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PubMed2004

Continuous renal replacement therapy after heart transplantation.

BACKGROUND: Renal failure following heart transplantation carries a poor prognosis. The objectives of this study were to determine risk factors for renal failure requiring continuous renal replacement therapy (CRRT), to describe the management strategies regarding immunosuppressive therapy and to examine the short-term prognosis. METHODS: Fifty-six patients who underwent heart transplantation from 1998 to 2002 at the Montreal Heart Institute were retrospectively analyzed. RESULTS: Six of 56 patients (11%) underwent CRRT after heart transplantation. Patients who underwent CRRT had lower preoperative creatinine clearance than those who did not (median 44 versus 59 mL/min, P=0.04) and lower first two-week postoperative creatinine clearance (median 23 versus 42 mL/min, P<0.01) compared with patients without CRRT. The total duration of CRRT ranged between two and 60 days (median 15 days). Cyclosporine was withheld for 12 days versus two days (P<0.01) and the time to achieve therapeutic levels of cyclosporine averaged 18 days versus nine days (P=0.01) among CRRT versus non-CRRT patients. Patients were administered thymoglobulin or basiliximab during cyclosporine withholding. The time to discharge from hospital after transplantation was longer in patients with CRRT (median 47 days versus 17 days, P<0.01). There was no mortality at three months in the CRRT group. CONCLUSION: Creatinine clearance is an important predictor of renal failure requiring renal replacement therapy. Although renal failure remains a serious complication after transplantation, the use of CRRT and antilymphocyte agents during cyclosporine A withholding is associated with a favourable short-term prognosis following heart transplantation.

Acute Kidney Injury↗
PubMedDate not supplied

The paediatric liver transplantation program at the Université catholique de Louvain.

The Paediatric Liver Transplant Program at Saint-Luc University Clinics constitutes a substantial single centre experience, including 667 transplantations performed between March 1984 and April 2003, and the history of this program reflects the tremendous progress in this field since twenty years. Liver transplantation in children constitutes a considerable undertaking and its results depend on multiple, intermingled risk factors. An analysis of the respective impact of several surgical and immunological parameters on patient/graft outcome and allograft rejection after paediatric liver transplantation showed a significant learning curve effect as well as the respective impact of pre-transplant diagnosis on survival and of primary immunosuppression on the rejection incidence. The introduction of living related liver transplantation in 1993 not only permitted to provide access to liver replacement in as many as 74% more candidate recipients, but also resulted in better graft survival and reduced retransplantation rate. The results of a recent pilot study suggest that steroid avoidance is not harmful, and could even be beneficial for paediatric liver recipients, particularly regarding growth, and that combining tacrolimus with basiliximab (anti-CD25 chimeric monoclonal antibody) for steroid substitution appears to constitute a safe alternative in this context. The long-term issues represent the main future challenges in the field, including the possibility of a full rehabilitation through immunosuppression withdrawal and tolerance induction, the development of adolescence transplant medicine, and the risk of early atherogenesis in the adulthood.

Adolescent↗
PubMed1998

Advances in transplantation and immunosuppression.

This report presents highlights from four sections of the 17th Annual Meeting of the American Society of Transplant Physicians (Chicago; May 9-13, 1998): immunosuppressive drugs; immunosuppressive protocols; basic immunology; and areas of clinical interest. Studies were presented on the immunosuppressive effects of tacrolimus, mycophenolate mofetil, sirolimus and analogues, daclizumab and basiliximab, among other compounds. Regarding immunosuppressive protocols, many studies focused on the need for steroid withdrawal a short period after renal transplantation; other subjects discussed were the avoidance of nephrotoxic drugs and the avoidance of acute graft rejection. The section on basic immunology covered transforming growth factor-beta chemotaxis, adhesion molecules and co-stimulation. Hepatitis C virus continues to be an area of current clinical interest, as is the problem of chronic rejection. Finally, lipids and statins were accorded great relevance at this meeting.

Journal Article↗
PubMed2003

Sirolimus: a current perspective.

Sirolimus, a macrocyclic lactone that displays a novel mechanism of immunosuppressive action, is a critical-dose drug requiring therapeutic drug monitoring for optimal outcomes. The compound was documented in two multicenter, blinded clinical trials to reduce the incidence of acute rejection episodes when used in combination with cyclosporine and steroids vs. azathioprine or placebo comparators. Furthermore, studies utilizing cyclosporine withdrawal documented a long-term benefit on renal function of chronic sirolimus therapy, albeit with a modestly enhanced incidence of acute rejection episodes. Although this application may be useful in selected cases, we believe that minimal initial cyclosporine exposures de novo mitigate the need for eventual withdrawal for chronic nephropathy, while preserving the immunosuppressive synergy during the maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to 6 months after cadaveric kidney transplantation with only a 5% risk of acute rejection episodes and 6% incidence of chronic reactions within 3 years. However, sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic proclivities of transplant recipients, as well as exerts myelosuppressive effects, which are augmented by concomitant therapy with azathioprine or, particularly, with mycophenolate mofetil. Due to its apparent lack of nephrotoxicity, sirolimus has been employed for induction therapy in a calcineurin antagonist-free regimen in combination with either basiliximab or rabbit antilymphocyte sera for weak or strong immune responders, respectively, followed by introduction of a calcineurin antagonist upon resolution of the ischemia-reperfusion injury. Therefore, sirolimus proffers a potent and unique platform for new immunosuppressive strategies in organ transplantation.

Clinical Trials as Topic↗
PubMed2003

ABO incompatible kidney transplantation --immunological aspect-.

ABO incompatible kidney transplantation (ABOINCKT) has been developed in Japan because of the shortage of cadaveric donors. We have performed 76 living-donor ABOINCKT in our center. Donor blood type antibody was removed by immunoadsorption or plasmapheresis and exchange. Immunosuppression consisted of cyclosporine or tacrolimus, steroid, and cyclophosphamide or azathioprine or mycophenolate mofetil and, recently, basiliximab. Splenectomy was routinely performed during the transplantation surgery. Donor blood type antigen was strongly expressed on the vascular endothelium at all time points and in all conditions posttransplantation. Red blood cell agglutination reaction (RBAR) was positive only in renal tissues from a patient with delayed hyperacute rejection. Donor specific antibody suppression was observed in 18 ABOINCKT recipients with blood type O from a donor with blood type A1 or B. ADCC activity was detected after pre-treatment. Acute humoral rejection in ABOINCKT can result from ADCC, as well as by antigen-antibody reaction. Five year graft and patient survival rates were 75% and 64% in 37 ABOINCKT recipients from June 1989 through December 1996, however they have been 100% in 39 ABOINCKT recipients since January 1997. Accommodation has been produced in ABOINCKT with the co-existence of blood type antigen and antibody. Currently, ABOINCKT is an alternative which should be considered, particularly for blood type O patients with extended waits for cadaveric transplantation and for pediatric patients.

ABO Blood-Group System↗
PubMed2005

Studies on post-transplant dyslipidemia in kidney transplant patients.

This study was performed to retrospectively compare changes in the levels of total cholesterol, non-HDL cholesterol, triglycerides, and immunosuppressive drugs, cyclosporine A and steroids in patients with living-relation renal transplants with those from non-heart-beating donors. We experienced 11 cases of kidney transplants from non-heart-beating donors during the period from April 1995 to May 2003. We evaluated 13 cases of kidney transplants from living-relation donors during the same period. The immunosuppressants used included mainly cyclosporine A as well as mycophenolate mofetil or azathioprine, steroid and ALG, or basiliximab. Over-night fasting lipids (total cholesterol, triglycerides and HDL cholesterol) were studied before renal transplantation and repeated after renal transplantation at 1, 3, 6 and 12 months. The levels of total cholesterol and triglycerides remained in the normal range before transplantation. However, the levels of total cholesterol increased siginificantly 1 and 3 months after transplantation from non-heart-beating donors and remained at higher levels up to 12 months after transplantation. A similar pattern in the levels of triglycerides was observed. The levels of HDL cholesterol remained unchanged and stayed in the normal range before and 1, 3, 6, and 12 months after transplantation from non-heart-beating donors. On the other hand, significant increases in non-HDL cholesterol were observed 3 and 6 months after transplantation from non-heart-beating donors. After transplantation from living-relation donors, levels of total cholesterol, triglycerides, and non-HDL cholesterol remained unchanged and remained in the normal range up to 12 months after transplantation. Although there were no significant differences in the total dosage of cyclosporine A between the patients with living-relation donors and those with non-heart-beating donors, a significant increase in the total dosage of methylprednisolone was observed in patients with non-heart-beating donors compared with those in the patients with living-relation donors. Renal function recovery in patients with living-relation donors was better than in those with non-heart-beating donors. These results may suggest that significant increases in total cholesterol, especially non-HDL cholesterol and triglycerides, were probably partly due to an increased use of immunosuppressants, steroids. It is necessary to aggressively control post-transplant hyperlipidemia and important to reduce or withdraw steroids in the selected, low-risk recipients as early as possible from the viewpoint of preventing post-transplant hyperlipidemia.

Adult↗
PubMed2005

[Renal transplantation].

Recent immunosuppressive drugs, including mycophenolate mofetil and basiliximab in addition to calcineurin inhibitors, have reduced the incidence and severity of acute allograft rejection in kidney transplants. This article introduces newly developed agents such as CTLA4-Ig, LEA29Y, rituximab, and FTY720 and also reviews immunosuppressive protocols which withdraw steroid or calcineurin inhibitors. Unrelated or ABO incompatible living donor kidney transplants have increased due to advancement of immunosuppressive

Calcineurin Inhibitors↗
PubMed2005

[Pediatric kidney transplantation].

Recently we achieved good outcomes in pediatric renal transplantation under basiliximab induction steroid withdrawal regimen including ciclosporin and mycophenolate mofetil (1 and 2 years patient/graft survival rates; 100%/96.6%). Steroid was withdrawn in 3 children and was given alternatively in 18 among 30 children under this regimen. Height standard deviation scores were significantly improved 1 year post-transplantation (-1.7+/-0.26 (mean+/-SE)), compared with those at transplantation (-2.1+/-0.23 (mean+/-SE)). Viral infection is still one of serious complications. Children tend to have symptomatic viral infection as a prime infection because of sero-negative antibodies against Cytomegalovirus (CMV) and Epstein-Barr virus(EBV). CMV was safely controlled with preemptive treatment monitoring with CMV antigenemia. EBV infection may result in posttransplant lymphoproliferative disease (PTLD). Ganciclovir for CMV and rituximab for EBV are useful. ABO blood group incompatible kidney transplantation demonstrated long-term better outcomes in children than adult. Pneumococcal infection was unexpectedly rare despite of splenectomy. Preemptive transplantation should be recommended to avoid dialysis for children regarding of good outcomes. Cadaver donor transplantation for a small child resulted in poor outcomes. Therefore living donor kidney transplantation for a small child is preferred. Management of cardiovascular monitoring with Swan-Ganz catheter and transesophageal ultrasound is important to overcome size mismatch between small body and a large kidney. It improves cardiac output and keeps good recirculation in an adult renal allograft. Kidney transplantation for children with end stage renal disease should be considered earlier and preemptively to improve growth retardation and provide better quality of life.

Adult↗
PubMedDate not supplied

New immunosuppressive therapies in renal transplantation: monoclonal antibodies.

Remarkable advances in understanding the mechanisms of immune recognition and allograft rejection have been made in the past few years, leading to the development of innovative immunosuppressive strategies in the field of renal transplantation. Monoclonal antibodies (mAbs) have emerged as a new class of immunosuppressive agents, which appear to be effective (in both the treatment and the prevention of acute rejection) and well-tolerated in renal transplant recipients. The highly specific effects of these drugs make them less toxic than the oral long-term maintenance agents such as corticosteroids and the calcineurin inhibitors. Some of these mAbs have already confirmed their efficacy in preventing acute rejection in clinical phase III studies, and are now part of the well-established immunosuppressive regimens; these are the anti-CD25 mAbs (basiliximab and daclizumab). Other recently developed mAbs, like anti-CD52 (Campath-1H), anti-CD20 (rituximab), anti-LFA-1, anti-ICAM-1 and anti-tumour necrosis factor (TNF)-alpha (infliximab), are currently being tested, and show encouraging immunosuppressive potential. Blocking either the binding of cell-surface molecules or intracellular signal transduction, these mAbs could become an effective method to promote the holy grail of solid-organ transplantation, antigen-specific tolerance.

Antibodies, Monoclonal↗
PubMedDate not supplied

The impact of biological agents interfering with receptor/ligand binding in the immune system.

We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules. This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system. In the first session, we discuss drugs targeting T-cell function by: (1) targeting CD28 mediated costimulation (Abatacept and Belatacept); (2) interfering with interleukin-2 receptor (Basiliximab and Daclizumab); (3) blocking cell adhesion and homing (Alefacept, Efalizumab, Natalizumab). The second session is dedicated to drugs targeting cytokines or their receptors. The best known and largely experimented case is represented by drugs targeting tumor necrosis factor (TNF) (Infliximab, Adalilumab, Certolizumab) or its p75 receptor (Etanercept). However, newer products are now available to target other inflammatory cytokines including IL-6, IL-8, IL-12, IL-15, IL-18, IL-23. These agents have the potential to become powerful tools in the control of several immune-mediated diseases, especially auto-immune and inflammatory ones. They traslate into reality the prediction that antibodies will eventually become "magic bullets which seek their own target" (P. Ehrich, 1906).

Binding, Competitive↗
PubMed2004

Clinical outcome and accommodation in ABO incompatible kidney transplantation.

We performed 84 ABO-incompatible kidney transplants at Toho University since 1989, with plasmapheresis and exchange replacing AB blood group plasma as pre-conditioning to reduce anti-donor blood group antibodies. Our current immunosuppression protocol consists of basiliximab, MMF, steroid, and cyclosporine or tacrolimus, including splenectomy. Overall patient/ graft survival rates (n=84) were 95/93 at one year, 94/92 at 3 years, 87/80 at 5 years, 87/75 at 7 years, and 83/67 at 10 years. The outcomes are similar to those of ABO-compatible living donor transplants. We have achieved 100% graft and patient survival rates (n=48) for the 7 years since January 1997. Our findings suggest that post-conditioning is not necessary to control titers of anti-donor blood group antibodies or to overcome acute humoral rejection. Infection control is critical in achieving good outcomes in ABO-incompatible transplants. We found that only anti-donor blood group antibodies in blood group O recipients of ABO-incompatible kidneys were specifically suppressed one year after transplantation. This appeared to be a type of accommodation in which there was no immunological response despite the co-existence of donor antigen and antibody, and might have been caused by down-regulation of B cells to produce anti-donor antibody.

ABO Blood-Group System↗
PubMed2004

[Favorable course of collagenofibrotic glomerulopathy after kidney transplantation and questionnaire survey about the prognosis of collagenofibrotic glomerulopathy].

Collagenofibrotic glomerulopathy is a recently recognized entity that is characterized by massive accumulation of collagen fibrils in the mesangial and subendothelial areas, and an elevated serum level of procollagen III peptide (PIIIP). We report the first case of a collagenofibrotic glomerulopathy patient who received a kidney transplantation. She received the kidney transplantation at the age of 18 years and the post-operative course was uneventful with good renal function on immunosuppression, which consisted of methylprednisolone, tacrolimus and basiliximab. Although urinary protein was negative, the serum level of PIIIP gradually elevated which suggests new collagen production in the graft. These findings indicate that the recipient had a systemic factor that stimulated collagen production. To investigate the prognosis of collagenofibrotic glomerulopathy, we carried out a questionnaire survey on 14 patients at 9 hospitals. None of these patients had received a kidney transplantation. However, 7 already had end-stage renal failure. Ten years after diagnosis, the renal survival rate was 49%. This rate is lower than cited in previous reports.

Adult↗
PubMed2006

Kidney transplantation in Libya: a North African and Middle Eastern perspective.

OBJECTIVES: In August 2004, a national organ transplant program utilizing the latest policies, procedures, and protocols was begun in Libya. During the first year of the program, 50 kidney transplantations from living donors were performed. MATERIALS AND METHODS: Forty-nine patients (aged 7 to 65 years) received kidneys from living-related donors (aged 19 to 54 years), and 1 husband received a kidney from his wife. Donor selection was based on human leukocyte antigen compatibility. Renal failure was due to chronic glomerulonephritis in most patients, diabetes in 5 adults, systemic lupus erythematosus in 2 adults, and congenital anomalies in 2 children. Sixteen patients matched the human leukocyte antigens of their donors, 28 matched 1 haplotype, and 6 did not match any haplotype. Immunosuppression was accomplished with methylprednisolone and basiliximab. Maintenance therapy was with mycophenolate mofetil, cyclosporine, and prednisone. The latter was completely discontinued 1 month after transplantation. In patients with resistant hypertension, unilateral native nephrectomy was carried out during transplantation. Donor nephrectomy was performed through an open mini-incision using a Thompson retractor. RESULTS: At the time of this writing, 49 patients are alive and well, and 48 of them have had functioning kidneys for 10 to 22 months. Three patients had acute rejections that were successfully treated with methylprednisolone (n=1) or methylprednisolone and antithymocyte globulin (n=2). At the time of this writing, all 46 adults and 2 pediatric recipients have excellent renal function and are living normal lives. CONCLUSIONS: In terms of patient survival and quality of life, transplantation is superior to dialysis. Also, transplantation is less expensive than dialysis. In Libya, establishing an active and successful transplant program with early steroid withdrawal has brought many benefits to patients and their families and great financial savings to the government. Our program hopefully will provide a model for similar programs in Asia and Africa and encourage local governments to legalize organ procurement from cadaveric donors.

Adolescent↗
PubMed2004

Use of fenoldopam to control renal dysfunction early after liver transplantation.

With the aim of assessing whether fenoldopam can help to preserve renal function after liver transplantation, we randomized 140 consecutive recipients with comparable preoperative renal function to receive fenoldopam 0.1 microg/kg/minute (group F, 46 patients), dopamine 3 microg/kg/minute (group D, 48 patients), or placebo (group P, 46 patients) from the time of anesthesia induction to 96 hours postoperatively. There were no differences between the groups in intraoperative urinary output or furosemide administration (both P =.1). Daily recordings made during the first 4 postoperative days revealed no significant differences in urinary output (P =.1), serum creatinine (P =.5), the incidence of renal insufficiency (P =.7), the need for loop diuretics (P =.9) or vasoactive drugs (P =.8). In comparison with preoperative levels, creatinine clearance at the end of the study in the patients receiving fenoldopam remained substantially unchanged, whereas it decreased by 39 and 12.3%, respectively, in the subjects receiving placebo or dopamine (P <.001); blood cyclosporine A (CsA) levels were similar in the 3 groups (P =.1). Three subjects died in the intensive care unit (1 in each group, P =.9), 2 of them had renal failure. In conclusion, our results confirm the inefficacy of dopamine in preventing or limiting early renal dysfunction after liver transplantation, and suggest that fenoldopam may preserve creatinine clearance by counterbalancing the renal vasoconstrictive effect of CsA, as it has been reported in previous experimental studies.

Adult↗
PubMed2005

Renal transplantation in adolescents.

Renal transplantation remains the goal for the pediatric patient with end-stage renal disease. Recent advances in technology and immunosuppression have greatly enhanced patient and graft survival, while reducing significant complications. However, transplantation of adolescents is still fraught with the potential for serious problems. The increased risk of graft loss, late acute rejection, and incomplete rejection reversal observed in the adolescent age group demands further investigation. Lack of adherence to immunosuppression regimens may be an important contributory factor. Strategies to address the unique concerns of this high-risk population, including the use of a multidisciplinary team, are essential to improving outcomes.

Adolescent↗
PubMed2004

Campath-1H in renal transplantation: The University of Wisconsin experience.

BACKGROUND: Immune cell depletion is known to prevent renal allograft rejection and injury. We evaluated the humanized monoclonal antibody Campath-1H (alemtuzumab; ILEX Oncology, San Antonio, Texas) in renal transplant recipients for its safety and efficacy in preventing rejection when used in combination with a calcineurin inhibitor, mycophenolate mofetil, and low-dose steroid therapy. METHODS: One hundred twenty-six consecutive renal allograft recipients received 2 doses of Campath-1H antibody on days 0 and 1. Outcomes were compared to patients who received an anti-CD25 antibody (n=799), Thymoglobulin (n=160), or other antibody treatment (n=156) in combination with a calcineurin inhibitor, mycophenolate mofetil, and higher dose steroids. RESULTS: The Campath-1H group overall experienced less rejection than the other 3 groups (P=.037). Patients with delayed graft function experienced less rejection with Campath-1H than control groups (P=.0096) and improved graft survival (P=.0119). There was no difference in infection or malignancies between the 4 groups. CONCLUSIONS: Campath-1H was well tolerated in renal transplant patients and led to significant reductions in incidence of rejection. Patients with delayed graft function experienced significantly improved graft survival.

Adult↗
PubMed2004

Simulect and HHV-6 in pediatric renal transplantation.

Herpes virus reactivation is of increasing interest as we aim to decrease morbidity and mortality in the pediatric renal transplant population. We previously reported increased reactivation of HHV-6 and Epstein Barr virus (EBV) with anti-thymocyte globulin/ALG induction therapy. HHV-6 reactivation and de novo infection has been monitored in 31 consecutive pediatric renal transplant patients receiving antibody induction with Simulect. Human Herpes virus-6 (HHV-6) was correlated with EBV reactivation and de novo infection rates, allograft function at 1 year, donor source and number, and patient age and gender. One HHV-6 de novo infection was associated with an early grade II rejection that was steroid resistant but ATG/ALG responsive. Sixteen of 31 (54.8%) patients had HHV-6 reactivation during the first year and eight patients had a prior reactivation profile before transplant. Thirteen patients (41.9%) were naïve to EBV infection prior to transplant with evidence of primary infection in 11 of 13 patients between 6 weeks and 1 year posttransplant. EBV reactivation was noted in four patients with past immunity to EBV. IgM Ab to EBV or HHV-6 during the first year posttransplant did not correlate with risk of rejection during the first year or graft function one year posttransplant. The only patient with positive HHV-6 IgM Ab in the first posttransplant month was a de novo infection in a 2-year-old boy who was naïve for HHV-6 at the time of transplant. Simulect appears safe in pediatric renal transplant with low risk of HHV-6 or EBV infection in the first 1 to 2 months posttransplant.

Adrenal Cortex Hormones↗