Chapter 119 The first successful renal transplant in companion animals was performed on a cat in 1984 by Dr. Clare Gregory and Dr. Ira Gorley at the University of California, Davis.29 Since that time, the procedure continues to remain a viable treatment option for patients in acute or chronic renal failure. The success of the technique has been attributed to several factors, including development of microsurgical techniques in veterinary practice, the ability to use an allograft from an unrelated or related donor, a better understanding of immune response to foreign tissue, and use of cyclosporine for immunosuppressive therapy in dogs and cats.28,31,33 Use of renal transplant as a treatment for renal failure is supported by recent literature; in a study comparing survival time of cats that had undergone a renal transplant to a control population of cats treated medically, renal transplantation appeared to prolong survival time and quality of life compared with medical management of the disease.87 In 1992, a retrospective study documented results from the first 23 cats undergoing renal transplantation as a treatment option for end-stage renal failure. In that study, 70% of the cats were discharged from the hospital. The mean survival period of all cats was 12 months; the cat that was the longest survivor lived 31 months.32 Four years later, a larger retrospective study evaluating 66 cases of feline renal transplantation (including the 23 cases that had been previously described) was published.66 The percentage of cats (71%) surviving to discharge was similar to that in the first report; more notably, however, the perioperative survival rate during the 9-year study period improved from 64% in the first 33 cats to 79% for the last 33 cats.66 In a more recent report, 77.5% of cats survived to discharge.87 The median survival time was 613 days; overall, 6-month and 3-year survival rates were 65% and 40%, respectively.87 Appropriate screening of a potential transplant candidate is performed by the referring veterinarian and the transplant surgeon to decrease the incidence of postoperative morbidity and mortality. Surgical intervention is recommended in cats with irreversible acute renal failure or early decompensated chronic kidney disease.30,64 Indications of decompensation include continued weight loss and worsening of anemia and azotemia in the face of medical therapy. It is important to note that some clinically stable candidates can rapidly deteriorate and die without prior evidence that decompensation was present. At one facility, serum creatinine greater than 4 mg/dL or significant aberrations in calcium and phosphorus levels were also indications for transplantation.45 Although attempts at altering physical deterioration are reportedly unsuccessful, some potential feline renal transplant candidates have been medically managed for up to 2 years with nutritional, drug, and fluid supplementation through an esophagostomy tube or percutaneous endoscopic gastrostomy tube.30,64,65 Screening of potential candidates includes physical and biochemical parameters; however, limited information exists regarding risk factors associated with postoperative morbidity and mortality. By themselves, azotemia, anemia, urine specific gravity, and age do not determine the suitability of a patient for transplantation; however, some of these factors have been associated with survival. Recipient age has been identified as a factor associated with survival after discharge.1,87 In one study, cats older than 10 years of age had greater mortality rates, particularly during the first 6 months after surgery.1 In another study, median survival times decreased with age, with median survival times of 1423, 613, and 150 days, respectively, for cats younger than 5 years of age, between the ages of 5 and 10 years, and older than 10 years of age.87 To date, the oldest cat that has been transplanted at our facility was 18 years of age. The severity of azotemia before transplantation was also found to be a risk factor: in one study, cats with creatinine above 10 and increased blood urea nitrogen (BUN; value not given) were more likely to die before discharge.87 In another study, the severity of azotemia was not related to long-term survival but significantly increased the risk of neurologic complications in the perioperative period.1 Similar to the case in humans, use of preoperative hemodialysis to reduce azotemia before transplantation may be warranted to reduce morbidity and mortality. Finally, preoperative blood pressure and weight have also been shown to influence overall survival.87 Current evaluation at our facility involves various laboratory tests (complete blood count [CBC], chemistry, blood type and cross-match, and thyroid evaluation), evaluation of the urinary tract (urinalysis, urine culture, urine protein : creatinine ratio, abdominal radiography, and abdominal ultrasonography), evaluation for cardiovascular disease (thoracic radiography, electrocardiography, echocardiography, and blood pressure), and screening for infectious disease (feline leukemia virus, feline immunodeficiency virus, and serologic testing for toxoplasmosis; see Box 119-1). Evaluation of the urinary tract is essential to rule out any underlying infection, neoplastic disease, or obstruction before transplantation. Abdominal ultrasonography and radiography are performed; if neoplasia or feline infectious peritonitis is suspected based on results, a fine-needle aspirate or a biopsy is recommended. Patients previously diagnosed with a urinary tract infection should be treated with appropriate antibiotic therapy based on culture and sensitivity testing before presentation. If a patient has recently been treated for a urinary tract infection or has had recurrent urinary tract infections and has a negative urine culture result at the time of presentation, a cyclosporine (CsA; Neoral, Sandoz Pharmaceuticals) challenge is indicated. Cyclosporine is administered for approximately 2 weeks at the recommended dose for transplantation immunosuppression. Urine is subsequently evaluated for the presence of an infection after therapeutic cyclosporine blood levels have been obtained and at the end of the 2-week period. Although negative urine culture results will not guarantee that a patient will remain infection free after transplantation and chronic immunosuppression, positive culture results will eliminate as candidates cats and dogs with occult infections. Another option is to place all potential candidates on cyclosporine for 2 weeks before surgery to attempt to identify an occult infection.64 Calcium oxalate urolithiasis has been noted with increasing incidence as the cause of renal failure and subsequent presentation of a cat for renal transplantation. Renal transplantation is considered a treatment option for cats whose underlying cause of renal failure was associated with calcium oxalate urolithiasis.10 If hydronephrosis is identified on abdominal ultrasonography during the transplant screening process, culture of urine obtained by pyelocentesis is recommended before transplantation. The authors have identified five cats with obstructive calcium oxalate urolithiasis that had negative culture results for urine collected from the urinary bladder and positive culture results for urine collected by pyelocentesis.4 Infection must be identified and cleared before transplantation because immunosuppression in a patient harboring an infection can potentiate the rejection process and lead to increased morbidity and mortality. Although information exists in human medicine regarding the effects of pre- and postoperative hypertension on outcome,26 information for companion animals is limited. Pre- and postoperative hypertension are common in humans undergoing renal transplants, and postoperative hypertension has been associated with graft damage and less than optimal outcomes.23,24,77,81 Effects in cats are variable: in one feline study, preoperative blood pressure influenced overall survival.87 In a second study, preoperative hypertension did not predict postoperative episodes of hypertension, and administration of antihypertensive medication preoperatively did not significantly decrease postoperative incidence of the condition.1 On presentation for transplantation, many cats have systolic murmurs. These murmurs may be physiologic and associated with anemia of chronic renal failure and may not represent significant heart disease.30 Historically, cats with underlying heart disease were rejected as potential recipients because of complications associated with transplants in cats with hypertrophic cardiomyopathy. In a recent study from the University of California, Davis, of 84 potential transplant recipients, only 22% of cats were found to have a normal heart on echocardiographic examination.2 The most common abnormalities were papillary muscle and septal muscle hypertrophy; it was suggested that these changes might be related to hypertension, chronic uremia, age, or early changes of hypertrophic cardiomyopathy.2 In that study, an analysis of preoperative echocardiographic changes in transplant recipients found no significant predictors of 1-month survival. Another study found that increased left ventricular wall thickness and increased duration of intraoperative hypotension were risk factors for perioperative mortality.87 Cats that are feline leukemia virus positive or have an active feline immunodeficiency virus infection are declined as candidates for transplantation. Currently, all potential donors and recipients undergo serologic testing (IgG and IgM) for toxoplasmosis. Toxoplasma gondii can cause significant morbidity and mortality in immunocompromised human and veterinary patients. Toxoplasmosis is an uncommon infection in humans receiving transplants. Infected patients often display clinical signs within the first 3 months after surgery because this is the period of maximum immunosuppression.82 In a report of three cats and one dog, disseminated toxoplasmosis occurred within 3 weeks to 6 months after transplantation. Serologic testing was not performed before surgery in these patients; thus, preoperative T. gondii status was unknown.14 As a matter of policy at the authors’ facility, seropositive recipients are placed on lifelong prophylactic clindamycin (25 mg PO q12hr), which is started when immunosuppression is initiated. Trimethoprim-sulfa (15 mg/kg PO q12hr) has also been used in cats that did not tolerate clindamycin. Although we no longer use seropositive donors for seronegative recipients, we have successfully used a seropositive donor for a seropositive recipient. To date, 13 recipients with positive IgG or IgM titers have been placed on prophylactic clindamycin therapy.7 Two cats are currently alive at 425 and 1565 days, and nine cats died a median of 396 days after transplantation. Two other cats died more than 1 year after transplantation; the exact time was unknown. Causes of death included lymphosarcoma (three cats), cardiomyopathy (one cat), presumed antibiotic toxicity (one cat), feline infectious peritonitis (one cat), systemic Klebsiella pneumonia infection (one cat), accidental avulsion of the allograft (one cat), chronic retroperitoneal fibrosis (one cat), chronic pyelonephritis (one cat), and allograft failure (one cat). None of the cats died from an active T. gondii infection.4 Three cats seronegative at admission developed fatal T. gondii infections 24, 60, and 390 days after transplantation. The patient that died 60 days after transplantation developed pyogranulomatous cystitis associated with T. gondii, an unusual manifestation of this infection.76 All three donors were seronegative. It is unclear if the sensitivity of the screening tests did not detect the infection initially or if affected cats were exposed after surgery. In some ways, clinicians performing renal transplantation have become more stringent in case selection. With the availability of hemodialysis and the increasing experience of the clinicians who manage these cases, however, some have “pushed the envelope” a bit by performing transplants on animals that might be considered marginal recipients. Findings that preclude renal transplantation at our facility include underlying neoplastic disease, severe cardiac disease, positive feline leukemia virus status, active feline immunodeficiency virus infection, recurrent or existing urinary tract infection that fails medical therapy or a cyclosporine challenge, uncontrolled hyperthyroidism, and a fractious temperament (Box 119-2). Many grey areas still exist, however, including the presence of inflammatory bowel disease, diabetes, or echocardiographic abnormalities in patients unable to handle fluid therapy. Kidney donors are typically between 1 and 3 years of age and in excellent health. Standard screening includes a serum chemistry profile, CBC, blood type, urinalysis and culture, feline leukemia virus and feline immunodeficiency virus testing, and a toxoplasmosis titer (IgG and IgM). In humans, routine donor–recipient matching tests include RBC cross-match, lymphocytotoxic cross-match to detect antibodies against lymphocytes, and a mixed lymphocyte reaction to match the major histocompatibility complex. A method for a lymphocytotoxic cross-match test for feline renal transplantation has been described for investigation of antilymphocyte antibodies in cats.54 Currently, determination of compatibility between the feline kidney donor and recipient is routinely limited to blood type and RBC cross-match. Although rare, incompatible cross-match tests between AB compatible donor and recipient pairs have been identified. Absence of a novel RBC antigen, identified as Mik, has resulted in naturally occurring anti-Mik alloantibodies after an AB-matched blood transfusion.91 At our facility, a mixed lymphocyte reaction to match the major histocompatibility complex is performed between canine donor and recipient pairs. Additionally, we currently perform computed tomography (CT) angiography on all of the donors to evaluate the renal vasculature and parenchyma for any abnormalities.18 This technique has allowed us to identify patients unsuitable for donation before surgery, including patients with multiple renal arteries bilaterally or renal infarcts. In a recent study characterizing normal feline renal vascular anatomy using CT angiography, 45 of 114 cats had multiplicity of the right renal vein, and 8 of 114 cats had multiple left renal arteries.21 A suitable home is found for any donor that fails the screening process. In the only study to date evaluating the long-term effects of unilateral nephrectomy in healthy cats, 16 donors were followed between 24 and 67 months after surgery.61 Fifteen of the 16 cats were clinically normal, and serum creatinine concentrations for these cats remained within the reference range. One cat was diagnosed with chronic renal insufficiency 52 months after surgery. In a study evaluating 14 canine donors, renal and hematologic variables were within reference ranges in dogs evaluated up to 2.5 years after unilateral nephrectomy. Although renal donation does not appear to affect normal life expectancy in dogs or cats, long-term monitoring is recommended in these patients.89 The prescribed preoperative care may vary depending on the stability of the patient. At some centers, preoperative hemodialysis is performed in cats with severe azotemia (blood urea nitrogen [BUN] >100 mg/dL; creatinine >8 mg/dL).1 Upon admission, if hemodialysis is not indicated, the recipient is typically placed on intravenous fluid therapy of a balanced electrolyte solution at 1.5 to 2.0 times the daily maintenance requirements. In some cases, underlying cardiac disease precludes this rate of fluid therapy because of the risk of pulmonary edema and pleural effusion. In one study, cats that died before discharge were more likely to receive hetastarch as part of their therapeutic protocol.87 Most likely, cats that have borderline cardiac dysfunction are more susceptible to fluid overload with oncotic agents or RBC transfusions; however, the use of these therapies might also indicate a less stable perioperative condition. For hypertensive cats, the calcium channel blocker amlodipine (Norvasc, Pfizer; 0.625 mg/cat PO q24hr) may be indicated before surgery. The most common immunosuppressive protocol for feline renal transplant recipients includes cyclosporine and the corticosteroid prednisolone, which are used together for their synergistic effects. Cyclosporine, in combination with corticosteroids, has been an essential component in many immunosuppressive protocols for organ transplantation in humans, cats, and dogs. It acts by inhibiting calcineurin, thus preventing activation of a number of transcription factors regulating genes for cytokines, including interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor, which play roles in allograft rejection.39,44,48 Corticosteroids also inhibit these cytokines; the exact mechanism of action is not fully understood. Cytokines IL-2, IFN-γ, and granulocyte-macrophage colony-stimulating factor are potential therapeutic targets in transplantation medicine. Cytokines IFN-γ and IL-2 are thought to play an important role in acute allograft rejection in humans. Granulocyte-macrophage colony-stimulating factor stimulates proliferation and differentiation of hematopoietic stem cells into granulocytes and macrophages responsible for responding to foreign tissue. Inhibition of these cytokines is thought to be critical to graft survival. Two recent reports12,51 have evaluated the effects of current immunosuppressive therapy on feline cytokine production in vitro. In one report, cyclosporine inhibited expression of mRNA for IL-2, IL-4, IFN-γ, and TNF-α in a dose-dependent manner.51 In a second report, use of cyclosporine significantly decreased production of IFN-γ, IL-2, and granulocyte-macrophage colony-stimulating factor.12 Dexamethasone alone suppressed production of only granulocyte-macrophage colony-stimulating factor; when combined with cyclosporine, however, a significant decrease in production of IFN-γ, IL-2, and granulocyte-macrophage colony-stimulating factor occurred.12 In cats, an oral liquid formulation of cyclosporine is used so that the dose can be titrated for each individual. Currently, the oral liquid formulation Neoral (100 mg/mL) is recommended. Neoral is a microemulsified formulation and is preferred over the other oral liquid formulation, Sandimmune (Novartis Pharmaceuticals), because of better gastrointestinal absorption, which provides more predictable and sustained blood concentrations.30 Additionally, the dose of Neoral necessary to maintain similar blood concentrations is smaller compared with Sandimmune, making the drug more economical for clients. Neoral can be diluted in water or other oral solutions but must be administered immediately after dilution.30 Depending on the transplant facility, cyclosporine therapy is initiated 24 to 96 hours before transplantation. Neoral is administered at a dose of 1 to 4 mg/kg PO q12hr, depending on the patient’s appetite. It has been the authors’ experience that cats that are anorectic or hyporexic have a much lower drug requirement to obtain appropriate preoperative drug levels. A 12-hour, whole-blood, trough concentration is obtained either 1 day before surgery to allow adjustment of the preoperative oral dose or is measured the morning of the surgical procedure. The ideal 12-hour, whole-blood, trough concentration, measured by high-pressure liquid chromatography, is 300 to 500 ng/mL before surgery.16 This level is maintained for approximately 1 to 3 months after surgery and then tapered to approximately 250 ng/mL for maintenance therapy. Prednisolone is preferred over prednisone for immunosuppression in feline renal transplant recipients. In a recent abstract evaluating the bioavailability and activity of these two drugs in cats, serum prednisolone concentrations were significantly greater for oral prednisolone than oral prednisone.27 These differences may be related to decreased gastrointestinal absorption of prednisone or decreased hepatic conversion of prednisone to prednisolone in some individuals. Protocols for cyclosporine and prednisolone vary among transplantation facilities. Previously reported prednisolone protocols have ranged from 0.25 to 2.5 mg/kg PO q12hr starting the morning of surgery and tapering to 0.25 mg/kg PO q24hr by 1 month after surgery.15,28,31 At our facility, prednisolone therapy is begun the morning of surgery at 0.5 to 1.0 mg/kg PO q12hr and continued at that dose for the first 3 months; the dose is then tapered to once daily. The purine analogue azathioprine (Imuran, Glaxo Wellcome) has also been used successfully in combination with cyclosporine and prednisolone to reverse or control allograft rejection in cats. The dosage is 0.3 mg/kg every third day; it is adjusted to maintain a white blood cell count (WBC) equal to or greater than 3000 cells/uL.30 Side effects of azathioprine in cats include bone marrow suppression, hepatotoxicity, and acute pancreatitis. The authors have used this protocol successfully in four cats without complications. One of the four cats has been on this protocol for more than 10 years. Novel immunosuppressants approved for use in humans include tacrolimus (FK506), mycophenolate mofetil, sirolimus (rapamycin), and leflunomide. These drugs have been shown to inhibit in vitro mitogen-stimulated proliferation of feline lymphocytes but have not yet been investigated in vivo in feline transplant recipients.60 The mechanism of action of tacrolimus is similar to cyclosporine: it binds to the immunophilin FK-binding protein in the cytosol of lymphocytes. This complex then binds to calcineurin, inhibiting gene expression of various lymphokines responsible for lymphocyte activation, expression of cell surface activation molecules, and lymphocyte cell cycle progression from G0 to G1. Sirolimus also binds to FK-binding protein; the resultant complex inhibits proteins involved in cell proliferation and subsequently inhibits IL-2 and other signal transduction pathways. Sirolimus prevents lymphocyte cell cycle progression from G1 to S phase. Mycophenolate mofetil is converted by the liver and plasma esterases to mycophenolic acid, an active metabolite that inhibits de novo purine synthesis. It is also a selective inhibitor of B- and T-lymphocytes and blocks cell cycle progression of lymphocytes through the S phase. Leflunomide is converted in plasma and intestinal tract mucosa to a compound that inhibits de novo pyrimidine synthesis and, at high concentrations, tyrosine kinase, which is involved in T-cell receptor and growth factor signal transduction. It also arrests progression of T- and B-lymphocytes in the late G1 phase and is especially effective in inhibiting B-cell proliferation and antibody production. In an in vitro study comparing antiproliferative effects of immunosuppressive drugs in cats, tacrolimus was found to be 5.0 to 6.8 times more potent than cyclosporine, depending on the mitogen used.60 In another study of six healthy research cats that received an imunogenically mismatched renal allograft, tacrolimus significantly extended median survival compared with a historical control group of cats that did not receive immunosuppressive therapy.56 In humans, tacrolimus is superior to cyclosporine for reversing ongoing rejection.30 Other novel immunosuppressants include (hu)CTLA4-Ig (abatacept) and LEA29Y (Belatacept), which selectively block T-cell activation. (hu)CTLA4-Ig has been approved for use in the treatment of rheumatoid arthritis in humans; both drugs are being investigated alone and in combination with other immunosuppressants in clinical and experimental transplantation trials. In animal models of transplantation, (hu)CTLA4-Ig has been shown to inhibit acute rejection, prevent development of graft arteriosclerosis associated with chronic rejection, inhibit T-cell–dependent antibody responses, induce allograft tolerance, and significantly prolong transplanted organ survival times.* In a feline study, (hu)CTLA4-Ig selectively inhibited proliferation of lymphocytes in vitro but had a sparing effect on antigen-specific proliferation of memory cells.8 The specificity of its mechanism of action suggests that (hu)CTLA4-Ig may prevent allograft rejection but leave memory responses to previously encountered antigens intact. Additionally, the addition of (hu)CTLA4-Ig to feline lymphocyte resulted in a significant decrease in production of cytokines critical to the rejection process, including IL-2, IFN-γ, and granulocyte-macrophage colony-stimulating factor.12 It is unknown whether any of these novel drugs will reduce the incidence of acute or chronic rejection and improve allograft survival in cats compared with use of cyclosporine. Another option for immunosuppression currently in clinical use permits once-daily administration of medications. With this protocol, ketoconazole (10 mg/kg PO q24hr) is administered in addition to cyclosporine and prednisolone.46,69 After ketoconazole has been added to the immunosuppressive protocol, cyclosporine and prednisolone are administered once a day, and cyclosporine doses are adjusted into the therapeutic range by measuring 24-hour whole-blood trough levels. Ketoconazole is an antifungal agent that can affect cyclosporine metabolism by inhibiting hepatic and intestinal cytochrome P450 oxidase activity, resulting in increased blood cyclosporine concentrations.69 This protocol reduces the cost of posttransplantation immunosuppression and may be more appealing for owners whose work schedules do not permit twice-daily dosing or whose cats are difficult to medicate. If twice-daily dosing of cyclosporine is required, the ketoconazole dose can also be split and delivered twice daily. If signs of hepatotoxicity are identified, ketoconazole administration should be discontinued. High-pressure liquid chromatography is the method of choice for measurement of whole-blood cyclosporine concentrations in cats. This technique measures only the parent compound and not the metabolites of cyclosporine, which vary with individual metabolism.68 Monoclonal or polyclonal antibody fluorescent immunoassay methods have also been used for measuring cyclosporine concentration. Antibodies used with this method may cross-react with metabolites of cyclosporine, resulting in higher and more variable cyclosporine concentrations than results obtained with high-pressure liquid chromatography. Although high-pressure liquid chromatography is the preferred method for humans and companion animals, immunoassay methods can still be used. One immunoassay method (TDxFLx assay, Abbott Laboratories) permitted accurate estimation of the high-pressure liquid chromatography cyclosporine concentrations in cats because of high correlation among individuals.68 Whole-blood cyclosporine levels measured by immunoassay will be 1.5 to 4.2 times higher than levels measured with the high-pressure liquid chromatography method.46,68 Currently in cats, 12-hour trough cyclosporine concentrations are used to adjust the dosing regimen and maintain therapeutic levels. In a recent study of cyclosporine disposition after IV and multidose oral administration in cats, substantial individual variation in oral absorption was identified. Results suggested that evaluation of a 2-hour cyclosporine blood concentration may be better for estimating drug exposure than 12-hour whole-blood trough concentration.70 In humans, 12-hour trough cyclosporine concentrations do not correlate well with allograft rejection, drug exposure, or toxicity. More work in this area is required before changing current drug monitoring protocols.
Renal Transplant
Evaluation of A Potential Recipient
Evaluation of the Urinary Tract
Cardiovascular Disease and Hypertension
Infectious Disease
Evaluation of A Potential Donor
Preoperative Treatment
Feline Immunosuppression
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