated with amoxicillin-clavulanic acid (14 mg/kg PO q12h for 6 weeks) and marbofloxacin (8 mg/kg PO q24h for 6 weeks). At presentation to the NCSU-VTH, no abnormalities were detected during physical examination. Results of a CBC and biochemical profile were unremarkable. Urinalysis of a sample collected by cystocentesis indicated urine specific gravity of 1.014, urine pH of 8.0, trace bacteruria, and 0–5 white blood cells per high-power field. An aliquot of the same urine sample was submitted for microbial culture and resulted in light growth of a resistant strain of Enterococcus faecium. Abdominal ultrasonography identified a thickened irregular urinary bladder wall and small cystic calculi. A hyperemic bladder and urethral mucosa consistent with urinary tract inflammation, as well as particulate matter were identified during cystourethroscopy. Analysis of the particulate matter by the Minnesota Urolith Center identified a gelatinous material not consistent with urinary calculi, but rather a conglomerate of fungal hyphae, bacterial rods and cocci, and cellular material. A positive contrast retrograde urethrocystogram was performed after cystourethroscopy with fluoroscopic guidance. Approximately 20 mL of iohexold (240 mg/mL diluted with 0.9% saline to a concentration of 120 mg/mL) was infused over a 3–5-minute period through an 8-french Foley catheter placed into the urethra. The catheter balloon was positioned and inflated approximately 1 in. distal to the ischiatic tuberosity. At the level of the prostate gland, contrast medium exited the urethra within a tract that extended caudally and emptied into the rectum, indicating the presence of a rectourethral fistula. The dog represented 7 days later for surgical correction of the rectourethral fistula. Based on the owner's desire for a minimally invasive approach, initially laparoscopy was performed. Laparoscopic exploration of the area dorsal to the urethra failed to identify an obvious fistula, and the procedure was converted to a standard ventral midline laparotomy. A red rubber urinary catheter was placed to fill the bladder with saline. Pressure was applied to the urinary bladder while digitally obstructing the urethra in an attempt to force saline into the fistula as an aid to its identification. No abnormal tissue could be identified. Because of the potential risk to neurovascular structures associated with further dissection, and the potential morbidity associated with pelvic osteotomies, the decision was made to recover the animal from anesthesia and attempt to further characterize the anatomic location of the fistula with additional diagnostic techniques at a future date. The dog was discharged from the hospital the next day with instructions to be given amoxicillin-clavulanic acid (14 mg/kg PO q12h for 10 days). Thirty days after the initial surgery, colonoscopy was performed using a 1,680 mm length flexible Olympuse colonoscope with an outer diameter of 12.2 mm in an attempt to locate the fistula. Patient preparation consisted of a combination of a 24-hour fast, oral polyethylene glycol solution,f and warm water enemas. During colonoscopy, many small raised areas consistent with lymphoid follicles were noted, but a fistula was not visualized. After colonoscopy, cystourethroscopy was performed with a 600 mm length flexible Storzg cystoscope with an outer diameter of 3.8 mm. In another attempt to identify the location of the fistula, new methylene blue was instilled into the colon during urethroscopsy. A 24-french Foley catheter was advanced approximately 10 in. aborally into the descending colon. A 2nd 24-french Foley catheter was positioned in at the level of the rectum. The balloon of each catheter was filled with 30 mm 0.9% saline. Thirty milliliters of new methylene blue was diluted 1 : 1 with 0.9% saline to a total volume of 60 mm and instilled through the distal catheter, over a period of 10–15 seconds, into the space between the 2 catheter balloons where the fistula was believed to be located. The urine in the urethra became blue-tinged within minutes confirming translocation of the new methylene blue from the colon into the urethra. At the level of the prostatic urethra, several small depressions of the urethral mucosa were noted (Fig 1). Although the largest of these depressions was believed to be associated with the fistula, there was no definitive evidence of new methylene blue entering the urethra through these areas. Thus, the new methylene blue was useful in confirming the presence of the fistula but did not identify its location. Figure 1Open in figure viewerPowerPoint (A) Cystourethroscopy before new methylene blue infusion. There are several small depressions and one larger depression in the urethral mucosa. The larger depression is believed to be associated with the fistula. (B) Cystourethroscopy after new methylene blue infusion. The urine became blue-tinged consistent with passage of new methylene blue from the colon to the urethra. 101 × 76 mm (300 × 300 DPI). After cystourethroscopy, CTh scanning was performed in conjunction with a positive contrast retrograde urethrogram. Iohexol was diluted and administered at a concentration of 80 mg of iodine per milliliter through an 8-french Foley catheter placed in the urethra. Contrast medium was present within the urethra, urinary bladder, colon, and rectum. A fistulous tract oriented in a caudodorsal direction connecting the urethra to the rectum immediately caudal to the prostate was readily apparent (2, 3). Figure 2Open in figure viewerPowerPoint Retrograde urography. One millimeter transverse image of intrapelvic urethra and rectum immediately cranial to the coxofemoral joints. The white arrow is the urethra. The black arrow is the fistulous tract extending caudodorsally on the right. Contrast medium within the terminal colon is readily apparent. 101 × 76 mm (300 × 300 DPI). Figure 3Open in figure viewerPowerPoint Sagittal CT reconstruction. There is contrast medium within the tract between the urethra and rectum. White arrows are urethra. Black arrows are the fistulous tract. 101 × 76 mm (300 × 300 DPI). The CT scan allowed more accurate anatomic localization and the dog was returned to surgery in a 2nd attempt to ligate the fistula, this time using a perineal approach. A lumen was identified and catheterized with an 8-french red rubber catheter directed toward the urethra. Both the rectal end and urethral end of the fistula were ligated and oversewn. A total of 6 urine samples were obtained by cystocentesis and submitted for microbial culture over the next year while the dog was not receiving antibiotics. All were negative for bacterial growth. A 1-year follow-up conversation with the owner indicated that the dog no longer had any clinical signs related to the lower urinary tract. Rectourethral fistulas are persistent communications between the rectum and urethra. Of the 13 dogs reported with rectourethral fistulas, 11 were suspected to be congenital in nature.2-10 The exact embryologic formation of a rectourethral fistula is not known. During normal canine development, the urorectal fold contacts the cloacal membrane, which subsequently ruptures, resulting in separate urogenital and digestive orifices. The caudal portion of the urogenital orifice further differentiates into the urethra. Fistulas can occur either secondary to failure of the urorectal septum to separate the cloaca into ventral urethrovesical and dorsal rectal segments or due to rupture of the cloacal membrane before contacting the urorectal fold.3, 20 Additionally, infectious or inflammatory processes can occur in utero that could lead to perforation of the rectum and subsequent fistula formation.10 In both humans and dogs with rectourethral fistulas, the most common presenting clinical signs are caused by recurrent cystitis and include dysuria, hematuria, pollakiuria, or stranguria.3-10, 13, 21 Ten of the 13 canine rectourethral fistulas reports included aerobic urine culture results. Aerobic culture yielded growth of ≥ 2 bacterial species in 6 of these reports.2, 4, 6, 8-10 The most common bacterial organisms reported were E. coli and Proteus spp.1-10 Neither of the dogs with acquired fistulas had positive aerobic urine cultures.1, 11 In 1 study of dogs with recurrent or persistent urinary tract infections, approximately 25% of the urine specimens yielded the growth of ≥ 2 bacterial species by aerobic bacterial culture, as was noted in the dog of this report.12 The presence of multiple organisms on urine culture specimen may raise clinical suspicion of systemic immunocompromise, anatomic defects along the lower urinary tract, or external contamination of the urine sample. Rectourethral fistula is an uncommon anatomic defect that can lead to recurrent or persistent urinary tract infections. In this dog, the fistula was oriented in a cranioventral to caudodorsal direction running between the prostatic urethra and the caudoventral rectum. This orientation made identification of the fistula at surgery difficult because it was closely associated with the dorsal aspect of the urethra cranioventrally. After CT scan, a different surgical approach was used and resulted in successful repair of the fistula. To the authors' knowledge, this is the 1st report of CT scanning and colorectal infusion of new methylene blue during cystourethroscopy for the evaluation of rectourethral fistulas in a dog, although these techniques have been described in humans.18, 22 Since evaluating the dog of this case report, we have performed colorectal infusion of new methylene blue in 2 additional young dogs that were presented for evaluation of recurrent urinary tract infections. Neither of these dogs had any discoloration of the urine after infusion with new methylene blue nor did they have fistulas. The infusion is an easily performed technique that can be incorporated into cystourethroscopy to identify if there is an abnormal communication between the urethra and rectum or colon. Specific patient preparation for this technique includes enemas to evacuate the descending colon and the placement of 2 Foley catheters. Although the location of the fistula may not be readily identifiable, a color change of the urine indicates the presence of an abnormal communication between the urinary and gastrointestinal tracts. In the dog of this report, advanced imaging was needed for precise anatomical localization. CT scanning may be useful to accurately localize the fistula, which can aid surgical planning and successful repair. Footnotes aNew Methylene Blue 1% solution, Taylor Pharmaceuticals, Decatur, IL bClavamox; Pfizer Animal Health, Exton, PA cUniversity of Minnesota, St Paul, MN dOmnipaque 240 mg/mL, GE Healthcare, Princeton, NJ eOlympus America Inc, Center Valley, PA fGoLYTELY (PEG-3350 and electrolytes), Braintree Laboratories Inc, Braintree, MA gKarl Storz Endoscope, Roswell, GA hSiemens Sensation 16, Siemens Medical Solutions USA Inc, Malvern, PA Acknowledgment This study was not supported by a grant. References 1 Agut A, Lucas X, Castro A, et al. A urethrorectal fistula due to prostatic abscess associated with urolithiasis in a dog. Reprod Domest Anim 2006; 41: 247– 250 PubMed. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2 Ralphs SC, Kramek BA. Novel perineal approach for repair of a urethrorectal fistula in a bulldog. Can Vet J 2003; 44: 822– 823. PubMedWeb of Science®Google Scholar 3 Chandler JC, MacPhail CM. Congenital urethrorectal fistulas. Comp Cont Ed Sm Anim Pract 2001; 23: 995– 1000. Web of Science®Google Scholar 4 Silverstone A, Adams WA. Radiographic diagnosis of a rectourethral fistula in a dog. J Am Anim Hosp Assoc 2001; 37: 573– 576 PubMed. CrossrefCASPubMedWeb of Science®Google Scholar 5 Tobias KS, Barbee D. Abnormal micturition and recurrent cystitis associated with multiple congenital anomalies of the lower urinary tract in a dog. J Am Vet Med Assoc 1995; 207: 191– 193 PubMed. CASPubMedWeb of Science®Google Scholar 6 Osuna DJ, Stone EA, Metcalf MR. A urethrorectal fistula with concurrent urolithiasis in a dog. J Am Anim Hosp Assoc 1989; 25: 35– 39 PubMed. Web of Science®Google Scholar 7 Whitney WO, Schrader LA. Urethrorectal fistulectomy in a dog, using a perineal approach. J Am Vet Med Assoc 1988; 193: 568– 569 PubMed. CASPubMedWeb of Science®Google Scholar 8 Miller CF. Urethrorectal fistula with concurrent urolithiasis in a dog. Vet Med Small Anim Clin 1980; 75: 73– 76. CASPubMedWeb of Science®Google Scholar 9 Osborne CA, Engen MH, Yano BL, et al. Congenital urethrorectal fistula in two dogs. J Am Vet Med Assoc 1975; 166: 999– 1002 PubMed. CASPubMedWeb of Science®Google Scholar 10 Goulden B, Bergman MM, Wyburn RS. Canine urethrorectal fistulae. J Small Anim Pract 1973; 14: 143– 150 PubMed. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 11 Rawlings CA. Extraperitoneal urinary bladder rupture and urinary fistula in a dog. J Am Vet Med Assoc 1969; 155: 123– 128 PubMed. CASPubMedWeb of Science®Google Scholar 12 Norris CR, Williams BJ, Ling GV, et al. Recurrent and persistent urinary tract infections in dogs: 383 cases. J Am Anim Hosp Assoc 2000; 36: 484– 492 PubMed. CASWeb of Science®Google Scholar 13 Crippa A, Dall'Oglio MF, Nesrallah LJ, et al. The York-Mason technique for rectourethral fistulas. Clinics 2007; 62: 699– 704 PubMed. CrossrefPubMedWeb of Science®Google Scholar 14 Hong AR, Croitoru DP, Nguyen LT, et al. Congenital urethral fistula with normal anus: A report of two cases. J Pediat Surg 1992; 27: 1278– 1280 PubMed. CASPubMedWeb of Science®Google Scholar 15 Nyam DC, Pemberton JH. Management of iatrogenic rectourethral fistula. Dis Colon Rectum 1999; 42: 994– 999 PubMed. CrossrefCASPubMedWeb of Science®Google Scholar 16 Kohda E, Fujioka M, Ikawa H, Yokoyama J. Congenital anorectal anomaly: CT evaluation. Radiology 1985; 157: 349– 352 PubMed. CASPubMedWeb of Science®Google Scholar 17 Berrocal T, Lamas M, Gutierrez J, et al. Congenital anomalies of the small intestine, colon, and rectum. Radiographics 1999; 19: 1219– 1236 PubMed. CrossrefCASPubMedWeb of Science®Google Scholar 18 Sotelo R, Mirandolino M, Trujillo G, et al. Laparoscopic repair of rectourethral fistulas after prostate surgery. Urology 2007; 70: 515– 518 PubMed. CrossrefPubMedWeb of Science®Google Scholar 19 Gupta AK, Guglani B. Imaging of congenital anomalies of the gastrointestinal tract. Indian J Pediatr 2005; 72: 403– 414 PubMed. CrossrefPubMedGoogle Scholar 20 Kruger JM, Osborne CA, Lulich JP. Inherited and congenital disease of the lower urinary tract. In: CA Osborne, DR Finco, eds. Canine and Feline Nephrology and Urology. Philadelphia, PA: Lea and Febiger; 1995: 688. Google Scholar 21 Culkin DJ, Ramsey CE. Urethrorectal fistula: Transanal, transsphincteric approach with locally based pedicle interposition flaps. J Urol 2003; 169: 2181– 2183. PubMedWeb of Science®Google Scholar 22 Miller BA. New diagnostic technics for an obscure vesicovaginal fistula. A case report. Obstet Gynecol 1971; 38: 436– 439 PubMed. CASPubMedWeb of Science®Google Scholar Citing Literature Volume23, Issue4July/August 2009Pages 931-934 FiguresReferencesRelatedInformation}, number={4}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Cruse, A. M. and Vaden, S. L. and Mathews, K. G. and Hill, T. L. and Robertson, I. D.}, year={2009}, pages={931–934} }
 @article{hill_breitschwerdt_cecere_vaden_2008, title={Concurrent Hepatic Copper Toxicosis and Fanconi's Syndrome in a Dog}, volume={22}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2007.0040.x}, DOI={10.1111/j.1939-1676.2007.0040.x}, abstractNote={A3-year-old male castrated West Highland White Terrier was presented to the Veterinary Teaching Hospital at North Carolina State University with a 1-week history of intermittent vomiting, polyuria and polydypsia, progressive anorexia, and lethargy. No treatment was administered by the primary veterinarian before referral. The dog was adopted as a puppy and had lived exclusively in North Carolina. The dog received no other medications and had no previous illnesses, except for a transient decrease in appetite 1 year earlier. On physical examination, the dog weighed 8.2 kg, had a body condition score of 6/9, but was approximately 5% dehydrated. Hematologic abnormalities included neutrophilia (14,293 cells/μL, reference range 2,529–12,876 cells/μL) with a left shift (642 band neutrophils/μL) and immature granulocytes (161/μL). Biochemical abnormalities included increased ALT activity (456 U/L; reference range, 16–73 U/L), hyperbilirubinemia (0.3 mg/dL; reference range, 0–0.2 mg/dL), hypokalemia (3.8 mEq/L; reference range, 3.9–5.2 mEq/L), hyperchloremia (121 mEq/L; reference range, 104–117 mEq/L), and increased lipase activity (715 U/L; reference range, 22–216 U/L). Urinalysis findings included a specific gravity of 1.022, pH of 8, 2+ proteinuria, 2+ ketones, 2+ blood, 4+ glucose, 0–2 coarse granular casts/hpf, 0–5 white cells/hpf, and 5–10 red cells/hpf. The urine protein : creatinine ratio was 1.7. A urine sample submitted for bacterial culture yielded no growth. There was mild metabolic acidemia (blood pH 7.26; reference range, 7.36–7.47), bicarbonate 16.2 mEq/L (reference range, 19.8–26.2 mEq/L), and PCO2 36 mmHg (reference range, 30–40 mmHg), on a venous blood sample. Abdominal ultrasonographic findings included periportal lymph node enlargement, microhepatica, and mildly hyperechoic kidneys bilaterally. Fasting and postprandial serum bile acid concentrations were within reference range. The dog was treated with an IV infusion of lactated Ringer's solution containing 30 mEq/L KCl for dehydration, hypokalemia, and metabolic acidosis. Within 48 hours of hospitalization, sodium bicarbonate at 3 mEq/kg/d was administered as a continuous rate infusion to correct the persistent metabolic acidosis. In addition, the dog was treated with a metoclopramide constant rate infusion of 1 mg/kg/d and famotidine 0.5 mg/kg IV q12h. During the 1st 48 hours of hospitalization, the dog remained anorexic and frequently vomited bile; dolasetron 0.6 mg/kg IV q24h and sucralfate 500 mg PO q8h were administered. The dog was supplemented nutritionally by nasoesophageal feeding a liquid diet (Perativea), the continuous rate of which was adjusted to minimize vomiting. Serial assessment of urine dipstick tests and serum glucose measurements indicated that the dog was persistently ketonuric and glucosuric, with normal serum glucose concentrations. Despite a metabolic acidosis, urine pH ranged from 7.0 to 8.0. The findings of proteinuria, glucosuria with normoglycemia, and hyperchloremic metabolic acidosis with alkaline urine supported a diagnosis of Fanconi's syndrome. Results of a urine metabolic profile, performed at the University of Pennsylvania, also were consistent with Fanconi's syndrome with severe generalized amino aciduria and marked glucosuria. By the 4th day of hospitalization, the dog became febrile (103.6°F). An abdominal ultrasound examination indicated mild thickening of the gallbladder wall. Antibiotic therapy was initiated with ampicillin and sulbactam (Unasyn,b 30 mg/kg IV q8h); the fever resolved within 36 hours. Because of the dog's refractory vomiting and unknown underlying hepatic pathology, an exploratory laparotomy was performed on the 5th day of hospitalization. Biopsy specimens were taken of the liver, stomach, duodenum, jejunum, and left kidney. The gallbladder was aspirated and 1 aliquot of bile was submitted for cytologic analysis; another aliquot was submitted for aerobic microbial culture. Gastrostomy and jejunostomy tubes were placed. Recovery from surgery was uneventful. Perativea liquid diet was administered continuously through the jejunostomy tube throughout the remainder of hospitalization without incident. The volume administered was gradually increased to basal energy requirements. Ketonuria resolved within 24 hours after feeding basal energy requirements. Dexamethasone (0.08 mg/kg IV q24h), s-adenosylmethionine (22 mg/kg PO q24h), and ursodeoxycholic acid (15 mg/kg PO q24h) were administered on day 5 postoperatively. Within 24 hours, steady improvement was observed; the vomiting ceased, the dog was more active and alert, and began eating. IV bicarbonate supplementation was necessary to maintain a near normal serum pH. The bile fluid was cytologically unremarkable and bacterial growth was not observed. Lymphofollicular gastritis, which was attributed to refractory vomiting, and mild lymphocytic enteritis were observed histologically on full-thickness stomach and intestinal biopsy specimens. Centrilobular pyogranulomatous hepatitis, characterized by infiltrates of neutrophils, macrophages, and fewer lymphocytes and plasma cells associated with single cell hepatocyte necrosis, was present in liver wedge biopsy specimens. Abundant copper accumulation was present within centrilobular hepatocytes and macrophages (Fig 1). Copper was quantified at 1186 ppm dry weight. Histopathologic abnormalities in the kidney included diffuse mild to moderate tubular atrophy, multifocal tubular epithelial vacuolation, and tubular regeneration. Additionally, there was evidence of abnormal copper accumulation within vacuolated renal tubular epithelium (Fig 2). Liver, dog. (A) Centrilobular zone with individual hepatocellular necrosis (arrow) and infiltrates of macrophages, neutrophils, lymphocytes, and plasma cells. H&E stain. Scale bar = 50 μm. (B) Same section as A with numerous well-demarcated, red–brown copper-containing granules present in the cytoplasm of macrophages and hepatocytes. Rhodanine stain. Scale bar = 50 μm. Kidney, dog. (A) Tubules lined by plump vacuolated epithelial cells (arrow) or mildly atrophied epithelium (arrowhead). H&E stain. Scale bar = 20 μm. (B) Renal tubular epithelial cells containing multiple cytoplasmic well-demarcated, red–brown copper-containing granules. Rhodanine stain. Scale bar = 20 μm. The dog gradually was transitioned to oral medications administered through the gastrotomy tube, including 971 mg of bicarbonate q12h, s-adenosylmethionine, ursodeoxycholic acid, prednisone 0.6 mg/kg q12h that was tapered over the next 4 weeks, famotidine 0.6 mg/kg q12h for 2 weeks, amoxicillin–clavulanic acid 12 mg/kg q12h for 2 weeks, ciprofloxacin 8 mg/kg q12h for 2 weeks, and Marinc 1 medium dog tablet daily for 2 months. d-Penicillamine was given at a dosage of 10 mg/kg PO q12h for 3 months, with no reported adverse effects. After 2 weeks of treatment, the dog was no longer proteinuric, glucosuric, or ketonuric. Venous pH was 7.36 and bicarbonate was 26.6 mEq/L. ALT activity had decreased from 456 to 81 U/L. Ursodeoxycholic acid, s-adenosylmethionine, Marin, bicarbonate, and d-penicillamine therapy were continued. Monthly venous blood gas analysis disclosed normal pH while receiving oral bicarbonate supplementation. At the 3-month recheck examination, the bicarbonate dosage was reduced by half and d-penicillamine was discontinued. Repeat biopsies of the liver and kidney were declined by the owner. Zinc acetate was prescribed (10 mg/kg orally q12h); s-adenosylmethionine, ursodeoxycholic acid, and Marin were continued. Three weeks after decreasing the oral bicarbonate supplementation, venous pH was 7.4 and bicarbonate was 27.9 mEq/L and bicarbonate supplementation was discontinued, but zinc acetate supplementation was continued indefinitely. Thirteen months after initial diagnosis and treatment, the dog was doing well with no clinical signs reported. Copper storage diseases (CSDs) have been described in several breeds, including the Bedlington Terrier, West Highland White Terrier, Skye Terrier, Doberman Pinscher, Labrador Retriever, and Dalmatian, as well as other species, including humans, rats, and sheep. With CSD, copper accumulates in the liver, leading to hepatitis and eventually cirrhosis of the hepatic parenchyma.1 As yet, the genetic basis of CSD has been elucidated only in the Bedlington Terrier, where it is related to a defect in the MURR-1 gene.2 CSD in the Bedlington Terrier results in copper accumulation in the liver as well as renal cortical tissue in some patients.3 We describe a West Highland White Terrier with CSDand concurrent Fanconi's syndrome, which resolved after copper chelation therapy. A genetic mutation that causes abnormal copper accumulation has yet to be identified in West Highland White Terrier. Unlike the Bedlington Terrier, there does not seem to be a correlation between age and hepatic copper concentration in the West Highland White Terrier. In addition, the total hepatic copper concentration is lower in the majority of affected West Highland White Terriers; most West Highland White Terriers have copper concentrations <1,500 ppm dry weight.4, 5 Copper concentrations up to 500 ppm dry weight may occur in normal dogs.6 Thornburg describes the histopathologic lesions of copper toxicosis in West Highland White Terriers as being characterized by multifocal centrilobular hepatitis and cirrhosis. In this dog, the findings were consistent with previous reports, including multifocal centrilobular hepatitis and a copper concentration of 1,186 ppm. It is unclear whether copper toxicosis was the direct cause of Fanconi's syndrome in this dog, because several medical therapies, including antibiotics, steroids, and penicillamine, may have contributed to resolution of Fanconi's syndrome regardless of treating copper toxicosis. The presence of copper in the renal tubules and resolution of Fanconi's syndrome after copper chelation therapy suggest that copper toxicosis may be a cause of Fanconi's syndrome in dogs. In other reports, dogs with copper toxicosis had abnormalities indicative of proximal tubular dysfunction.7, 8 In a study of 10 Dalmatians with copper toxicosis, 3 dogs had proteinuria without pyuria, 2 had glucosuria with normoglycemia, and 1 had renal tubular necrosis with granular casts.7 In a separate report, a 1.5-year-old Dalmatian had copper toxicosis with a positive metabolic screen for Fanconi's syndrome.8 This dog was euthanized because the dog continued to decline clinically. In the dog reported here, glucosuria, metabolic acidosis, amino aciduria, and copper accumulation in the renal tubules were documented with resolution of Fanconi's syndrome after copper chelation therapy. Wilson's disease is a CSD in humans in which copper accumulates to toxic concentrations in the liver and secondarily in the central nervous system and kidneys because of a mutation in the ATP7B gene, which normally allows for copper excretion into the bile and for production of ceruloplasmin. As a result, patients with Wilson's disease have copper accumulation in the liver and in other tissues, including the brain, kidney, red blood cells, and eye. Neurologic signs develop including speech disorders and dysphagia, abnormal and uncoordinated gait, and tremors.9 Renal complications, including urolithiasis and Fanconi's syndrome, have been reported in human patients with Wilson's disease.10, 11 As is reported in association with Wilson's disease in human patients, this dog may represent a subset of patients with copper storage disease that have concurrent renal tubular dysfunction in association with copper accumulation in the proximal tubular epithelium. Several types of proximal renal tubular dysfunction have been described in association with Wilson's disease in humans: failure of renal acidification, amino aciduria, glucosuria, and phosphaturia.11-15 Resolution of proximal tubular dysfunction also may occur after treatment for copper toxicosis with penicillamine.11, 13-15 A renal biopsy in 1 patient, with prior documentation of renal tubular copper accumulation, demonstrated normal proximal tubular ultrastructure 2 years after initiation of penicillamine therapy. Penicillamine therapy was discontinued because of adverse effects, including glomerulonephritis and systemic lupus erythematosus. Eighteen months later, the patient again showed signs of Wilson's disease, and a renal biopsy was repeated. Electron-dense bodies, consistent with copper-bound metalloprotein, were evident in the subapical cytoplasm of the tubular cells, although copper quantification was not performed to confirm increased copper concentrations in the kidney.11 The effect of copper loading has been examined in the rat kidney as a model for copper toxicosis in humans and other species. Rats supplemented with excessive copper, either by injection or by dietary supplementation, develop copper staining in the liver and in the proximal convoluted tubular epithelium.16-18 Haywood demonstrated an increase in copper content of the kidney in rats fed excess copper as well as copper staining granules confined to the proximal tubule. There also were degenerative changes of the tubular cells as well as copper-staining debris in the tubular lumen, suggesting active exocytosis of copper-bound metallothionein.17 A later report of copper loading in the rat kidney described increased copper in renal tubular lysosomes. With time and increased copper concentrations, there was progressive nuclear degeneration in proximal tubular cells and disruption of the mitochondrial membrane.18 These findings are consistent with the observation that copper acts as a prooxidant, disrupting cell membranes and damaging DNA. Eventually, the rats extruded copper-stained lysosomes and copper-laden pinocytotic vesicles into the tubular lumen. After this time point, the copper concentration in the kidney began to decrease and the tubular epithelium recovered to nearly normal. The localization of copper to the renal tubular epithelium, later exocytosis of copper-bound organelles, and recovery of the tubular epithelium suggest a mechanism by which the rat seems able to cope with increased dietary copper intake. Copper also may alter the function of Na-K-ATPase in the proximal tubular epithelium. In vitro, for both rat kidney tissue homogenate and rat synaptic plasma membrane, copper has an inhibitory effect on the function of this important enzyme in a concentration-dependent manner.19, 20 As copper stores accumulate in the canine liver, the kidney may attempt exocytosis of excess copper as occurs in the copper-loaded rat. Exocytosis of copper-bound organelles in the canine and human kidney may be less effective than in the rat, because tubular debris is not described in any published reports of copper-stained kidneys from rats. Because copper accumulates in the kidney as well as the liver, it then may have several effects that ultimately lead to proximal tubular dysfunction and Fanconi's syndrome: necrosis and apoptosis of epithelial cells because copper acts as a pro-oxidant, disrupting mitochondrial membranes and DNA, inducing inflammation that may affect epithelial function, and inhibiting the function of Na-K-ATPase in a concentration-dependent manner that would alter transport mechanisms in the proximal tubule. These effects all may lead to decreased reabsorption of glucose, amino acids, phosphate, and bicarbonate from the tubular lumen. These may be the mechanisms by which copper toxicosis in this West Highland White Terrier resulted in proximal tubular dysfunction characterized as Fanconi's syndrome. Few controlled studies are available in human and canine medicine that describe renal pathology with copper toxicosis or the effect of copper chelation therapy. Additional study is needed to definitively confirm a link between Fanconi's syndrome and copper storage disease in dogs as suggested by this dog, and to elucidate the nature of that association. In dogs with suspected copper storage disease and evidence of tubular dysfunction that are undergoing liver biopsy, it may be warranted to perform a renal biopsy to allow for histopathologic examination of the renal parenchyma, as well as renal copper quantification, which was not performed here. Sequential urine metabolic screening or urinalyses with protein quantification may be a useful diagnostic and therapeutic monitoring tool in those patients with evidence of tubular dysfunction. Additionally, liver and kidney biopsies after 3 months of d-penicillamine therapy may have been informative to document the histological response to treatment. The authors gratefully acknowledge the assistance of the veterinarians involved in the treatment and referral of the dog. Our appreciation is extended to Dr Herman Jeffers, Dr Karyn Harrell, and Dr Sally Bissett. aPerative Specialized Nutrition, Abbot Laboratories, Ross Products Division, Columbus, OH bUnasyn, Pfizer Roerig, Pfizer Inc, New York cMarin, Nutramax Laboratories Inc, Edgewood, MD}, number={1}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Hill, T.L. and Breitschwerdt, E.B. and Cecere, T. and Vaden, S.}, year={2008}, month={Jan}, pages={219–222} }