ORGAN TRANSPLANTATION – CLINICAL RENAL TRANSPLANTATION IN THE

                                                DOG AND CAT...
therapy have been exhausted. The authors consider body weight to be a very important

indication of the status of the rena...
examination and intestinal biopsies should be performed if neoplasia or inflammatory bowel

disease is suspected. Immunosu...
should have a renal biopsy performed and be subject to a 2 week cyclosporine challenge prior to

surgery. Cyclosporine is ...
size of the recipient. The renal donor should have a normal life expectancy following unilateral

nephrectomy.7 Elevation ...
immunosuppressive protocol. Cats receiving azathioprine should have blood cell counts and

serum chemistry profiles perfor...
during harvest. Mannitol significantly reduces the incidence and duration of acute tubular

necrosis associated with warm ...
Using the template created by measuring the donor renal vein, an oval defect is created in the

caudal vena cava. The vena...
The kidney capsule is fixed to the abdominal wall by creating a peritoneal/transversus

abdominus muscle flap based on a v...
via free catch of the urine. Urine specific gravity is usually > 1.020 by the third postoperative

day. Packed blood cell ...
hydralazine therapy, acetylpromazine (0.01 mg/kg, intravenously, subcutaneously) is

administered. Rarely, transplant pati...
During the first year after transplantation, the most common complications that occur are

acute rejection, infections, an...
develop diabetes mellitus with an increased frequency. Diabetes can be temporary or a chronic

problem. Insulin therapy ca...
and the second is placed proximately. A section of the wall is excised from the iliac vein that is

slightly larger than t...
transplants have been performed clinically for canine renal failure patients. The primary

difference in transplantation b...
perioperative anticoagulation therapy must be employed (Gregory CR et al. Unpublished paper

in review).

        Canine r...
2 . Gregory CR: Renal transplantation in the cat. Comp Cont Ed Pract Vet

15:1325, 1993

3. Gregory CR, Gourley IM: Organ ...
11. Gregory CR et al: A mucosal apposition technique for ureteroneocystostomy after renal

transplantation in cats. Vet Su...
22. Pollard R et al: Ultrasonographic evaluation of renal autografts in normal

cats. Vet Radiol Ultrasound 40:380-385, 19...
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Apostila 1 - Clinical Transplantation

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Apostila 1 - Clinical Transplantation

  1. 1. ORGAN TRANSPLANTATION – CLINICAL RENAL TRANSPLANTATION IN THE DOG AND CAT Clare R. Gregory, DVM, Diplomate ACVS The Comparative Transplantation Laboratory in the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California 95616-8745 Clinical Renal Transplantation in Cats Criteria for the renal recipient.1, 2, 3, 4,5 Renal transplantation is one method of treatment for renal insufficiency. It cannot be regarded as an emergency treatment or "last-ditch" effort to save the life of a critically ill, malnourished patient. Surgical intervention has to take place before all medical means of 1
  2. 2. therapy have been exhausted. The authors consider body weight to be a very important indication of the status of the renal transplant candidate. If a cat has been in compensated renal failure and starts to lose body weight, or presents in renal failure with a history of chronic weight loss, transplantation should be considered as an option before further weight loss occurs. In the critically ill human surgical patient, maximum physical performance deteriorates after a 10% loss in normal body weight. Greater than a 40% weight loss is usually lethal. Previous attempts by the authors to alter the course of physical deterioration due to decompensated renal failure via enteral or parenteral alimentation prior to transplantation have failed. Hemodialysis, however, is very effective in managing severely uremic patients several days prior to surgery. The authors use hemodialysis to correct electrolyte and acid/base imbalances and lower the blood urea nitrogen concentration to 100 mg/dl or less. Blood urea nitrogen concentrations greater than 100 mg/dl predispose cats to postoperative cerebral edema and seizures due to rapid clearance of the blood urea nitrogen by a normally functioning renal graft. Age, plasma creatinine, blood urea nitrogen, and other clinical pathologic assessments of renal function cannot in themselves select a suitable patient for transplantation. All physical and biochemical parameters must be assessed to determine the overall suitability of a candidate. Feline candidates for renal transplantation should be free of Feline Leukemia Virus infection, active Acquired Immunodeficiency Syndrome and free of other complicating diseases. It appears that renal insufficiency can produce systemic hypertension in the feline patient leading to congestive heart failure. Cats in renal failure often have systolic murmurs secondary to anemia that may not represent significant cardiac disease. Cardiac enlargement determined by ultrasonographic examination, gallop rhythms, and/or electrocardiographic abnormalities are possible indications to decline a candidate for transplantation. An abdominal ultrasonographic 2
  3. 3. examination and intestinal biopsies should be performed if neoplasia or inflammatory bowel disease is suspected. Immunosuppression often enhances tumor growth and inflammatory bowel disease appears to promote acute allograft rejection. The feline renal donor/recipient pair do not have to be related or tissue matched, but they must be blood cross matched. The antigens present on red blood cells are also present on the endothelium of the graft blood vessels. Preformed antibodies to these antigens will cause clotting of the graft vessels and infarcts of the organ at the time of surgery. The feline renal recipient must also be blood cross matched to 2 to 3 blood donor cats. The primary reason for this is the anemia that accompanies chronic renal failure. Following rehydration of a patient prior to surgery, packed red blood cell volumes may fall as low as 12 to 15%. One hundred eighty to 250 milliliters of whole blood may be required to attain a packed red blood cell volume of 30% in the renal recipient prior to surgery. Also, in our experience, some cats in chronic renal failure are unable to accept blood transfusions, i.e. all cross match assays show agglutination of donor red cells. In two instances, the renal disease was secondary to Lupus erythematosus. In one other, however, no cause for the coagulopathy could be found. All cats were of the same blood type (A). This is an important consideration if the transplant patient is traveling a great distance to the transplant clinic. Cross matching should be done locally to ensure transfusions can be given prior to surgery. Erythropoietin can be very helpful in controlling the anemia associated with renal failure. Administration of erythropoietin starting 1 to 2 months prior to surgery can greatly reduce the need for blood products. Renal diseases successfully treated by renal transplantation in the cat include membranous glomerulonephropathy, chronic tubulointerstitial nephritis, polycystic renal disease, and ethylene glycol toxicosis. Cats with a suspected history of bacterial urinary tract infection 3
  4. 4. should have a renal biopsy performed and be subject to a 2 week cyclosporine challenge prior to surgery. Cyclosporine is administered orally at 4 mg/kg twice daily and urine cultures are performed 7 and 14 days following the initiation of cyclosporine treatment. Latent infections will often become active once cyclosporine is administered. Currently we are recommending renal transplantation for cats whose renal failure was secondary to obstruction by calcium oxalate uroliths. However, clients must be warned that some of these cats may form additional uroliths following transplantation that may obstruct and injure or destroy the transplanted kidney. Cats with renal failure whose kidneys are of normal or increased size should have a biopsy performed to rule out lymphosarcoma. In the past, cats that had positive serum titers for Toxoplasmosis, either IgG or IgM, were not considered candidates for immunosuppression and transplantation. Both cats and dogs have developed fatal Toxoplasmosis infections following renal transplantation and immunosuppression6. Currently animals with positive serum titers that undergo transplantation are administered clindamycin or trimethoprim/sulfadiazine prior to surgery and for the life of the patient. (LR Aronson, University of Pennsylvania, personal communication). Trimethoprim/sulfadiazine must be used with care since this drug can enhance cyclosporine nephrotoxicity. Criteria for the renal donor. The renal donor should be in excellent health and have no evidence of renal insufficiency based on clinical pathologic testing; complete blood count, serum chemistry panel, urinalysis and urine bacterial culture. An intravenous pyelograph is performed to assure that the donor has two, normally shaped, and well vascularized kidneys. The feline donor should be free of Feline Leukemia virus infection, and be blood cross match compatible and of similar weight and body 4
  5. 5. size of the recipient. The renal donor should have a normal life expectancy following unilateral nephrectomy.7 Elevation in serum creatinine levels and proteinuria have been reported in human kidney donors, and long-term monitoring of renal function has been recommended. Preoperative preparation of the recipient. Prior to surgery, the renal recipient is given balanced electrolyte solutions subcutaneously or intravenously at 1.5 to 2 times daily maintenance requirements. Whole blood or packed red blood cell transfusions are administered until a packed red cell volume of 25- 30% is achieved. Hemodialysis is employed for cats that maintain a blood urea nitrogen concentration > 120 mg/dl despite aggressive fluid diuresis. Forty-eight hours prior to surgery, cyclosporine oral solution (Neoral®) is administered at a dose of 3-5 mg/kg every 12 hours. The cyclosporine oral solution should be placed in gelatin capsules prior to administration. Capsule sizes #0 or #1 work well for most cats. Cyclosporine oral solution has a very unpleasant taste that causes some cats to salivate profusely, resulting in partial loss of the dose. Clindamycin is administered to animals with positive serum titers for Toxoplasmosis. The morning of surgery, a blood sample is taken from the recipient 12 hours following the last oral dose of cyclosporine. This will give a 12 hour trough blood concentration. The authors follow whole blood concentrations of cyclosporine assayed by High Pressure Liquid Chromatography. In cats, a concentration of 500ng/ml is maintained for the first 30 postoperative days, reducing to 250ng/ml by three months after transplantation. Prednisolone, 1 mg/kg/12 hours, orally, is also started the evening following surgery and is reduced to 0.5 to 1 mg/kg/24 hours by 1 month postoperatively if renal function is normal. If renal function starts to deteriorate in the first weeks to months following transplantation, i.e. serum creatinine concentrations begin to rise above 2 mg/dl, azathioprine (0.3 mg/kg/72hours) is added to the 5
  6. 6. immunosuppressive protocol. Cats receiving azathioprine should have blood cell counts and serum chemistry profiles performed weekly until a safe and effective dose is found. White blood cells counts should be maintained at >3000 /µl and serum chemistry profiles should be evaluated for evidence of hepatitis or pancreatitis. Surgery.2,3,5,8 Two teams perform renal transplantation; one team harvests the donor kidney and closes the abdominal wound, and one team prepares the recipient vessels and receives the kidney. The two team approach minimizes the warm ischemia time of the donor kidney, which should be kept to less than 60 minutes, unless preservation protocols are employed 9. The authors have not used perfusion solutions to maintain the kidney prior to vascularization, but iced heparinized saline solution is used to flush blood from the kidney following harvest. It is important to thoroughly cool the kidney immediately following excision from the donor. Cold sponges should be placed on the kidney during the implantation procedure to keep it from prematurely warming. Anesthesia protocols vary with each patient. In general, the recipient receives atropine (.03mg/kg) and oxymorphone (.05mg/kg) subcutaneously prior to induction. The cat is mask or boxed induced and anesthesia is maintained using isoflurane or sevoflurane inhalant anesthesia and oxygen. During the procedure, balanced electrolyte solutions and/or whole blood/packed red blood cells are administered intravenously. Systemic arterial pressure is monitored via direct arterial catheterization or by indirect measurement using Doppler ultrasonography. Hypotension can be managed using dopamine (5µg/kg/minute intravenously) and fluid boluses as necessary. Both cats receive broad spectrum antibiotics administered intravenously just prior to surgery. As the abdominal incision is made, the donor cat should receive mannitol ( 0.5 g/kg as a bolus followed by a constant infusion of 1mg/kg/minute) to protect the kidney to be transplanted 6
  7. 7. during harvest. Mannitol significantly reduces the incidence and duration of acute tubular necrosis associated with warm ischemia. The donor nephrectomy is performed via a ventral midline celiotomy. Magnifying loupes providing 3.3X to 4.5X magnification are recommended for the vascular dissection. The vascular pedicle of the donor kidney can contain only one artery. Renal arteries may bifurcate close to the aorta. A length of .5 cm or more is required for arterial anastomosis. If two or more veins are present, the largest is saved for venous anastomosis. The vascular pedicle should contain the longest vein possible, so the left kidney is explored first. Once the kidney to be harvested is selected, the recipient team should be informed so they can prepare the recipient vessels. It is very important to clean the donor renal artery and vein of as much fat and adventitia as possible. The large fat pad in the renal pelvis should be removed, being careful not to damage the ureter. Removal of the fat and adventitia from the vessels prior to nephrectomy reduces warm ischemia time. The renal vein diameter is measured and a sterile paper template is made to guide the size of the venotomy in the recipient’s caudal vena cava. The ureter is isolated to the bladder. Donor nephrectomy is performed when the recipient team is prepared to receive the kidney. Anastomosis of the renal vessels and the ureter in the small dog and cat requires 3X to 10X magnification. The higher magnification is necessary to suture the ureter to the bladder. The authors use an operating microscope. The recipient post renal aorta and vena cava area isolated via a ventral midline celiotomy. The kidney is implanted between the left renal artery and the caudal mesenteric artery. First the aorta is occluded using vascular occlusion clamps. Using an arterotomy clamp, a 1.5 to 2 mm defect is created in the aortic wall. The lumen of the aorta is flushed with heparinized saline solution. The caudal vena cava is then occluded adjacent to the arterotomy site in the aorta. 7
  8. 8. Using the template created by measuring the donor renal vein, an oval defect is created in the caudal vena cava. The vena cava is flushed with heparinized saline solution. Once the recipient vessels have been prepared for implantation of the graft, the donor kidney is harvested. The kidney is flushed with iced heparinized saline. The renal artery is gently dilated and adventitia is excised from the distal end. The artery is anastomosed to the aorta, end-to-side, using 8-0 nylon in a simple continuous pattern. The renal vein is then anastomosed to the vena cava using 7-0 silk or 8-0 nylon, depending on the size of the vein, in a simple continuous pattern. Due to a lack of visibility of the wall adjacent to the aorta, the first side of the vein closest to the aorta is sutured inside the lumen of the vessels (back-wall technique). Once the first side is sutured, the side away from the artery is sutured in a conventional manner. As soon as both the renal artery and vein are sutured, the venous occlusion clamp is removed, followed by the arterial occlusion clamp. Hemorrhage is controlled by pressure, or by the addition of simple interrupted sutures if needed. The ureter is sutured to the bladder in the following manner.1,10.11 A 1 centimeter incision is made in the seromuscular layer of the bladder on the ventral surface. The mucosa will bulge through the incision. A 3 to 4 mm incision is made in the mucosa at the caudal aspect of the seromuscular incision. The periureteral fat is excised from the distal 5 mm of the ureter, and the end of the ureter is spatulated. Using 8-0 vicryl in a simple interrupted pattern, the mucosa of the ureter is sutured to the mucosa of the bladder. The proximal and distal sutures are placed first. A 5-0 polypropylene stent is used to check patency of the stoma. Once the mucosal layers are opposed, the seromuscular layer is closed over the ureter using 4-0 absorbable suture in a simple interrupted pattern. 8
  9. 9. The kidney capsule is fixed to the abdominal wall by creating a peritoneal/transversus abdominus muscle flap based on a ventral pedicle. The flap is sutured to the renal capsule using simple interrupted sutures of 5-0 polypropylene. Fixing the kidney to the abdominal wall prevents torsion of the kidney on its pedicle with resulting ischemia and loss of the graft. To provide nutritional support during the postoperative period, a gastrostomy or esophagostomy tube is placed prior to recovery from anesthesia. In dogs, the transplanted kidney can be placed in the iliac fossa of the recipient. The renal vein is anastomosed end-to-side to the external iliac vein using 4-0 or 5-0 silk in a continuous pattern. The renal artery is anastomosed end-to-end with the external iliac artery using 4-0 or 5-0 polypropylene suture in a simple interrupted pattern. As in the cat, a peritoneal/ muscle flap is used to secure the kidney to the abdominal wall. The iliac vessels are no longer used as recipient vessels for feline transplant patients. While not a problem in dogs, loss of the iliac blood supply in cats can result in ipsilateral hind limb weakness, paralysis and ischemia.8 Unless there is evidence of bacterial nephritis or severely enlarged polycystic kidneys, the authors do not remove the recipient’s native kidneys at the time of transplantation. These kidneys are available to provide some support if the transplanted organ should fail, and can be removed at a later date if indicated. Postoperative care of the renal recipient. During and following surgery, it is imperative to keep the transplant patient warm and the hematocrit and systolic blood pressure within normal limits. Avoid unnecessary stress and handling. Postoperative pain is controlled by the administration of oxymorphone (0.05 mg/kg subcutaneously) as needed. The recipient receives balanced electrolyte solutions supplemented to correct electrolyte or acid/base abnormalities.1,11 Urine specific gravity is followed twice daily 9
  10. 10. via free catch of the urine. Urine specific gravity is usually > 1.020 by the third postoperative day. Packed blood cell volume, total plasma protein level, serum electrolyte levels and the plasma creatinine concentration are assessed 3 to 4 times daily until renal function is stable. During the early postoperative period needless venapuncture, blood sampling and patient handling should be avoided. If the surgery is a technical success, the urine specific gravity will be increased, and the plasma creatinine will be decreased by the third postoperative day. The recipient will look clinically improved and normal appetite usually returns by postoperative day 3 to 5. If the graft has failed or has delayed function, the recipient will be depressed and anorectic. The urine will remain isosthenuric. Approximately 3 days following surgery, an ultrasonographic examination of the transplanted kidney and ureter can be performed if renal function is not returning to normal. If there is good perfusion of the graft without evidence of hydronephrosis or hydroureter secondary to obstruction, the graft may have suffered acute tubular necrosis consistent with delayed graft function. As long as the kidney remains perfused, function can start as late as 3 weeks following surgery. Hypertension is a common complication that can occur within the first 72 hours after surgery.13,14 Cats can develop hypertension (systolic blood pressure > 170 mm/Hg) and are at higher risk for neurologic disorders such as ataxia, blindness, seizures and stupor. Occasionally, uncontrollable seizures and death can result. Controlling hypertension has significantly reduced the frequency of these complications. Indirect, systolic blood pressure is measured by ultrasonic Doppler every hour for at least 24 hours after surgery, and then at decreasing intervals over the next 48 hours. When the systolic blood pressure is > 170 mm/Hg, hydralazine (2.5 mg total dose/subcutaneously) is given. If the systolic blood pressure has not decreased to normal within 15 to 20 minutes, a second dose is given. In the rare case that the hypertension is refractory to 10
  11. 11. hydralazine therapy, acetylpromazine (0.01 mg/kg, intravenously, subcutaneously) is administered. Rarely, transplant patients can develop a lethal sensitivity to cyclosporine termed hemolytic uremic syndrome. 15 Cats become uremic with a coexisting hemolytic anemia and thrombocytopenia. The transplanted kidney is lost to ischemia produced by diffuse vascular thrombosis. Currently there is no treatment for this syndrome in cats. If the transplant recipient is not eating well by 24 hours following surgery, feedings are begun using the gastrostomy or esophagostomy tube. Normal caloric intake is attained over 24 to 48 hours. Cyclosporine is administered at levels necessary to achieve trough whole blood concentrations of 500 ng/ml. Prednisolone is administered at 1.0 mg/kg/12 hours, orally, and is tapered to 0.5 to 1 mg/kg/24 hours by four weeks postoperatively. Erythropoietin can be administered if the hematocrit remains below 25%. Transplant recipients are discharged from the hospital when they have achieved an adequate nutritional intake and the cyclosporine blood level has stabilized. The feeding tube is left in place until the cat has completely acclimated at home. Long-term management of the renal recipient. Management of the transplant patient must be coordinated with the client, the local veterinarian(s), and the transplant center. Examinations are initially performed weekly by the local veterinarian. Packed blood cell volume, total serum protein concentration, plasma creatinine concentration, whole blood cyclosporine concentration and a urinalysis are performed. Periods between examinations are gradually extended to 3 or 4 weeks. The authors recommend that a complete blood count should be performed monthly, and a serum chemistry panel, urinalysis with urine culture and cardiac consult be performed 3 times a year. 11
  12. 12. During the first year after transplantation, the most common complications that occur are acute rejection, infections, and the development of cancers.6,16,17,18,19,20 Acute rejection can often be attributed to poor owner compliance in giving medications and having cyclosporine blood concentration assays performed on a regular basis. Acute rejection is an emergency situation that must be treated quickly and aggressively with injectable cyclosporine (Sandimmune®, [Norvartis AG, Basel, Switzerland], 6.6 mg/kg once daily over 4 to 6 hours), corticosteroids and the intravenous administration of balance electrolyte solutions. Cats do not show illness associated with acute rejection, so rising creatinine concentrations are considered grounds for treatment unless obstructive uropathy can be proven by ultrasonographic evaluation of the kidney and ureter.21,22 In cats, slow, chronic elevations of serum creatinine, in the face of adequate blood levels of cyclosporine, are treated with the addition of azathioprine (0.3 mg/kg/72 hours) to the immunosuppressive protocol. The white blood cell count and hepatic enzyme concentrations must be monitored and the dose adjusted as necessary to prevent severe leukopenia (<3000 cells/µl) or hepatitis. Transplant patients are susceptible to infections. Viral, bacterial, parasitic, coccidian, protozoal, and fungal infections can all develop. When treating bacterial infections, aminoglycoside and trimethoprim/sulfa antibiotics must be avoided as they are nephrotoxic when combined with cyclosporine. When adding any medication to the immunosuppressive protocol, check the drug insert that is provided with cyclosporine. Many agents can raise or lower cyclosporine whole blood concentrations by interfering or promoting cytochrome P-450 enzyme activity. Immunosuppressed patients are also at an increased risk for the development of cancer. The most common types are lymphoma and squamous cell carcinoma. Transplant recipients also 12
  13. 13. develop diabetes mellitus with an increased frequency. Diabetes can be temporary or a chronic problem. Insulin therapy can provide long-term control. Clinical Renal Transplantation in the Dog There are only a few differences in the technical aspects of renal transplantation between the dog and the cat. Most dogs, due to their size, do not require magnification for anastomosis of the vessels, although 2X to 3X magnifying loops are very helpful. . In addition to implanting the graft on the terminal aorta and vena cava, the external iliac artery and vein can be used as recipient vessels for the transplanted kidney. The iliac vessels should not be used for the recipient vessels in cats since loss of the iliac blood supply in cats can result in rear limb weakness, paralysis or ischemia. 8 For ease of anastomosis, a left donor kidney is placed in the right iliac fossa of the recipient, and vise versa. If necessary, a donor kidney can be placed in the ipsilateral iliac fossa of the recipient, however, the arterial anastomosis will be more difficult to perform. The chosen iliac fossa is prepared for end to end anastomosis of the renal artery to the iliac artery and end to side anastomosis of the renal vein to the iliac vein. The iliac artery is isolated, and a bulldog or other vascular clamp is used to occlude it near the aortic bifurcation. The iliac artery is then ligated distally, near the femoral ring, and is severed. The free length of the artery is flushed clean of blood using heparinized saline solution. The end of the artery is gently dilated and the adventitia is excised from the proximal 3-5 mm. The iliac vein lies deep to the artery in fat and adventitia. It is isolated over the same area as the artery, gaining as much free length as possible. The iliac vein has multiple tributary veins in this region that must be ligated. Careful inspection dorsal and caudal to the vein will reveal these branches. Once the tributary veins have been ligated, two vascular clamps are placed on the iliac vein as far apart as possible. The first is placed distally, 13
  14. 14. and the second is placed proximately. A section of the wall is excised from the iliac vein that is slightly larger than the diameter of the donor renal vein. It is important to create a defect in the vein wall and not just a slit. The vein is flushed clean of blood using heparinized saline solution. Two 4-0 to 6-0 sutures of silk are placed at each end of the defect in the vein wall. Each suture is subsequently placed at the cranial or caudal aspect of the renal vein and tied. The renal vein is then anastomosed to the iliac vein using a simple continuous pattern on both the medial and lateral sides of the vessels. Following completion of the venous anastomosis, the renal artery and iliac artery are isolated near the midline of the recipient. The arteries are anastomosed using 5-0 to 8-0 nylon or polypropylene in a simple interrupted pattern. Once arterial anastomosis is complete, the vascular clamps are removed from the vein, and then the artery. Some hemorrhage is expected, can be controlled with light pressure, and should stop within a few minutes. Large defects in the arterial anastomosis will have to be controlled by placement of additional sutures. Ureteroneocystostomy is performed using the same method described for the cat. The kidney capsule is attached to the adjacent abdominal wall using simple interrupted sutures of 3-0 polypropylene or a peritoneal/transversus abdominis muscle flap. Following renal transplantation, dogs are highly likely to develop intestinal intussusceptions. Two treatments have resulted in the prevention of this condition that develops post-operatively. First, morphine, 0.5 mg/ml is administered subcutaneously as a premedication and postsurgically at 0.5 mg/kg subcutaneously every 3 to 4 hours to control pain.23 Second, enteroplication is performed after the renal transplant procedure is completed. The seromuscular layers of the bowel are joined using simple interrupted sutures of 3-0 polydioxanone. 24 Due to the difficulty of immunosuppressing the dog rejection response, few renal 14
  15. 15. transplants have been performed clinically for canine renal failure patients. The primary difference in transplantation between the dog and cat is selection of the donor. Using cyclosporine and prednisolone to achieve immunosuppression, the authors will only use mixed lymphocyte response matched, related donors. The new formulation of cyclosporine, with conventional or newly developed agents, has proven to successfully control the canine rejection response.25,26 With the use of MHC-nonmatched donors, the authors employ one of two immunosuppressive protocols: 1)cyclosporine and leflunomide (4-6 mg/kg/24 hours) or 2) cyclosporine (Neoral®), azathioprine (1-5 mg/kg every 48 hours) and prednisolone (1 mg/kg/24 hours). Cyclosporine is administered at a dose that will achieve a trough whole blood level of 500 ng/nl. Leflunomide is administered at a dose necessary to maintain a trough plasma blood concentration of 20 µg/ ml. Azathioprine dosage is adjusted to avoid leukopenia and hepatitis. The dose of prednisolone is reduced over 1 to 3 months depending on the serum creatinine concentration and degree of side effects suggestive of Cushing’s Syndrome. In a long on-going study, Mathews et al employed antithymocyte serum, cyclosporine, azathioprine and prednisolone for immunosuppression of unrelated dog donor-recipient pairs. A median survival time of 8 months was achieved with 2 dogs surviving more than 2 years.27 In a recently completed clinical study, the authors found that the combination of cyclosporine, azathioprine and prednisolone prevented renal allograft rejection in 15 dogs. Three dogs are currently alive 24 to 50 months following surgery. Five of the dogs died in the perioperative period due to the development of systemic thromboembolism. Four of the dogs died due to the development of lethal bacterial infections. Renal allograft rejection can be controlled in the dog. However, a balance must be maintained between the control of rejection and the development of lethal infections. Due to the hypercoagulable state present in the canine renal failure patient, 15
  16. 16. perioperative anticoagulation therapy must be employed (Gregory CR et al. Unpublished paper in review). Canine renal transplantation is still in the development phase. The work of Mathews et al and our own studies have been invaluable in highlighting the techniques and the difficulties, both clinically and financially. Over the next several years, case selection, immunosuppressive management and anticoagulation strategies will be further refined, and outcomes will improve. Client Education Before performing renal transplantation for the dog or cat, clients must be fully informed of the risks, responsibilities and costs associated with the procedure. Clients must be able to administer medications orally two times a day for the life of their pet. Fractious cats and dogs are not good candidates because of the extensive nursing required in the perioperative period and the need for regular examinations by the local veterinarian. Clients must have access to a 24 hour emergency facility. Finally, clients must understand that no matter how carefully selected and managed, their cat or dog may die due to the stress of the procedure or failure of the graft to function. Feline and canine renal transplantation is becoming more widely available in the United States and is also performed in Australia, Japan and Europe. Survival rates have improved with careful patient selection, better perioperative care and monitoring, and the introduction of the microemulsified form of cyclosporine (Neoral®). Renal transplantation can offer long-term survival with a normal quality of life for cats and dogs with renal failure. References: Bernsteen L, et al. Renal transplantation in cats. Clin Tech Sm An Prac 15:40, 2000 16
  17. 17. 2 . Gregory CR: Renal transplantation in the cat. Comp Cont Ed Pract Vet 15:1325, 1993 3. Gregory CR, Gourley IM: Organ transplantation in clinical veterinary medicine. In: Slatter D (ed): Textbook of Small Animal Surgery, 2nd Ed, WB Saunders Company, Philadelphia, 1993, pp 95-101. 4. Kochin E.J. and Gregory CR: Renal transplantation:patient selection and postoperative care. In: Consultations in Feline Internal Medicine, 2nd Ed, WB Saunders Company, Philadelphia, 1993 pp 339-342. 5. Gregory CR, Bernsteen L: Organ Transplantation in Clinical Veterinary Practice. In Slatter D, ed.: Textbook of Small Animal Surgery, 3rd ed. Philadelphia, WB Saunders Co, 2003, p 122. 6. Bernsteen L, et al: Acute toxoplasmosis following renal transplantation in three cats and a dog. JAVMA 215: 1123, 1999. 7. Lirtzman R A, Gregory CR. Long-term renal and hematologic effects of uninephectomy in healthy feline kidney donors. JAVMA 207: 1044, 1995. 8. Bernsteen L, et al: Comparison of two surgical techniques for renal transplantation in cats. Vet Surg 28:417, 1999 9. McAnulty JF: Hypothermic storage of feline kidneys for transplantation: successful ex vivo storage up to 7 hours. Vet Surg 27:312, 1998 10. Kochin E.J. and Gregory CR. Evaluation of a method of ureteroneocystotomy in the cat. JAVMA 202: 257,1993. 17
  18. 18. 11. Gregory CR et al: A mucosal apposition technique for ureteroneocystostomy after renal transplantation in cats. Vet Surg 25:13, 1995. 12. Wooldridge JD, Gregory CR: Ionized and total serum magnesium concentrations in feline renal transplant recipients. Vet Surg 28:31, 1999. 13. Gregory CR et al: Central nervous system disorders after renal transplantation in cats. Vet Surg 26:386, 1997 14. Kyles A E, et al: Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats. Vet Surg 28:436, 1999. 15. Aronson LR, Gregory CR: Possible hemolytic uremic syndrome in three cats after renal transplantation and cyclosporine therapy. Vet Surg 28:135, 1999. 16. Gregory CR et al. Preliminary results of clinical renal allograft transplantation in the dog and cat. J Vet Int Med 1:53, 1987 17. Gregory CR et al: Feline leukemia virus-associated lymphosarcoma following renal transplantation in a cat. Transplantation 52(6):1097, 1991 18. Gregory CR et al: Renal transplantation for treatment of end-stage renal failure in cats. JAVMA 201:285, 1992 19. Gregory CR et al: Oxalate nephrosis and renal sclerosis after renal transplantation in a cat. Vet Surg 22:221, 1993 20. Mathews KG, Gregory CR: Renal transplants in cats: 66 cases (1987- 1996). JAVMA 211:1432, 1997. 21. Nyland TG et al: Ultrasonographic evaluation of renal size in dogs with acute allograft rejection. Vet Radiol Ultrasound 38:55, 1997 18
  19. 19. 22. Pollard R et al: Ultrasonographic evaluation of renal autografts in normal cats. Vet Radiol Ultrasound 40:380-385, 1999. 23. McAnulty JF, Southard JH, Belzer FO: Prevention of postoperative intestinal intussusception by prophylactic morphine administration in dogs used for organ transplantation research. Surgery 105: 494, 1989 24. Kyles AE, Gregory CR, Griffey SM et al. Modified noble placation for the prevention of intestinal intussusception after renal transplantation in dogs. J Invest Surg 16: 161, 2003 25. Bernsteen L, Gregory CR, Kyles AE, et al. Microemulsified cyclosporine-based immunosuppression for the prevention of acute renal allograft rejection in unrelated dogs: preliminary experimental study. Vet Surg 32: 213, 2003 26. Kyles AE, Gregory CR, Griffey SM, et al. Immunosuppression with a combination of the leflunomide analog, FK778, and microemulsified cyclosporine for renal transplantation in mongrel dogs. Transplantation 27: 1128, 2003 27. Mathews KA et al. Kidney transplantation in dogs with naturally occurring end-stage renal disease. JAAHA 36: 294, 20 19

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