Use of capecitabine after renal allograft transplantation in dog erythrocyte antigen-matched dogs

OBJECTIVES: To investigate the use of a capecitabine (CAP)-based regimen after renal transplantation in dogs. STUDY DESIGN: Prospective, pilot study. ANIMALS: Healthy, unrelated, dog erythrocyte antigen (DEA)-matched, adult beagles. METHOD: Standard heterotopic renal transplantation with native nephrectomy was performed in 7 dogs. Dogs received oral, twice daily, CAP (250 mg/m2), cyclosporine-A (CsA) (4 mg/kg), ketoconazole (5 mg/kg), and prednisolone (0.25 mg/kg). After 90 days the surviving dogs were euthanatized and complete necropsy was performed. RESULTS: Seven transplants were performed. All dogs survived surgery. Six dogs had acute neurotoxicity, which resulted in death or euthanasia of 2 dogs within 2 days of surgery. In the remaining dogs, toxicity resolved rapidly with cessation of drug administration. Thereafter, modification of the regimen minimized toxicity. The 5 remaining dogs survived to study end; 4 dogs had no evidence of graft rejection. Necropsy examination was mostly unremarkable in all dogs. There were no major changes in CBC or biochemical values, except for a significant increase in serum calcium. CONCLUSIONS: CAP appeared well tolerated in most dogs. Toxicity occurred but abated with modification of the drug regimen. Efficacy for postoperative immunosuppression cannot be determined by this study, although results are promising. CLINICAL RELEVANCE: CAP-CsA-prednisolone is an effective, oral immunosuppressive regimen for prevention of acute allograft rejection in DEA-matched beagles. Further studies on dose, toxicity, and efficacy compared with current immunosuppressive regimens are needed before use in clinical practice.     

Acute vascular and interstitial rejection following renal allograft transplantation in dogs

Renal allograft transplantation was performed in four beagles. Immunosuppressive treatment using cyclosporine, mizoribin and prednisolone was continued from Day 5 pre- until Day 20 post-transplantation. Between Days 28 and 32 post-transplantation, an abrupt elevation of the serum creatinine values followed by the development of uremia was seen in all recipients. Histopathology of the allografts examined between Days 28 and 37 revealed edema, necrosis, hemorrhage and severe diffuse interstitial cellular infiltration as well as tubulitis. Glomerular changes notably included swelling of the tufts due to hypercellularity, which was consistent with transplant glomerulitis. The intrarenal arteries exhibited fibrinoid necrosis of the walls and intimal or transmural cellular infiltration. These renal lesions were consistent with those of acute vascular and interstitial rejection in humans.     

犬同种异体半月板的移植

为了探索犬半月板损伤的有效治疗方法,本研究建立了犬半月板缺损模型,并采用同种异体半月板全移植和半移植2种方式修复半月板缺损。术后第5周末,所有移植犬站立、行走和上台阶均趋于正常,但不移植的半月板缺损对照犬行走时仍有轻度跛行,上台阶困难。术后第6周膝关节功能Lysholm评分,全移植组和半移植组与正常对照组差异不显著,不移植组与对照组差异显著。肉眼检查见供体半月板在受体内生长良好。半移植组供体半月板的色泽和弹性更接近正常半月板。组织学观察,供体半月板和受体关节囊、供体半月板和保留的受体半月板接合良好,接合处组织生长旺盛。胫骨平台软骨Mankins评分,全移植组和半移植组与对照组差异不显著,不移植组与对照组差异显著。本研究结果表明同种异体半月板移植可有效保护胫骨平台软骨、改善膝关节功能,完全可以用于犬半月板损伤的治疗。     

Use of capecitabine to prevent acute renal allograft rejection in dog erythrocyte antigen-mismatched mongrel dogs

OBJECTIVE: To assess efficacy and toxicity of a capecitabine (CAP)-based regimen for preventing rejection of renal allografts in dog erythrocyte antigen (DEA)-mismatched mongrel dogs. STUDY DESIGN: Prospective, pilot study. ANIMALS: Eight healthy, unrelated, DEA mismatched, adult mongrel dogs. METHODS: All dogs received CAP, starting at 50 mg/m2 PO b.i.d. 4 days preoperatively, increasing to 200 mg/m2 PO b.i.d. by the day of surgery. All dogs received cyclosporine-A (CsA) and prednisolone starting 2 days preoperatively. Standard heterotopic renal transplantation with native nephrectomy was performed. After 90 days, surviving dogs were euthanatized and histopathologic examination was performed. RESULTS: Two of 8 dogs developed acute neurotoxicity leading to death or euthanasia within 5 days of surgery. For the 6 remaining dogs, there were no statistically significant changes in complete blood count or serum biochemical values. No opportunistic infections developed during the study period. Five of 6 dogs had no to minimal evidence of graft rejection. Two of 6 dogs developed superficial and pigmentary keratitis. Significant histopathologic findings in all dogs included mild lymphoplasmacytic gastroenteritis, steroid hepatopathy, and corneal epithelial thinning. One dog had moderate interstitial nephritis and pyelitis. CONCLUSIONS: In this experimental model, a CAP-CsA-prednisolone immunosuppressive regimen was effective in preventing rejection of allografts in DEA-mismatched dogs. Severe, unpredictable neurotoxicity and variable ocular toxicity significantly limit clinical applications at this time. CLINICAL RELEVANCE: A CAP-CsA-prednisolone protocol is an effective, oral immunosuppressive regimen for prevention of allograft rejection in DEA-mismatched mongrel dogs. For clinical application, identification of patients susceptible to toxic side effects would be necessary.     

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.     

Pathogenesis of canine parvovirus-2 in dogs: histopathology and antigen identification in tissues

The pathogenesis of canine parvovirus-2 was studied in orally inoculated conventional dogs using histopathological and peroxidase anti-peroxidase staining techniques. Lymphoid necrosis and depletion of lymphocytes from lymphoid tissues were most notable on days 5 and 6 after exposure. Lymphocyte hyperplasia occurred following day 7. Epithelial cell changes in segments of the small intestine were more severe on days 6 to 9 after exposure in areas associated with Peyer's patches and in the upper segments of the small intestine. The lymphocyte was the primary infected cell. Virus infected cryptal epithelial cells were not detected until 24 hours after the identification of infected cells in lymphoid tissues on day 4 after exposure. The majority of virus infected epithelial cells were found in crypts intimately associated with or adjacent to Peyer's patches in the upper segments of the small intestine.     

Lesions in dogs following renal transplantation and immunosuppression

Renal allografts were transplanted into 20 dogs (12 beagles, eight mongrels) following a prescribed protocol for pre-transplantation blood transfusions and kidney exchange. Immunosuppressive therapy (azathioprine and prednisone) was modified as needed for each dog. Seven of the beagle dogs survived for 1 year and were then euthanized; all other dogs died or were euthanized prior to 1 year post-transplantation. Graft rejection and renal failure were the greatest causes of mortality. Renal lesions which contributed to the death of some animals included renal vein thrombosis, nephrosis, and pyelonephritis. Inflammation of the lower respiratory tract (bronchitis, pneumonia, and pleuritis) was a contributory cause of death in some dogs. Cystitis and ureteritis occurred in almost half of the dogs. Prostatitis was seen in six of the 16 male dogs. Adrenal cortical atrophy, parathyroid gland hyperplasia, and bone marrow hypocellularity were seen in a majority of the dogs which survived 1 year.     

Comparative aspects of renal transplantation in man and dog*

The present situation in human renal transplantation is described and the difficulties are emphasized. The value of canine experiments in solving the problems is explained. Résumé. On décrit la situation actuelle en matière de greffes rénales chez l'homme et on souligne les difficultés rencontrées. On explique l'apport que les experiénces sur les chiens pourrait faire à la solution des problèmes. Zusammenfassung. Die gegenwärtige Situation hinsichtlich der Nierentransplantation beim Menschen wird beschrieben und die Schwieregkeiten werden betont. Der Wert der Tierversuche mit Hunden für die Lösung der Probleme wird erläutert.     

Kidney transplantation in dogs with naturally occurring end-stage renal disease

Renal allografts were performed between unrelated donors and 15 dogs with naturally occurring end-stage renal disease. Donor selection was based on compatible dog erythrocyte antigen typing and cross-matching. An immunosuppressive protocol consisting of rabbit antidog antithymocyte serum, cyclosporin-A, azathioprine, and prednisone was used to control postoperative rejection of the donated kidney. Although seven animals died because of technical failures or rejection episodes, a median survival time of eight months has been achieved, with two dogs living for longer than five years after surgery. Long-term survivors have died from a variety of problems not related to renal allograft rejection.     

Intussusception following renal transplantation in dogs (author's transl)]

In a consecutive and non-selected study of 54 kidney transplanted dogs, 12 cases of intussusception of the small intestine developed in 8 dogs. The patogenesis is still unknown. It has been postulated that the time of the operation (4--7 hours) and the segmental termination of the post-operative atony in the intestine are essential factors in this fatal complication. The last 16 dogs in this material were peroperatively treated with antikolinergics (Mestinon NFN), which was continued until normal function of the intestine. In these dogs there were no evidence of intussusception. The value of this profylaxis is open to discussion and it is essential to solve the problem of intussusception through a "blind" and controlled trial.     

Renal handling of calcium and phosphorus in experimental renal hyperparathyroidism in dogs

Twenty-four hour urinary excretion, fractional excretion and the filtered load of calcium and phosphorus were monitored as hyperparathyroidism evolved in a model of progressive canine renal failure. Thirteen beagles of both sexes aged four and a half months were used. Nine of them were subjected to a renal damaging schedule (neomycine, 60 mg/kg/48 h, IM, 32 weeks) in order to induce chronic renal failure leading to secondary hyperparathyroidism (2HPT group). The remaining four were kept as the control group. The experiment was conducted over 32 weeks. Blood and 24 h urine were collected every four weeks. Calcium, phosphorus and creatinine were analyzed. Plasma parathormone and calcitonin were determined at weeks 0, 12, 24 and 32. The level of renal function in the 2HPT animals was reduced to 25% of that of the controls (endogenous creatinine clearance was 0.45 +/- 0.22 mL/min/kg as opposed to 1.81 +/- 0.54 mL/min/kg). Hyperparathyroidism was confirmed by a progressive increase in the levels of the parathyroid hormone. Calcitonin levels were not modified. A tendency to hypocalcaemia was observed, reaching statistically significant levels from the twenty-eighth week of the study, when hyperphosphataemia also became significant. Daily urinary excretion of calcium and phosphorus remained at values considered normal throughout the experiment with no alteration imputable to the impaired renal function. This is explained by the decrease in the filtered load of these elements (in both cases statistically significant from the 24th week on) being associated with an increase in their fractional excretion. Thus, calcium and phosphorus urinary excretion values could be maintained in a normal range up to the end of the experiment, showing that renal calcium handling in dogs with experimentally induced renal failure seems to differ from that observed in human patients.     

Evaluation of renal biopsies in cats and dogs — histopathology in comparison with clinical data

Histopathological findings of renal biopsies in cats and dogs with diffuse nephropathies generally lead to an exact diagnosis and facilitate prognostic judgements. Complications following renal biopsy are usually slight, provided the biopsy is performed properly. Routine renal laboratory data have been compared with histopathological findings. High urine protein values are often the result of glomerular lesions, whereas high creatinine values are frequently related to tubulointerstitial lesions. In general, there is no relationship between different types of nephropathy and age; nevertheless animals with chronic tubulointerstitial nephritis were, on average, older than animals with glomerulopathies.     

Renal transplantation for treatment of end-stage renal failure in cats.

Renal transplantation was performed as treatment of end-stage renal failure in 23 cats. Twenty-two cats had chronic renal disease and 1 cat had acute renal disease associated with ethylene glycol-induced toxicosis. Sixteen cats were discharged from the hospital. Nine survived a mean of 8.4 +/- 6.5 months, and 7 cats continue to survive at the time of this report (mean 12.6 months). Seven cats died within 2 weeks of surgery. All renal allografts were obtained from unrelated blood-crossmatch-compatible donors. No deaths were attributable to acute renal allograft rejection, demonstrating the successful maintenance of renal allografts by use of cyclosporine and prednisolone immunosuppression in cats.     

Ocular histopathology of Ehrlichial infections in the dog

Histologic examination of eyes and brains of 27 dogs experimentally infected with either Ehrlichia canis, E. ewingii, E. chaffeensis, or human granulocytic ehrlichia (HGE) was conducted in the course of several experiments, the primary objectives of which were to investigate the susceptibility of the domestic dog to infection with various ehrlichial species and to assess the ability of ixodid tick species to acquire and transmit those infections. Uveitis and meningitis occurred in each of the dogs infected with E. canis but was not observed in dogs infected with the other Ehrlichia species. The inflammatory infiltrate was predominantly lymphocytic, monocytic, and plasmacytic; granulocytes were notably few. Ocular inflammation was most common and most intense in the ciliary body, becoming less intense in the choroid, iris, and retina, respectively. Meningitis was often accompanied by mild neuroparenchymal vascular cuffing and gliosis. The meningeal inflammatory cell infiltrate included a prominent monocyte population. Ocular and meningeal lesions were present in all E. canis-infected dogs from 22 through 200 days postexposure. Neither ocular nor brain lesions were observed with any of the other ehrlichial infections.     

Acute toxoplasmosis following renal transplantation in three cats and a dog.

Three cats and 1 dog that had undergone renal transplantation because of end-stage renal disease were examined because of complications 3 to 6 weeks after surgery. One cat died prior to treatment of the complications; Toxoplasma cysts were found in sections of the renal allograft, and Toxoplasma tachyzoites were found in other organs. The other 2 cats and the dog died despite treatment, and protozoal cysts, as well as tachyzoites, were identified in other organs but not within the allografts, suggesting that reactivation of latent infection following immunosuppression was the most likely cause of disseminated toxoplasmosis. These cases illustrate that toxoplasmosis can be a fatal complication in renal transplant recipients. We currently recommend that feline and canine donors and recipients undergo serologic testing for toxoplasmosis prior to surgery. In addition, we suggest that seropositive donors not be used for seronegative recipients and that seropositive recipients and that seropositive recipients be monitored closely after surgery for clinical signs of toxoplasmosis.