Differences in gastric motor activity in renal transplant recipients treated with FK-506 versus cyclosporine

BACKGROUND: Little is known concerning gastric motility after renal transplantation and on the impact of immunosuppressants on gastric emptying. METHODS: Gastric emptying was measured in renal transplant recipients, taking different immunosuppressive therapy (steroids and cyclosporine/azathioprine/FK-506), and compared with normal volunteers. RESULTS: After renal transplantation, gastric emptying of liquids was normal, irrespective of the type of immunosuppression. However, solid gastric emptying was significantly faster in FK-506-treated patients compared with patients taking cyclosporine for all measured emptying parameters. Compared with normal volunteers solid gastric emptying was slower in patients taking cyclosporine, comparable in azathioprine treated patients, and characterized by an unusual short lag phase in patients taking FK-506. CONCLUSIONS: In stable renal transplant recipients gastric emptying of solids was significantly faster in patients on FK-506 compared with patients taking cyclosporine. Therefore, FK-506 may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastroparesis.     

Immediate post-transplant nephrosis in a patient with congenital nephrotic syndrome

A 19-month-old girl with congenital nephrotic syndrome of the Finnish type underwent a living-related renal transplant; 24 h after transplantation she became massively nephrotic. She did not respond to steroids, plasmapheresis, and high-dose cyclosporine. A month later, a renal biopsy showed only glomerular foot process effacement. She was treated with high-dose methylprednisolone pulses and oral cyclophosphamide. She rapidly went into complete remission with no further relapses. Graft function has been stable 2 years after transplantation. Received: 24 June 1999 / Revised: 21 February 2001 / Accepted: 23 February 2001     

Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing pneumonia without everolimus discontinuation

The use of proliferative signal inhibitors (PSIs) in immunosuppression-related malignancies opens new roads for increasing the survival and quality of life in patients with solid organ transplantation. A 56-year-old female recipient of a living donor renal allograft (1990), who was immunosuppressed with cyclosporine (CsA; Neoral), azathioprine, and steroids, did initially well with acceptable renal function. During the last 5 years she required local therapy due to posterior vaginal lip human papillomavirus (HPV) lesions. In 2000, she discontinued azathioprine and the CsA doses were reduced to 100 mg daily. The local lesion showed a good response to reduced immunosuppression. In February 2005, the lesion reappeared and a biopsy showed malignancy. Local surgery was performed and CsA was replaced by everolimus (EVL; Certican). Two months after treatment initiation, the patient developed cough, dyspnea, and low-grade fever. Chest X-ray showed a lesion at the base of the left lung compatible with pneumonitis. After fiberbronchoscopy a diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP) was obtained. She was treated with increased doses of oral steroids. EVL was never discontinued. The radiological lesion disappeared and the malignancy is currently in remission. In summary, a case of gynecological cancer in a renal transplant recipient was treated by surgical removal. After 1 year of immunosuppression with EVL, no recurrence has been observed. The adverse event (BOOP) was probably related to the PSI treatment and was controlled with an increased dose of steroids without discontinuing EVL.     

Sirolimus used during pregnancy in a living related renal transplant recipient: a case report

OBJECTIVES: The majority of pregnancies after transplantation reported in the literature occurred in patients treated with a combination of calcineurin inhibitors, prednisolone, and azathioprine. There is little experience with newer drugs. We report a successful pregnancy in a kidney recipient with exposure to sirolimus-based immunosuppression. METHODS: We describe a case of successful delivery in a 30-year-old woman who became pregnant 1 year and 8 months after a living related renal transplantation. She received sirolimus, cyclosporine, and prednisolone before conception and during the first and second trimesters of gestation. RESULTS: The female recipient received sirolimus in combination with cyclosporine and prednisolone. During follow-up, her serum creatinine values were stable with pregnancy occurring at 1 year and 8 months after transplantation. At 27 gestational weeks, sirolimus was discontinued and she was maintained on cyclosporine and prednisolone. There were no signs or symptoms of graft rejection. A Cesarean section was performed at 39 weeks of gestation to deliver a healthy, 2994-g, Apgar 10, male infant. The renal function of the female recipient continued to be stable after delivery. CONCLUSION: To date, pregnancies in renal transplant recipients are still considered high risk. The U.S. National Transplantation Pregnancy Registry (NTPR) has reported increased rates of maternal and fetal complications. There have been no live births reported to the NTPR about female recipients exposed to sirolimus throughout gestation. We report a live birth without a structural defects with successful delivery after sirolimus use during the first and second trimesters of gestation.     

Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation

Recent reports have intimated that the use of antilymphocyte globulin in combination with azathioprine and steroids has ameliorated the beneficial affects of cyclosporine. We believe that even in the absence of significant statistical differences between patient survival rates and graft survival rates of cyclosporine-treated renal transplant patients compared with conventionally treated renal transplant patients, there are distinct advantages to cyclosporine use in renal transplantation. Twenty-three consecutive cadaveric renal transplant patients who received azathioprine, prednisone, and antilymphoblast globulin were compared with 23 cadaveric renal transplant patients who received cyclosporine and prednisone. Fewer statistically significant rejection episodes, multiple rejection episodes, and cytomegalovirus infections were demonstrated in those who received cyclosporine. Most notably, cyclosporine decreased the initial hospital stay, was associated with fewer readmissions, and therefore markedly reduced the initial cost of transplantation.     

Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation

The following investigation was performed to establish whether renal transplant patients treated with cyclosporine and prednisone have a decreased prednisolone catabolism and/or an increased systemic availability of oral prednisone when compared with patients treated with azathioprine and prednisone. Therefore we assessed, by HPLC and equilibrium dialysis, the total concentrations of prednisolone and prednisone and the unbound concentrations of prednisolone in plasma samples collected over 24 hr, and the 24-hr urinary excretion of prednisolone, prednisone, and 6 beta-hydroxyprednisolone after an i.v. dose of prednisolone and an equal oral dose of prednisone in 25 renal transplant patients on cyclosporine and in 25 patients on azathioprine and prednisone one month after transplantation. The metabolic clearance, the renal clearance, the volume of distribution, and the systemic availability of total and unbound prednisolone were identical in patients with and without cyclosporine. The apparent activities of the oxidoreductases involved in the biotransformation of prednisone into prednisolone and vice-versa were not affected by cyclosporine therapy. The fractional urinary excretions of 6 beta-hydroxyprednisolone increased with increasing metabolic clearance rate of prednisolone (r = 0.50, P less than 0.001). This relationship was not modulated by cyclosporine, indicating that cyclosporine does not affect the activity of the microsomal P-450-dependent 6 beta-hydroxylase. Thus, early after transplantation, patients on cyclosporine have a normal metabolism of prednisolone.     

Posterior Reversible Encephalopathy Syndrome Independently Associated With Tacrolimus and Sirolimus After Multivisceral Transplantation

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5–5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49‐year‐old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition–related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12–15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus‐associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.     

Metastatic melanoma within a transplanted kidney: a case report

A 57-year-old woman recipient of a cadaveric renal allograft displayed metastatic melanoma within the transplant. The patient, who received imunnosuppressive therapy with cyclosporine, azathioprine, and prednisone, displayed normal renal function for 10 months posttransplantation. She was admitted due to multiple, large, rapidly growing skin nodules over the lower abdomen and to dyspnea. After a diagnostic evaluation, the renal graft was removed, revealing metastatic melanoma within the transplanted kidney and 2 focal points of melanoma within the skin lesions. The patient returned to hemodialysis, received chemotherapy and interferon A, but failed to respond and died 11 days after the nephrectomy.     

Pneumonia Due to Varicella-Zoster Virus Reinfection in a Renal Transplant Recipient

Varicella pneumonia is one of the serious complications of primary varicella zoster virus (VZV) infection in adults. A 36-year-old woman with end-stage renal disease underwent renal transplantation from a living donor in 1998, receiving immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and methylprednisolone. She had a history of VZV infection during childhood. The patient developed an intractable cough on December 10, 2006, but there were no abnormalities in the laboratory data or chest radiograph for several weeks. On January 1, 2007, she was admitted to our hospital with cutaneous vesicles covering the entire body. We learnt that when her symptoms developed, her son was diagnosed with varicella. The chest radiograph at this stage showed a diffuse miliary pattern in the entire lung field. We started intravenous administration of acyclovir. VZV antigen was detected in the cutaneous lesions and VZV antibody in the serum after the start of these treatments, so we continued to administer acyclovir for 18 days. The cutaneous lesions healed and the pneumonia improved based on the chest radiograph. She was discharged from the hospital on January 19, 2007. In conclusion, this report documents VZV reinfection in a transplant patient.     

Lupus nephritis in a pediatric renal transplant recipient

A case of aggressive lupus nephritis in a pediatric renal transplant patient is described. She initially presented with end-stage glomerulonephritis for which an underlying etiology could not be determined. Ten months after cadaveric renal transplantation, systemic lupus erythematosus was diagnosed, when she developed diffuse proliferative glomerulonephritis in association with antinuclear antibody, anti-double-stranded DNA antibody and extrarenal manifestations of lupus. It is plausible that she developed recurrent rather thande novo lupus nephritis following transplantation. Reactivation of lupus nephritis in a renal transplant is unusual in adults, and is previously unreported in children.     

Cyclosporine in the treatment of azathioprine-induced red cell aplasia following renal transplantation

Azathioprine, a well-known immunosuppressive agent, is used extensively in renal transplantation. There have been several case reports of pure red cell aplasia induced by this drug following a successful kidney transplant. Previous management of azathioprine-induced red cell aplasia included reduction of azathioprine dose, or treatment with cyclophosphamide. We propose the substitution of cyclosporine for azathioprine, in this clinical setting. Not only does cyclosporine allow recovery of bone marrow function, but it maintains a level of immunosuppression which stabilizes renal function in the post-transplant patient.     

Declining incidence of wound infection in cadaveric renal transplant recipient

Over a five-year period 100 cadaveric renal transplants were performed. In 91 of these recipients, a prophylactic parenteral antibiotic (cefoperazone) was administered and closed wound drainage was used. Of these 91 patients, 33 received azathioprine/prednisone immunosuppression, whereas cyclosporine/prednisone with or without azathioprine was used in the remaining 58. The incidence of wound infections was significantly reduced from 12 per cent (4/33) in the azathioprine group to 1.7 per cent (1/58) in the cyclosporine group (p less than 0.01). When conventional immunosuppression (azathioprine/prednisone) is employed in renal transplantation, triple antibiotic prophylaxis that includes an aminoglycoside is most effective in preventing wound infections. A single non-nephrotoxic antibiotic, cefoperazone, offers similar protection in the cyclosporine/prednisone-treated renal transplant recipient.     

Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.     

Serum potassium concentrations in cyclosporine- and azathioprine-treated renal transplant patients

Hyperkalemia was commonly observed in successful renal transplant patients treated with cyclosporine and prednisone. At 1, 3 and 6 months after transplantation, 13 of 50, 9 of 50, and 5 of 50 patients, respectively, had serum concentrations of potassium greater than 5 mEq/1. This contrasts with the finding of hyperkalemia in only 1 of 13 comparable patients treated with azathioprine and prednisone. Mean serum concentrations of potassium at these dates were significantly higher in cyclosporine-treated patients than azathioprine-treated patients. The 2 patient groups had similar mean serum concentrations of chloride, bicarbonate and creatinine, and mean creatinine clearances at 1 and 3 months. Exposure to diuretic agents and antihypertensive agents was similar in the 2 groups. Serum concentrations of electrolytes and renal function data in hyperkalemic and normokalemic transplant patients receiving cyclosporine were similar. These observations suggest an association between cyclosporine administration and hyperkalemia in renal transplant recipients.     

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Child's classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.     

Conventional immunosuppression after deliberate third party transfusions versus cyclosporine in living related renal transplant recipients

A total of 93 recipients of either HLA-identical (34) or 1-haplotype matched (59) living related donor renal transplants was assigned prospectively into immunosuppressive treatment groups on the basis of transfusion histories obtained at the initial evaluation for transplantation. Patients who received 0 to 2 third party transfusions were given no further transfusion, and received cyclosporine and prednisone immunosuppression after transplantation (cyclosporine group). Patients who received 3 or 4 third party transfusions were given additional transfusions until 5 had been received, and were managed with azathioprine and prednisone after transplantation (azathioprine group). Patients who already received 5 or more third party transfusions had no additional transfusions and were assigned to the azathioprine group. No patient had a positive crossmatch to the potential donor after initial evaluation and confirmation of a negative crossmatch. The number of rejection episodes per patient after transplantation was significantly higher in the azathioprine group for HLA-identical (p equals 0.001) and 1-haplotype (p equals 0.003) recipients. One-year patient survival rats for the HLA-identical cyclosporine and azathioprine groups were 100 and 94 per cent, respectively, with respective 1-year allograft survivals of 100 and 89 per cent in the 2 groups. In the 1-haplotype group 1-year patient survival rates were 95 and 94 per cent for the cyclosporine and azathioprine groups, respectively; allograft survival was 81 per cent for the cyclosporine group and 91 per cent for the azathioprine group. None of the observed differences in graft or patient survival between the 2 groups was statistically significant. Deliberate third party transfusions with conventional immunosuppression and cyclosporine immunosuppression are effective methods to treat recipients of living related donor renal transplants.     

Renal transplantation in a patient with common variable immunodeficiency

A 15-year-old girl developed end-stage renal disease requiring renal transplantation. Posttransplantation immunosuppression therapy consisted of antithymocyte globulin, glucocorticosteroids, cyclosporine A, and azathioprine. The patient's clinical course after transplantation was complicated by several episodes of graft rejection, chronic anemia, oral candidiasis, and numerous infections of the sinopulmonary tract that were recalcitrant to antibiotics and surgical intervention. An immunologic evaluation showed marked immune abnormalities beyond that expected by the transplant immunosuppression. Examination of serum samples taken before the transplant confirmed a diagnosis of common variable immunodeficiency. The difficulties of managing posttransplantation immunosuppression in a patient with a primary immunodeficiency are discussed. Patients with end-stage renal disease and a history of recurrent sinopulmonary infections may require immunologic screening before renal transplantation.     

Report of a renal transplanted patient with fibroadenoma occurring in a short time

The incidence of breast cancer in renal transplant patients is similar to that of general population. But fibroadenomas may be seen as a result of exposure to cyclosporine (CyA). Herein we report the case of a 32-year-old woman who received a renal transplant and had a breast fibroadenoma. She had been prescribed CyA, azathioprine, and steroids for 4 years. At the end of the first year a palpable mass had been detected in her right breast; the pathologic diagnosis was fibroadenoma. At the 4th year after transplantation, immunosuppressive treatment was switched to CyA and mycopholate mofetil (MMF) because of an increased serum creatinine level. Two years later seven breast nodes from both breasts were detected by ultrasonography. Totally excision was performed revealing a histopathologic diagnosis of fibroademata as before. In this case, the combination of CyA and MMF administration seemed to cause an increase in the number of nodules in a short time. The cause of fibroadenomas may be related to drug-induced secretion of proliferative or anti-apoptotic cytokines.     

Renal transplant arterial thrombosis: association with cyclosporine

Of 136 patients who received a renal transplant between January 1984 and August 1988, there were six cases (4.4%) of allograft arterial thrombosis (AAT) occurring a mean of 23 days after transplantation. All were maintained on cyclosporine A(CsA) in addition to prednisone and azathioprine. All transplants were performed by the same transplant surgeon. Five of the six episodes (83%) were in allografts that had multiple renal arteries (MRA), giving an incidence of AAT in that group of 36%. Only one of 122 (0.8%) allografts with a single renal artery experienced thrombosis. CsA was started a mean of 9 days after transplantation (range, 16 to 33 days). There was no correlation of AAT to CsA levels. AAT appears to be an early complication of allografts with MRA in patients maintained on CsA.     

Renal failure after liver transplantation: outcome after calcineurin inhibitor withdrawal

Chronic nephrotoxicity is one of the most serious side-effects of calcineurin inhibitor treatment and a factor in mortality and morbidity after liver transplantation. In our transplant centre, among patients who underwent a liver transplantation between January 1989 and December 2000, 14 liver graft recipients (6.86%) developed de novo severe renal dysfunction as defined by a serum creatinine concentration above 200 micromol/L. Renal biopsy was performed in nine cases and evidenced histological lesions compatible with chronic nephrotoxicity related to calcineurin inhibitor treatment. For nine patients, we report the results of a prospective non-randomized study consisting of cyclosporine or tacrolimus withdrawal associated with administration of mycophenolate mofetil or azathioprine. Despite this therapeutic modification, we did not observe a significant renal function improvement but on the other hand, there was no graft rejection.