Human tissue-engineered blood vessels for adult arterial revascularization.

There is a crucial need for alternatives to native vein or artery for vascular surgery. The clinical efficacy of synthetic, allogeneic or xenogeneic vessels has been limited by thrombosis, rejection, chronic inflammation and poor mechanical properties. Using adult human fibroblasts extracted from skin biopsies harvested from individuals with advanced cardiovascular disease, we constructed tissue-engineered blood vessels (TEBVs) that serve as arterial bypass grafts in long-term animal models. These TEBVs have mechanical properties similar to human blood vessels, without relying upon synthetic or exogenous scaffolding. The TEBVs are antithrombogenic and mechanically stable for 8 months in vivo. Histological analysis showed complete tissue integration and formation of vasa vasorum. The endothelium was confluent and positive for von Willebrand factor. A smooth muscle-specific alpha-actin-positive cell population developed within the TEBV, suggesting regeneration of a vascular media. Electron microscopy showed an endothelial basement membrane, elastogenesis and a complex collagen network. These results indicate that a completely biological and clinically relevant TEBV can be assembled exclusively from an individual's own cells.

Outcome of laryngeal web resection with mucosal apposition for treatment of airway obstruction in dogs: 15 cases (1992--2006).

OBJECTIVE: To evaluate long-term clinical outcome in dogs with upper airway obstruction treated with laryngeal web resection and mucosal apposition. DESIGN: Retrospective case series. ANIMALS: 15 client-owned dogs with laryngeal web formation. PROCEDURES: Medical records of dogs with laryngeal webs treated with a single procedure of web resection with mucosal apposition by use of a ventral laryngotomy were reviewed. Signalment, history, clinical signs, intraoperative complications, postoperative complications, and hospitalization time were recorded. Owners were interviewed 6 months to 6 years after surgery. RESULTS: Most dogs had a history of oral ventriculocordectomy. Duration of clinical signs ranged from 3 months to 3 years. The most common clinical sign reported was exercise intolerance. Postoperative complications were observed in 4 dogs. Follow-up information was available in 10 dogs, and clinical outcome was classified as excellent in 7 and good in 3. CONCLUSIONS AND CLINICAL RELEVANCE: A single surgical procedure of web resection with mucosal apposition for the treatment of laryngeal web formation in dogs resulted in low morbidity and was associated with a good to excellent outcome.

Detection of mixed infections with "Candidatus Mycoplasma haemominutum" and Mycoplasma haemofelis using real-time TaqMan polymerase chain reaction.

The objective of this study was to evaluate the use of real-time TaqMan PCR assays for detection of coinfections with "Candidatus Mycoplasma haemominutum" (Mhm), and Mycoplasma haemofelis (Mhf), in vitro and over time in experimentally infected cats. First, the ability of each real-time PCR assay to detect and quantify mixed infections was determined in vitro by testing mixtures of plasmids containing Mhm and Mhf 16S rDNA with each assay. Subsequently, 4 specific pathogen-free (SPF) cats, 2 of which were splenectomized, were inoculated with blood from a cat infected with both Mhm and Mhf. Sixteen blood samples were then collected from each cat over a 55-day period. Each of the 64 postinoculation samples was tested using both conventional polymerase chain reaction (cPCR) and real-time PCR for the 16S rRNA gene of each organism. When applied to mixtures of plasmid DNA from each species, the results of quantitation with each of the real-time PCR assays approximately reflected the number of plasmid copies present. Forty-nine of 64 post-inoculation samples (77%) were positive using both cPCR and real-time PCR, 4 (6%) were positive using cPCR only, and 3 (5%) were positive using real-time PCR only. Both organisms were detected in 23 samples using real-time PCR. Mixed infections were not detected using cPCR. The size of the corresponding cPCR products suggested infection with Mhm in 4 and Mhf in 18 of these samples. The use of multiple separate real-time PCR assays rather than cPCR alone should thus be considered for epidemiologic studies of hemoplasmosis in cats.

In vitro effects of the active metabolite of leflunomide, A77 1726, on feline herpesvirus-1.

OBJECTIVE: To determine whether the active metabolite of leflunomide, A77 1726 (A77), inhibits replication of feline herpesvirus-1 (FHV-1) in cell culture. STUDY POPULATION: Crandell Rees feline kidney (CRFK) cell cultures. PROCEDURES: Cell cultures were inoculated with FHV-1 and treated simultaneously with concentrations of A77 ranging from 0 to 200microM. The antiviral effect of A77 was determined by use of conventional plaque reduction assays. The effect of A77 on viral load was determined via real-time PCR analysis, and transmission electron microscopy was used to evaluate the effect of A77 on viral morphology. To determine whether the antiviral effect was attributable to alterations in CRFK cell viability and number, CRFK cells were treated with various concentrations of A77 and stained with Annexin V and propidium iodide to assess apoptosis and a mitochondrial function assay was used to determine cell viability. RESULTS: Concentrations of A77 > or = 20microM were associated with substantial reduction in plaque number and viral load. Concentrations > or = 100microM were associated with complete suppression of plaque formation. At low concentrations of A77, clusters of intracytoplasmic virus particles that appeared to lack tegument and an external membrane were detected. Treatment of uninfected CRFK cell monolayers with A77 was associated with reduction in mitochondrial function with minimal evidence of apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE: Leflunomide may be an alternative to current calcineurin-based immunosuppressive protocols used in feline organ transplantation because of its antiherpesviral activity.

Incidence of and risk factors for diabetes mellitus in cats that have undergone renal transplantation: 187 cases (1986-2005).

OBJECTIVE: To compare incidence of diabetes mellitus in cats that had undergone renal transplantation with incidence in cats with chronic renal failure, compare mortality rates in cats that underwent renal transplantation and did or did not develop diabetes mellitus, and identify potential risk factors for development of posttransplantation diabetes mellitus (PTDM) in cats. DESIGN: Retrospective case series. ANIMALS: 187 cats that underwent renal transplantation. PROCEDURES: Medical records were reviewed. RESULTS: 26 of the 187 (13.9%) cats developed PTDM, with the incidence of PTDM being 66 cases/1,000 cat years at risk. By contrast, the incidence of diabetes mellitus among a comparison population of 178 cats with chronic renal failure that did not undergo renal transplantation was 17.9 cases/1,000 cat years at risk, and cats that underwent renal trans-plantation were 5.45 times as likely to develop diabetes mellitus as were control cats with chronic renal failure. The mortality rate among cats with PTDM was 2.38 times the rate among cats that underwent renal transplantation but did not develop PTDM. Age, sex, body weight, and percentage change in body weight were not found to be significantly associated with development of PTDM. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cats that undergo renal transplantation have an increased risk of developing diabetes mellitus, compared with cats with chronic renal failure, and that mortality rate is higher for cats that develop PTDM than for cats that do not.

Surgical correction of colonic duplication in a cat.

A 2-year-old, castrated male Manx cat was presented for anorexia, obstipation, and straining to defecate. Imaging tests revealed a cystic mass associated with the descending colon. Three surgical explorations over several years were performed before complete resection of the cystic mass was achieved. Histopathology of the mass revealed normal colonic structures consistent with colonic duplication. Complete resection of a noncommunicating duplicate colon may allow successful treatment of this condition and resolution of associated clinical signs.

Adrenalectomy and caval thrombectomy in a cat with primary hyperaldosteronism.

A 13-year-old, castrated male, domestic longhaired cat was diagnosed with primary hyperaldosteronism from an adrenal gland tumor and a thrombus in the caudal vena cava. Clinical signs included cervical ventriflexion, lethargy, weakness, inappetence, and diarrhea. Laboratory tests revealed hypokalemia, normonatremia, hyperglycemia, hypophosphatemia, and elevated creatine kinase activity. Hypokalemia worsened despite oral potassium supplementation. An adrenalectomy and caval thrombectomy were successfully performed utilizing deliberate hypothermia followed by progressive rewarming.

Similarities in the immunoglobulin response and VH gene usage in rhesus monkeys and humans exposed to porcine hepatocytes.

BACKGROUND: The use of porcine cells and organs as a source of xenografts for human patients would vastly increase the donor pool; however, both humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose alpha (1,3) galactose (alphaGal) present on the surface of many porcine cells. We previously examined the xenoantibody response in patients exposed to porcine hepatocytes via treatment(s) with bioartficial liver devices (BALs), composed of porcine cells in a support matrix. We determined that xenoantibodies in BAL-treated patients are predominantly directed at porcine alphaGal carbohydrate epitopes, and are encoded by a small number of germline heavy chain variable region (VH) immunoglobulin genes. The studies described in this manuscript were designed to identify whether the xenoantibody responses and the IgVH genes encoding antibodies to porcine hepatocytes in non-human primates used as preclinical models are similar to those in humans. Adult non-immunosuppressed rhesus monkeys (Macaca mulatta) were injected intra-portally with porcine hepatocytes or heterotopically transplanted with a porcine liver lobe. Peripheral blood leukocytes and serum were obtained prior to and at multiple time points after exposure, and the immune response was characterized, using ELISA to evaluate the levels and specificities of circulating xenoantibodies, and the production of cDNA libraries to determine the genes used by B cells to encode those antibodies. RESULTS: Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the VH3 family, with a minor contribution from the VH4 family. Immunoglobulin heavy-chain gene (VH) cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, VH3-11cyno, has not been previously identified, and encodes xenoantibodies at later time points post-transplant. Sequencing of IgG clones revealed increased usage of the monkey germline progenitor most similar to human IGHV3-11 and the onset of mutations. CONCLUSION: The small number of IGVH genes encoding xenoantibodies to porcine hepatocytes in non-human primates and humans is highly conserved. Rhesus monkeys are an appropriate preclinical model for testing novel reagents such as those developed using structure-based drug design to target and deplete antibodies to porcine xenografts.

Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism.

The purpose of this prospective clinical trial was to evaluate the safety and efficacy of a commercially available rheolytic thrombectomy system in the treatment of naturally occurring feline aortic thromboembolic disease. All 6 cats enrolled in the investigation were affected at the level of the distal aorta and had signs of the disease affecting both pelvic limbs. Cats were anesthetized and an arteriotomy was performed on 1 carotid artery to gain access to the arterial system. Selective arterial angiography was used to confirm the presence of thromboembolic disease. The thrombectomy system was advanced to the level of the thrombus using fluoroscopic guidance. Repeat angiography was used intermittently to assess progress of thromboembolus dissolution throughout the procedure. The use of the rheolytic thrombectomy system resulted in successful thrombus dissolution in 5 of 6 cats. Three of 6 cats survived to discharge. Both of these results compare favorably with conventional therapies used in the treatment of this disease. Feline distal aortic thromboembolism is a frustrating disease that warrants a guarded to poor prognosis. Rheolytic thrombectomy may provide veterinarians with an alternative therapy in the treatment of thromboembolic diseases, including feline distal aortic thromboembolism.

Dried solidified blood calculi in the urinary tract of cats.

We have noted an increased number of calculi submitted to the Gerald V. Ling Urinary Stone Analysis Laboratory, University of California, Davis, that do not contain crystalline material but appear to be composed of dried solidified blood (DSB). Canine and feline laboratory records from 1986-2003 were reviewed for samples composed of >99% DSB. No calculi from dogs were found, but specimens from 49 cats were composed of >99% DSB, of which almost half (n = 22) had been submitted after 2001. The DSB calculi had been removed surgically or by postmortem examination from all areas of the upper and lower urinary tract. All samples were well formed and could be divided in half with Rongeur forceps. Detailed case information was available for 12 cats. Urinalyses were available for 9 of the 12 cats, and the mean specific gravity was 1.017 (range, 1.009-1.032). Red blood cells were reported in the sediment of all cats, with most containing >100 RBC/hpf. Ureteral obstructions but no radio-opaque calculi were visible by radiography, including radiographic contrast studies. Reports of ultrasound examinations were available for 10 cats, and discrete calculi were not recorded. In addition to polarized light microscopy, infrared spectroscopy and electron probe microanalysis were performed on a subset (n = 6, DSB calculi; n = 3, control calculi) of samples. Significantly more carbon, nitrogen, and sulfur (P = .012, P = .02, and P = .012, respectively) were present in the elemental analysis of the DSB calculi than in the control calculi, suggesting that the DSB calculi are primarily formed from organic material. At this time, we are uncertain why these DSB calculi become solidified, and we recommend that samples be submitted both in formalin and preservative free to further investigate their etiology.

In vitro evaluation of the effect of a novel immunosuppressive agent, FTY720, on the function of feline neutrophils.

OBJECTIVE: To use in vitro assays to evaluate the effects of a novel immunosuppressive agent, FTY720, on biological functions (migration, phagocytosis, and production of reactive-oxygen species [ROS]) of feline peripheral neutrophils and determine the cytotoxic effects of FTY720 on feline peripheral neutrophils. SAMPLE POPULATION: Peripheral neutrophils obtained from 8 healthy cats. PROCEDURE: Peripheral neutrophils were isolated from blood samples obtained from the 8 cats and exposed to the phosphorylated form of FTY720 (FTY720-P). A fluorescence-based in vitro evaluation of migration was performed. Phagocytosis of microbes and production of ROS were evaluated by use of a 2-color flow cytometry system. Samples of whole blood obtained from the cats were incubated with various concentrations of FTY720-P, fluorescein-labeled Staphylococcus aureus, and dihydroethidium. Cytotoxic effects were evaluated by use of propidium iodide staining. RESULTS: Addition of FTY720-P caused a slight non-significant decrease in phagocytosis and production of ROS by feline peripheral neutrophils. Migration activity of feline peripheral neutrophils was significantly increased by the addition of FTY720-P. Addition of FTY720-P at concentrations considered for clinical use did not increase the death rate of feline peripheral neutrophils. CONCLUSIONS AND CLINICAL RELEVANCE: FTY720 does not inhibit critical functions of feline peripheral neutrophils in vitro.

Renal transplantation in cats with calcium oxalate urolithiasis: 19 cases (1997-2004).

OBJECTIVE: To determine outcome of renal transplantation in cats with renal failure associated with calcium oxalate urolithiasis. DESIGN: Retrospective case series. ANIMALS: 19 cats. PROCEDURE: Medical records were reviewed for evaluation of signalment, preoperative clinical signs, physical examination results, dietary history, clinicopathologic data, abdominal imaging, postoperative diet, complications, and long-term outcome. RESULTS: The domestic shorthair was the most common breed represented. There were 13 spayed females and 7 castrated males. Mean age was 6.8 years. Clinical signs included weight loss, lethargy, vomiting, anorexia, polyuria, and polydipsia. Before surgery, cats received commercially available canned or dry food (n = 10), a prescription renal failure diet (5), a commercial diet to manage struvite crystalluria (1), or an unknown diet (3). Seventeen cats were anemic. All cats were azotemic. Hypercalcemia was detected in 7 cats. Abdominal imaging revealed nephrolithiasis, ureterolithiasis, or both in all cats. Median duration of survival of all cats was 605 days. Eight cats were alive 282 to 2,005 days (median, 1,305 days) after surgery. Eleven cats died 2 to 1,197 days (median, 300 days) after surgery. Five cats formed calculi in their allograft (120 to 665 days). Two of the 5 cats that formed calculi were hypercalcemic. Four of the 5 cats died following complications associated with formation of calculi. CONCLUSIONS AND CLINICAL RELEVANCE: Renal transplantation appears to be a viable option for cats in renal failure secondary to calcium oxalate urolithiasis. In addition to reported complications in renal transplant recipients, formation of calculi within the allograft may also occur.

Evaluation of the prevalence of infections in cats after renal transplantation: 169 cases (1987-2003).

OBJECTIVE: To determine the prevalence of infections developing postoperatively, document the contribution of infection to increased risk of death, and identify risk factors associated with the development of infectious complications in cats after renal transplantation. DESIGN: Retrospective study. ANIMALS: 169 cats that received renal allograft transplants. PROCEDURES: Medical records of cats receiving renal transplants at the University of California from January 1987 through December 2003 were reviewed. RESULTS: 47 infections developed in 43 of 169 cats. Bacterial infections were most common (25/47 cats), followed by viral (13/47), fungal (6/47), and protozoal (3/47) infections. The median duration from transplant surgery to development of infection was 2.5 months. Infection was the second most common cause of death after acute rejection of the transplant, accounting for 14% of deaths overall. Cats with concurrent diabetes mellitus had a significantly increased risk of developing an infection after renal transplantation. Sex, increasing age, concurrent neoplasia, and previous treatment for transplant rejection were not associated with development of infection. CONCLUSIONS AND CLINICAL RELEVANCE: Infection was a common complication and an important cause of death or euthanasia in cats after renal transplantation. Development of diabetes mellitus after transplantation significantly increased the risk of infection.

Evaluation of ameroid ring constrictors for treatment for single extrahepatic portosystemic shunts in dogs: 168 cases (1995-2001).

OBJECTIVES: To evaluate use of an ameroid ring constrictor (ARC) for treatment for single extrahepatic portosystemic shunts (PSSs) and identify factors associated with postoperative death, continued portosystemic shunting, and long-term outcome in dogs. DESIGN: Retrospective study. ANIMALS: 168 dogs with a single extrahepatic PSS. PROCEDURE: Medical records of dogs that had a single extrahepatic PSS and were treated with an ARC were reviewed. Signalment, history, clinical signs, results of preoperative blood analyses and portal pressure measurements, PSS location, ARC size, postoperative complications, and postoperative scintigraphy results were recorded. Owners were interviewed 6 months to 6 years after surgery. Results-Postoperative complications developed in 10% of dogs. Postoperative mortality rate was 7.1%. Predictive factors for postoperative death included high preoperative WBC count and postoperative complications. Twenty-one percent of dogs in which portal scintigraphy was performed 6 to 10 weeks after surgery had continued shunting. Predictive factors for persistent shunting included low preoperative plasma albumin concentration, high portal pressure after complete occlusion, and high portal pressure difference (postocclusion minus baseline). Clinical outcome in 108 dogs was classified as excellent (80%), good (14%), or poor (6%). Predictive factors for excellent long-term clinical outcome included high preoperative plasma albumin concentration, low preoperative leukocytosis, low portal pressure after complete occlusion, absence of postoperative seizures, and absence of continued shunting. CONCLUSIONS AND CLINICAL RELEVANCE: Use of an ARC for treatment for a single extrahepatic PSS resulted in low morbidity and mortality rates. Certain preoperative factors were associated with increased risk of postoperative death, continued portosystemic shunting, and long-term outcome.

Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in cats with ureteral calculi: 163 cases (1984-2002).

OBJECTIVE: To determine clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in cats with ureteral calculi. DESIGN: Retrospective study. ANIMALS: 163 client-owned cats. PROCEDURE: Medical records were reviewed, and information on signalment, history, clinical signs, and results of clinicopathologic testing and diagnostic imaging was obtained. RESULTS: The number of cats in which ureterolithiasis was diagnosed each year increased progressively during the study period. Clinical signs tended to be non-specific and included inappetence, vomiting, lethargy, and weight loss. A combination of survey radiography and abdominal ultrasonography revealed ureteral calculi in 66 of 73 (90%) cats in which the diagnosis was confirmed at surgery or necropsy. Ultrasonography revealed that ureteral calculi were causing ureteral obstruction in 143 of 155 (92%) cats. One hundred thirty-four of 162 (83%) cats had azotemia, 84 of 156 (54%) had hyperphosphatemia, and 22 of 152 (14%) had hypercalcemia. Urinary tract infection was documented in 10 of 119 (8%). Fifty-eight of 76 (76%) cats with unilateral ureterolithiasis had azotemia and 33 (43%) had hyperphosphatemia, indicating impairment of renal function in the contralateral kidney or prerenal azotemia. Ultrasonographic imaging of the contralateral kidney in cats with unilateral ureteral calculi suggested that preexisting renal parenchymal disease was common in cats with ureterolithiasis. Ninety-one of 93 (98%) ureteral calculi contained calcium oxalate. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that abdominal imaging should be performed in all cats with chronic nonspecific signs or with acute or chronic renal failure to rule out ureterolithiasis. Preexisting renal disease may be common in cats with ureteral calculi.

Management and outcome of cats with ureteral calculi: 153 cases (1984-2002).

OBJECTIVE: To determine outcome of medical and surgical treatment in cats with ureteral calculi. DESIGN: Retrospective study. ANIMALS: 153 cats. PROCEDURE: Medical records were reviewed. Owners and referring veterinarians were contacted for follow-up information. RESULTS: All cats were initially treated medically before a decision was made to perform surgery. Medical treatment included parenteral administration of fluids and diuretics to promote urine production and passage of the ureteral calculus and supportive treatment for renal failure. Ureteral calculi in the proximal portion of the ureter were typically removed by ureterotomy, whereas ureteral calculi in the distal portion of the ureter were more likely to be removed by partial ureterectomy and ureteroneocystostomy. Ureterotomy could be performed without placement of a nephrostomy tube for postoperative urine diversion. Postoperative complication rate and perioperative mortality rate were 31% and 18%, respectively. The most common postoperative complications were urine leakage and persistent ureteral obstruction after surgery. Chronic renal failure was common at the time of diagnosis and continued after treatment, with serum creatinine concentration remaining greater than the upper reference limit in approximately half the cats. Twelve-month survival rates after medical and surgical treatment were 66% and 91%, respectively, with a number of cats dying of causes related to urinary tract disorders, including ureteral calculus recurrence and worsening of chronic renal failure. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that medical and surgical management of ureteral calculi in cats are associated with high morbidity and mortality rates. Treatment can stabilize renal function, although many surviving cats will continue to have impaired renal function.

Immunosuppression with a combination of the leflunomide analog, FK778, and microemulsified cyclosporine for renal transplantation in mongrel dogs.

BACKGROUND: The leflunomide analog, FK778, is a selective pyrimidine synthesis inhibitor. In rodent models, FK778 is efficacious in the prevention of allograft and xenograft rejection, and a combination of FK778 and cyclosporine has synergistic immunosuppressive efficacy. METHODS: Heterotopic renal transplantation was performed in 20 dogs. Dogs were randomly assigned to three treatment groups: Neoral alone (n=6), FK778 alone (n=7), or a combination of Neoral and FK778 (n=7). Dogs were killed when the plasma creatinine concentration exceeded 7 mg/dL. A complete postmortem examination was performed and the type of acute-active allograft rejection described. RESULTS: A combination of Neoral and FK778 significantly prolonged allograft survival (P=0.0007), with median survival times of 14.5 days for Neoral alone, 7 days for FK778 alone, and 36 days for Neoral and FK778. Allograft histologic changes were consistent with acute-active allograft rejection in 19 of 20 dogs: in the Neoral-alone group, four dogs were type IB, and two were type IIA; in the FK778-alone group, five dogs were type IB, and one was type IIB; and in the Neoral and FK778 group, three dogs were type IB, three were IIA, and one dog was type III. The dog with type III rejection appeared to experience acute sepsis before rejection. Vomiting, diarrhea, and histologic gastritis and enteritis were commonly observed in dogs treated with the combination of Neoral and FK778. CONCLUSIONS: A combination of Neoral and FK778 prolonged allograft survival in a robust rejection model. Further investigation of FK778 in organ transplantation is warranted.

Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model.

BACKGROUND: ISATX247 is a novel calcineurin inhibitor that has shown more potency than cyclosporine in vitro. This is the first study to compare the survival times of renal allografts in nonhuman primates treated with either ISATX247 or cyclosporine. METHODS: Adult, male cynomolgus monkeys were divided into blood-group compatible and mixed-lymphocyte, stimulation-mismatched, donor-recipient pairs. Heterotopic renal transplantation and bilateral native nephrectomies were performed. The monkeys were placed into either an ISATX247 or cyclosporine treatment group. Both groups were dosed twice daily to maintain a 12-hour drug-trough level of 150 ng/mL. Whole-blood concentrations of ISATX247 and cyclosporine, complete blood counts, and serum chemistry profiles were performed three times a week. Euthanasia was performed if the serum creatinine concentration became 7 or more mg/dL or a serious complication developed. RESULTS: The group receiving ISATX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISATX247 was 120 +/- 32 ng/mL and cyclosporine was 189 +/- 130 ng/mL. The average area under the curve 0-12 for ISATX247 was 6045 +/- 1679 ng/mL/hr and for cyclosporine was 4919 +/- 823 ng/mL/hr. The average calcineurin inhibition at trough blood concentrations was 80 +/- 11% for ISATX247 and 48 +/- 12% for cyclosporine. CONCLUSIONS: Allografts in monkeys treated with ISATX247 survived significantly longer than those treated with cyclosporine. On the basis of survival times and degree of calcineurin inhibition, ISATX247 is a more potent immunosuppressive agent than cyclosporine in this nonhuman primate model of renal-allograft transplantation.

Modified noble plication for the prevention of intestinal intussusception after renal transplantation in dogs.

Intestinal intussusception is a frequent problem after experimental transplantation in dogs. This report describes the safety and efficacy of performing a modified Noble plication for the prevention of intussusception. Heterotopic renal transplantation and plication was performed in 20 dogs. Dogs were killed when the serum creatinine concentration exceeded 7 mg/dL because of acute rejection (19 dogs) or venous occlusion (1 dog). Gastrointestinal signs were commonly observed, but no dog experienced an intestinal intussusception, compared to 3 of 14 dogs (21%) previously treated using a similar immunosuppressive regimen. This study supports the routine use of enteroplication in dogs undergoing renal transplantation.

Pharmacokinetics of tacrolimus after multidose oral administration and efficacy in the prevention of allograft rejection in cats with renal transplants.

OBJECTIVE: To describe pharmacokinetics of multi-dose oral administration of tacrolimus in healthy cats and evaluate the efficacy of tacrolimus in the prevention of allograft rejection in cats with renal transplants. ANIMALS: 6 healthy research cats. PROCEDURE: Cats received tacrolimus (0.375 mg/kg, PO, q 12 h) for 14 days. Blood tacrolimus concentrations were measured by a high performance liquid chromatography-mass spectrometry assay. Each cat received an immunogenically mismatched renal allograft and native kidney nephrectomy. Tacrolimus dosage was modified to maintain a target blood concentration of 5 to 10 ng/mL. Cats were euthanatized if plasma creatinine concentration exceeded 7 mg/dL, body weight loss exceeded 20%, or on day 50 after surgery. Kaplan-Meier survival curves were plotted for 6 cats treated with tacrolimus and for 8 cats with renal transplants that did not receive immunosuppressive treatment. RESULTS: Mean (+/- SD) values of elimination half-life, time to maximum concentration, maximum blood concentration, and area under the concentration versus time curve from the last dose of tacrolimus to 12 hours later were 20.5 +/- 9.8 hours, 0.77 +/- 0.37 hours, 27.5 +/- 31.8 ng/mL, and 161 +/- 168 hours x ng/mL, respectively. Tacrolimus treated cats survived longer (median, 44 days; range, 24 to 52 days) than untreated cats (median, 23 days; range, 8 to 34 days). On histologic evaluation, 3 cats had evidence of acute-active rejection, 1 cat had necrotizing vasculitis, and 2 cats euthanatized at study termination had normal appearing allografts. CONCLUSIONS AND CLINICAL RELEVANCE: Tacrolimus may be an effective immunosuppressive agent for renal transplantation in cats.