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Biomedical subjects

Stephen M Griffey

Publications and source records attributed to Stephen M Griffey.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of the effects of ischemic injury and ureteral obstruction on delayed graft function in cats after renal autotransplantation.

OBJECTIVE: To determine the relative importance of ischemic injury to delayed graft function (DGF) in cats. STUDY DESIGN: Experimental study. ANIMALS: Six intact female cats. METHODS: Cats had renal autograft transplantation without ureteral transection and reimplantation and a contralateral nephrectomy. Serum creatinine and blood urea nitrogen (BUN) concentrations were measured regularly and abdominal ultrasound was performed before surgery, the day after surgery and twice weekly thereafter. Ultrasound-guided renal biopsy was performed on day 7. Cats were euthanatized on day 21. Histology of the autograft, ureter, bladder, vascular anastomoses sites, and contralateral kidney were performed. Observations were compared with those from an historic group of research cats that had extravesicular ureteroneocystostomy and contralateral nephrectomy. RESULTS: Five cats completed the study. Serum creatinine and BUN concentrations increased after surgery, peaking at 3.2+/-0.8 and 77.6+/-15.9 mg/dL, respectively, 1-2 days after surgery. Serum creatinine concentration returned to the reference interval by 6 days after surgery. BUN gradually decreased in all cats but did not return to the reference interval by study end. Serum creatinine and BUN concentrations were consistently lower but not significantly so (P=.29 and .56, respectively) compared with the historic ureteroneocystostomy group. No ultrasonographic abnormalities or renal biopsy histologic abnormalities were observed. At necropsy, 1 autograft had generalized interstitial fibrosis. CONCLUSION: Harvesting the renal graft and the ischemia before revascularization causes impaired renal function after engraftment. CLINICAL RELEVANCE: The process of harvesting and reimplanting the renal graft can contribute to DGF in cats, independent of ureteral obstruction.

Animals↗
PubMed2005

Movement disorders in the Hfe knockout mouse.

The Hfe(- /-) mouse is a model for human hereditary hemochromatosis (HHH). The accumulation of tissue iron in this condition has led to the suggestion that HHH patients may be at higher risk for neurodegenerative diseases. In this study, adult male Hfe(-/-) mice and wildtype controls (n = 12/group) were evaluated for impairment with motor tests (stride length, landing footsplay, rotarod) as well as a general observational battery (Functional Observational Battery, FOB). Hfe(-/-) mice were characterized by more falls from the rotarod, wider forelimb landing footsplay and hypersensitivity to proximal stimulation. Iron accumulation in brain was not detected by histopathology. These data suggest that a motor syndrome may be associated with HHH that could be further understood through the Hfe(-/-) mouse model.

Animals↗
PubMed2005

Simultaneous serodetection of 10 highly prevalent mouse infectious pathogens in a single reaction by multiplex analysis.

Under current practices of mouse colony maintenance, sera from mice are analyzed for antibodies against several widespread infectious pathogens by conventional immunoassays, generally enzyme-linked immunosorbent assay (ELISA). To test for multiple agents, these methods consume large volumes of mouse serum and are laborious and time-consuming. More efficient immunoassays, using small amounts of sample, are therefore needed. Accordingly, we have developed a novel multiplex diagnostic system that employs fluorescent microbeads, coated with purified antigens, for simultaneous serodetection of 10 mouse infectious agents. Individually identifiable, fluorescent microbeads were coated with antigens from Sendai virus, mouse hepatitis virus, Theiler's mouse encephalomyelitis virus/GDVII strain, mouse minute virus, mouse cytomegalovirus, respiratory enteric orphan virus (Reo-3 virus), mouse parvovirus, calf rotavirus for epizootic diarrhea virus of infant mice, vaccinia virus for ectromelia virus, and Mycoplasma pulmonis. Standard sera, singly positive for antibodies to individual infectious agents, were generated by inoculation of BALB/cj and C57BL/6j mice. Sera from these experimentally infected mice, as well as sera from naturally infected mice, were analyzed using a mixture of microbeads coated with antigens of the 10 infectious agents listed above. Results demonstrated that the multiplex assay was at least as sensitive and specific as ELISA for serodetection. Importantly, the multiplex assay required only 1 microliter of serum for simultaneous serodetection of the 10 mouse infectious agents in one reaction vessel. Thus, this multiplex microbead assay is a reliable, efficient, and cost-effective diagnostic modality that will impact serosurveillance of mice used in research.

Animals↗
PubMed2004

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.

Animals↗
PubMed2004

Occult pretransplantation systemic inflammation and posttransplantation vascular changes in a primate arterial allograft model.

BACKGROUND: Occult systemic inflammation, as manifested by increased levels of C-reactive protein (CRP), identify patients at increased risk for renal allograft rejection. The mechanisms linking occult systemic inflammation to these adverse outcomes remain unclear. The purpose of this study was to examine the anatomic and physiologic effects of occult pretransplantation systemic inflammation on posttransplantation allograft outcome in a nonhuman primate model. METHODS: Seventy-one healthy male Rhesus macaques were stratified into quartiles based on serum CRP. Five high quartile and six low quartile animals underwent common iliac artery transplantation from male donors. Duplex ultrasound measured graft flow at 3 weeks postoperatively; luminal narrowing was assessed by graft/femoral peak systolic velocity ratio. At 6 weeks, the grafts were harvested and morphometry studies were performed. Vessel wall changes were assessed by measuring the intimal medial area. RESULTS: The allografts placed in high CRP quartile animals had more luminal narrowing by 3 weeks than those placed in low quartile animals, as evidenced by a higher mean graft/femoral peak systolic velocity ratio (1.6 vs. 0.90, P=0.006). Morphometry studies after graft harvest showed increased vessel wall area in the high quartile group versus the low quartile group (1.39 mm vs. 1.03 mm, P=0.018). CONCLUSIONS: Occult pretransplantation systemic inflammation is associated with increased intimal thickening and stenosis after arterial allograft transplantation in a primate model. Additional studies are needed to confirm these results and to further investigate potential mechanisms linking pretransplantation systemic inflammation to adverse outcomes after transplantation.

Animals↗
PubMed2003

Clinicopathologic and radiographic features and etiologic agents in cats with histologically confirmed infectious pneumonia: 39 cases (1991-2000).

OBJECTIVE: To determine clinicopathologic and radiographic features and etiologic agents in cats that died as a result of infectious pneumonia. DESIGN: Retrospective study. ANIMALS: 39 cats. PROCEDURE: Medical records of cats in which infectious pneumonia was confirmed by histologic examination of necropsy specimens were reviewed. Signalment, clinical signs, and results of a CBC, viral serologic tests, and thoracic radiography were evaluated. Infectious agents were classified as bacterial, viral, fungal, protozoal, or parasitic. Histologic features (severity, duration, anatomic location, and distribution) were analyzed. RESULTS: Clinical signs referable to the respiratory tract were not detected in 14 of 39 (36%) cats, and results of a CBC (4/18 cats) and radiography (3/13) were unremarkable. Sixteen of 39 (41%) cats lacked clinical signs of systemic illness. Etiologic agents identified included bacteria (n = 21), viruses (11), fungi (6), protozoa (2), and parasites (1). Cats with clinical signs related to the respiratory tract (19/24 [79%] cats) were more likely to have severe histologic changes than cats without signs related to the respiratory system (6/14). Twenty-nine of 38 (76%) cats had histologic evidence of systemic disease, whereas the remaining cats had lesions limited to the respiratory tract. CONCLUSIONS AND CLINICAL RELEVANCE: Infectious pneumonia is uncommon in cats. Cats with infectious pneumonia may lack clinical signs and have unremarkable results for a CBC and thoracic radiography, yet frequently have systemic infections. Therefore, clinicians should maintain an index of suspicion for pneumonia and evaluate the respiratory tract when infection is detected in other organ systems.

Animals↗
PubMed2003

Contrast-enhanced US of microcirculation of superficially implanted tumors in rats.

PURPOSE: To determine the ability of contrast material-enhanced ultrasonography (US) to assess replenishment time in a rat kidney and adenocarcinoma tumor model. MATERIALS AND METHODS: Mammary adenocarcinoma cells were implanted into the subcutaneous tissues of the flank of 11 rats. Resultant tumors were imaged serially with contrast-enhanced US and compared with images of the rat kidney, a highly perfused normal organ. The US acquisition and processing methods yield images of perfused tumor regions and the times required to achieve 80% replenishment. Findings at contrast-enhanced computed tomography (CT) and light microscopy of hematoxylin-eosin-stained tumor tissue were compared. Paired Student t test was performed to compare the accuracy of US with that of histologic examination and CT in the detection of viable tumor regions. RESULTS: Replenishment of the kidney cortex microvasculature requires 1-5 seconds compared with a replenishment time of 6-14 seconds in tumors. Over the time course of tumor growth, the mean perfusion time becomes progressively longer, and a wider range of perfusion times is detected. Comparison of findings at US, CT, and histologic examination suggested that all three methods yield correlated estimates of the percentage of viable perfused tumor cells. Results of the t test suggested that the viable tumor percentages observed at US are not significantly different from those observed at CT and histologic examination (US vs CT, P =.92; US vs histologic examination, P =.94). CONCLUSION: Repeated measurements of microvascular flow rate can be accomplished in a rat animal model with a minimally invasive technique.

Adenocarcinoma↗
PubMed2003

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.

Alkynes↗
PubMed2003

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.

Administration, Oral↗
PubMed2002

Use of keyhole lung biopsy for diagnosis of interstitial lung diseases in dogs and cats: 13 cases (1998-2001).

OBJECTIVE: To characterize interstitial lung diseases (ILDs) and evaluate use of keyhole lung biopsy for diagnosis of ILDs in dogs and cats. DESIGN: Retrospective study. ANIMALS: 11 dogs and 2 cats. PROCEDURE: Medical records of dogs and cats undergoing keyhole lung biopsy to confirm ILDs were reviewed. Signalment, clinical signs, results of thoracic radiography and other respiratory diagnostic tests, postoperative complications, and patient outcome were analyzed. RESULTS: Clinical respiratory signs included cough, tachypnea, exercise intolerance, and hemoptysis. Thoracic radiographic abnormalities included interstitial, alveolar, and bronchointerstitial patterns and multiple discrete pulmonary nodules. Lung biopsy and histologic examination revealed interstitial pulmonary fibrosis, bronchiolitis obliterans with organizing pneumonia, or unclassified lesions. Outcome after biopsy included no response to treatment, euthanasia, partial or complete remission while receiving medication, and cure. CONCLUSIONS AND CLINICAL RELEVANCE: Recognition and classification of ILDs in dogs and cats are likely to be important in guiding appropriate treatment and providing accurate prognostic information. Ancillary respiratory diagnostic tests are beneficial in ruling out infectious and neoplastic disorders that may mimic ILDs; however, their present use in the diagnosis of ILDs is limited. Results suggest that keyhole lung biopsy is an effective means for obtaining a specimen for histologic diagnosis in dogs and cats with ILDs.

Animals↗
PubMed2002

Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.

Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24(-/-)) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24(-/-) mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice. Zmpste24(-/-) mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24(-/-) mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.

Age Factors↗
PubMed2002

Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver.

In in vitro experiments, prenylcysteine lyase (Pcly) cleaves the thioether bond of prenylcysteines to yield free cysteine and the aldehyde of the isoprenoid lipid. However, the importance of this enzyme has not yet been fully defined at the biochemical or physiologic level. In this study, we show that Pcly is expressed at high levels in mouse liver, kidney, heart, and brain. To test whether Pcly deficiency would cause prenylcysteines to accumulate in tissues and result in pathologic consequences, we produced Pcly-deficient cell lines and Pcly-deficient mice (Pcly-/-). Pcly activity levels were markedly reduced in Pcly-/- cells and tissues. Pcly-/- fibroblasts were more sensitive than wild-type fibroblasts to growth inhibition when prenylcysteines were added to the cell culture medium. To determine if the reduced Pcly enzyme activity levels led to an accumulation of prenylcysteines within cells, mass spectrometry was used to measure farnesylcysteine and geranylgeranylcysteine levels in the tissues of Pcly-/- mice and wild-type controls. These studies revealed a striking accumulation of both farnesylcysteine and geranylgeranylcysteine in the brain and liver of Pcly-/- mice. This accumulation did not appear to be accompanied by significant pathologic consequences. Pcly-/- mice were healthy and fertile, and surveys of more than 30 tissues did not uncover any abnormalities. We conclude that prenylcysteine lyase does play a physiologic role in cleaving prenylcysteines in mammals, but the absence of this activity does not lead to major pathologic consequences.

Amino Acid Sequence↗
PubMed2002

Effect of preexisting FeLV infection or FeLV and feline immunodeficiency virus coinfection on pathogenicity of the small variant of Haemobartonella felis in cats.

OBJECTIVE: To investigate the effects of preexisting FeLV infection or FeLV and feline immunodeficiency (FIV) coinfection on the pathogenicity of the small variant of Haemobartonella felis (Hfsm, California variant) in cats. ANIMALS: 20 FeLV infected, 5 FeLV-FIV coinfected, and 19 retrovirus-free cats. PROCEDURES: A client-owned cat, coinfected with FeLV and Hfsm, was the source for Hfsm. Inoculum 1 (FeLV free) was obtained by passage of source Hfsm through 4 FeLV-resistant cats. Inoculum 2 was obtained by further passage of Hfsm (inoculum 1) through 2 specific pathogen-free cats. RESULTS: A mild-to-moderate anemia started 21 days after inoculation, with its nadir occurring at 35 to 42 days after inoculation. Infection with Hfsm induced greater decrease in hemoglobin concentration in FeLV infected cats, compared with retrovirus free cats. Reticulocytosis, macrocytosis, and polychromasia of erythrocytes developed in anemic cats regardless of retrovirus infection status. Mean neutrophil counts decreased during the hemolytic episode. For most cats, the anemia was transient. Four FeLV infected cats, 1 of which was also FIV infected, developed fatal FeLV-associated myeloproliferative diseases. Of the surviving cats, 8 died over the next 24 months from other FeLV-related diseases. Hemolysis did not recur after the initial episode. Inoculum 1 induced more severe anemia than inoculum 2. CONCLUSIONS AND CLINICAL RELEVANCE: Our results support the clinical observation that cats coinfected with FeLV and H felis develop more severe anemia than cats infected with H felis alone. Infection with Hfsm may induce myeloproliferative disease in FeLV infected cats. The small variant of H felis may lose pathogenicity by passage through FeLV-free cats.

Anaplasmataceae↗
PubMed2002

Computer-assisted image analysis of neovascularization in thyroid neoplasms from dogs.

OBJECTIVE: To develop a computer-assisted image analysis procedure for quantitation of neovascularization in formalin-fixed paraffin-embedded specimens of thyroid gland tissue from dogs with and without thyroid gland neoplasia. SAMPLE POPULATION: 47 thyroid gland carcinomas, 8 thyroid gland adenomas, and 8 specimens of thyroid tissue from dogs without thyroid gland abnormalities (normal). PROCEDURE: Serial tissue sections were prepared and stained with antibodies against human CD31 or factor VIII-related antigen (factor VIII-rag). The areas of highest vascularity were identified in CD31-stained sections, and corresponding areas were then identified in factor VIII-rag-stained sections. Image analysis was used to calculate the total vascular density in each section, and neovascularization, expressed as a percentage, was determined as the absolute value of the total vascular density derived from factor VIII-rag-stained sections minus the vascular density derived from CD31-stained sections. RESULTS: Mean vascular density of thyroid gland carcinomas derived from CD31-stained sections was significantly greater than density derived from factor VII I-rag-stained sections. This incremental difference was presumed to represent degree of neovascularization. However, significant differences were not detected between vascular densities derived from CD31 and factor VIII-rag-stained sections for either normal thyroid gland tissue or thyroid gland adenomas. No significant correlations were found between vascular density in thyroid gland carcinomas and survival time following surgery. CONCLUSION AND CLINICAL RELEVANCE: A computer-assisted image analysis method was developed for quantifying neovascularization in thyroid gland tumors of dogs. This method may allow identification of dogs with tumors that are most likely to respond to treatment with novel antiangiogenesis agents.

Adenoma↗
PubMedDate not supplied

Evaluation of the clinical and histologic features of renal allograft rejection in cats.

OBJECTIVES: To describe the clinical signs and histopathologic features of renal allograft rejection in cats, and to provide a historical, untreated control group for use in future studies of feline renal allograft rejection. ANIMALS: Fourteen adult research cats. METHODS: Renal transplantation and bilateral nephrectomy were performed in pairs of immunogenically mismatched cats. A physical examination was performed, and packed cell volume, total protein, and plasma creatinine concentrations were measured each day after surgery. The cats were euthanatized when plasma creatinine concentration exceeded 7 mg/dL or when weight loss exceeded 20%. Renal histopathology was scored according to the Banff 97 criteria by 3 pathologists. RESULTS: Nine cats completed the study. Plasma creatinine exceeded 7 mg/dL in 5 cats, weight loss exceeded 20% in 3 cats, and 1 cat was found dead. Clinical signs in cats with rejection were nonspecific or absent. Rectal temperature decreased by 0.8 +/- 0.5 degrees C in the 24 hours before euthanasia. The pathologists agreed on the allograft histopathologic category in 6 of 9 cats. The histologic consensus was acute/active rejection in 8 cats and normal in 1 cat. Median survival time of the 8 cats with histologically confirmed allograft rejection was 23 days (range, 8-34 days). CONCLUSIONS AND CLINICAL RELEVANCE: Renal allograft rejection is associated with minimal clinical signs. Therefore, plasma creatinine concentration should be measured routinely in patients with a functioning allograft. An increase in plasma creatinine concentration is highly suspicious for allograft rejection, although a biopsy of the renal allograft is needed for definitive diagnosis.

Animals↗
PubMedDate not supplied

An evaluation of combined immunosuppression with MNA 715 and microemulsified cyclosporine on renal allograft rejection in mismatched mongrel dogs.

OBJECTIVE: To evaluate a combination of MNA 715 and microemulsifed cyclosporine for the prevention of renal allograft rejection in mismatched mongrel dogs. STUDY DESIGN: Randomized, experimental study. ANIMALS: Fourteen female mismatched mongrel dogs. METHODS: Heterotopic renal transplantation and bilateral nephrectomy were performed in each dog. Dogs were randomly assigned to receive either MNA 715 and cyclosporine (n = 8) or cyclosporine alone (n = 6). Dogs were killed at 100 days after transplantation or when plasma creatinine exceeded 7 mg/dL. RESULTS: In the cyclosporine and MNA 715 group: 4 dogs survived to 100 days with normal plasma creatinine concentrations; 2 dogs with intestinal intussusceptions were killed at 5 and 8 days, 1 dog with a wound infection and sepsis was killed at 14 days, and 1 dog with a serum creatinine concentration >7 mg/dL was killed at 51 days postoperatively. In the cyclosporine-alone group: 3 dogs with acute rejection were killed at 6 to 9 days and 3 dogs survived to 100 days. In dogs treated with cyclosporine and MNA 715, survival to histologically confirmed acute rejection was significantly longer (P =.044) and the degree of mononuclear cell infiltration was significantly reduced (P =.040), compared with dogs treated with cyclosporine alone. CONCLUSIONS: MNA 715 combined with cyclosporine prolonged allograft survival and reduced the severity of histologic rejection in a clinically relevant renal transplant model. CLINICAL RELEVANCE: An immunosuppressive regimen consisting of MNA715 and microemulsified cyclosporine may be effective in preventing allograft rejection in canine renal transplant patients.

Alkynes↗
PubMedDate not supplied

Microemulsified cyclosporine-based immunosuppression for the prevention of acute renal allograft rejection in unrelated dogs: preliminary experimental study.

OBJECTIVES: To determine whether the microemulsified formulation of cyclosporine (MCsA; Neoral; Novartis A.G.), combined with azathioprine (Imuran; Glaxo Wellcome), and prednisolone (Delta-Cortef; Upjohn), would be effective in preventing acute renal allograft rejection in unrelated mongrel dogs. To document any toxic effects associated with this drug combination. STUDY DESIGN: rospective, pilot study. ANIMALS: Four healthy, adult, mongrel, canine renal allograft recipients. METHODS: Heterotopic renal transplantation, with bilateral nephrectomy, was performed in 4 dogs. Allografts were harvested from 2 unrelated dogs that were to be euthanatized for reasons unrelated to this study. The dogs were treated for 100 days or until signs of illness or allograft rejection required euthanasia. Microemulsified cyclosporine (20 mg/kg/day), azathioprine (5 mg/kg every other day), and prednisolone (1 mg/kg/day) were administered for the prevention of acute rejection. Body weight, serum biochemistry profiles, complete blood counts, and trough whole-blood cyclosporine concentrations were measured throughout the study. Cyclosporine dose was adjusted to maintain a trough concentration of 400-500 ng/mL. Azathioprine dose was decreased if evidence of hepatotoxicity developed or if the total blood white cell count was <4,000 cells/micro L. The prednisolone was tapered by 0.25 mg/kg increments every 3 weeks and discontinued 14 days before the end of the study in the surviving dogs. Complications were recorded. A complete necropsy and histopathologic examination were performed in each recipient. RESULTS: Two of the 4 dogs survived the 100-day period. One dog was euthanatized at 8 days because of an intestinal intussusception. One dog was euthanatized at 64 days because of a severe upper respiratory infection. At the time of death, these 2 dogs had plasma creatinine concentrations of 1.5 and 2.6 mg/dL, respectively, with no histopathologic evidence of allograft rejection. All dogs had transient weight loss (range, 4.6%-17.7% of preoperative body weight) between days 7 and 14. Two dogs had evidence of hepatotoxicity. The 2 dogs surviving to 100 days had normal serum creatinine concentrations and no clinical signs of rejection. One of these dogs had evidence of a grade IIa acute/active rejection based on the modified BANFF 97 histopathologic classification. The second dog had no evidence of rejection or inflammation within the allograft. CONCLUSIONS: This preliminary experimental study shows that immunosuppression using MCsA, combined with azathioprine and prednisolone, may be effective in preventing acute renal allograft rejection in unrelated mongrel dogs for 100 days. Complications included ileocolic intussusception, upper respiratory infection, weight loss, and transient hepatotoxicity. CLINICAL RELEVANCE: Immunosuppression using MCsA, azathioprine, and prednisolone may be effective in preventing acute renal allograft rejection in unrelated, mongrel dogs. This triple drug protocol is cost-effective and was easy to administer. Further investigation is warranted to minimize toxic effects and to determine the efficacy of prophylactic renal biopsies to detect and treat subclinical acute/active rejection.

Administration, Oral↗