Polyclonal Antilymphocyte Antibodies Research Articles

Induction immunosuppression and post-transplant diabetes mellitus: a propensity-matched cohort study.

Post-transplant diabetes mellitus (PTDM) is a common complication among cardiac transplant recipients, causing diabetes-related complications and death. While certain maintenance immunosuppressive drugs increase PTDM risk, it is unclear whether induction immunosuppression can do the same. Therefore, we evaluated whether induction immunosuppression with IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, or Alemtuzumab given in the peri-transplant period is associated with PTDM. We used the Scientific Registry of Transplant Recipients database to conduct a cohort study of US adults who received cardiac transplants between January 2008-December 2018. We excluded patients with prior or multiple organ transplants and those with a history of diabetes, resulting in 17,142 recipients. We created propensity-matched cohorts (n=7,412) using predictors of induction immunosuppression and examined the association between post-transplant diabetes and induction immunosuppression by estimating hazard ratios using Cox proportional-hazards models. In the propensity-matched cohort, the average age was 52.5 (SD=13.2) years, 28.7% were female and 3,706 received induction immunosuppression. There were 867 incident cases of PTDM during 26,710 person-years of follow-up (32.5 cases/1,000 person-years). There was no association between induction immunosuppression and post-transplant diabetes (Hazard Ratio= 1.04, 95% confidence interval 0.91 - 1.19). Similarly, no associations were observed for each class of induction immunosuppression agents and post-transplant diabetes. The use of contemporary induction immunosuppression in cardiac transplant patients was not associated with post-transplant diabetes.

Abstract 11003: Racial Disparities in Induction Immunosuppression Use Among Heart Transplant Recipients in the United States

Introduction: Black heart transplant recipients have higher rates of acute rejection, graft failure, and mortality compared to other races. Induction immunosuppression in the immediate peri-transplant period may lower the risk of acute rejection among high-risk patients, including Black transplant recipients. However, it is not known whether the odds of receiving this treatment are different across races. Therefore, we evaluated whether there are disparities in the use of induction immunosuppression following heart transplants among Black patients compared to other races. Methods: We conducted a cross-sectional study of U.S. adults in the Scientific Registry of Transplant Recipients who received their first heart transplant between 2008 - 2018. We used mixed-effects logistic regression to compare the odds of receiving induction immunosuppression agents (IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, and CD52 monoclonal antibodies) across different races. Results: Among 23,935 adult heart transplant recipients, 5,160 (21.6%) were Black, including 2,797 (54.2%) who received induction immunosuppression, and 18,775 (78.4%) were non-Black, including 9,499 (50.6%) who received induction immunosuppression. After accounting for demographic and clinical characteristics and treatment center, Black race was associated with 28% higher odds (Odds Ratio=1.28, 95% CI 1.17-1.40) of induction immunosuppression use compared to other races. Similar results were observed when race was further stratified (Table 1). Conclusions: In our study, Black heart transplant recipients were more likely to receive induction immunosuppression than transplant recipients of other races. However, further research on post-transplant clinical outcomes including survival following induction immunosuppression among Black patients is needed to formulate treatment guidelines.

Pneumocystis jirovecii: The Changing Landscape for Prophylaxis.

Pneumocystis jirovecii: The Changing Landscape for Prophylaxis.

SUN-357 RABBIT ANTI-THYMOCYTE GLOBULIN INDUCTION THERAPY IN RENAL TRANSPLANTATION

Rabbit anti-thymocyte globulin (rATG) is a preparation of polyclonal antilymphocyte antibodies. It is used not only as an induction therapy to decrease delayed function or rejection of the graft, but also to reverse rejection, with slightly higher rates of complications such as infections and malignancy. The purpose of this study is to review the experience on the use of thymoglobulin as induction treatment in patients with renal transplantation in Cuenca, Ecuador. A retrospective study was conducted in a series of cases (June-September 2019) in the Departament of Nephrology. Universe consisted of 10 patients who underwent renal transplantation from cadaveric donors. All patients received Thymoglobulin induction (daily dose 1,5mg/Kg; 4 patients for 3 days and 6 patients for 5 days), tacrolimus (initial dose 0,075mg/kg per day; if renal function allowed it, dose was adjusted at day five after surgery, increasing it to 1mg/kg per day), mycophenolate (2g/day), and methylprednisolone (inicial daily dose 250mg intravenous for 3 days, then progressive decrease until reaching 20mg daily at first month of follow-up). Leukocyte, lymphocyte, platelet, hemoglobin, urea and creatinine levels were evaluated at five, ten and thirty days after transplantation. Patients age ranked between 20-60 years old (average of 38) and where predominantly female (70%). Hemodialysis (60%). Hypertension was the first cause of renal disease (30%) and cold ischemia time was between 5 to 10 hours. There was an average 50% histocompatibility between donor and recipient. Peak panel-reactive antibody presented in 4% cases. Marked lymphopenia and anemia were evidenced at 5 days with recovery at 10 and 30 days after transplantation. None showed platelet disease. Recovery of renal function became evident from day 5 (1.6mg/dl) presenting at 30 days an improved function of 1.27mg/dl. Infection rate was 50%. In this study, the use of thymoglobulin dose for 3 to 5 days does not represent a risk for infections, so it is considered effective and safe.

Aplastic Anemia in the Context of Hemolytic Paroxysmal Nocturnal Hemoglobinuria: Feasibility of Antibody-Based Intensive Immunosuppression during Eculizumab Treatment

Paroxysmal nocturnal hemoglobinuria (PNH) may present as hemolytic (classical PNH) or aplastic (AA/PNH syndrome) PNH. While classical PNH patients requires anti-complement treatment (eculizumab), the treatment of AA/PNH patients should target their bone marrow failure (BMF) by immunosuppression (IST), or even bone marrow transplantation (BMT). However, in a few patients clinically meaningful AA and hemolysis may be concomitant, eventually justifying both IST and eculizumab. To date there is no standard treatment for this rare condition. Here we investigated the prevalence of this condition based on a large cohort of PNH patients seen at our reference centers at St. Louis Hospital (Paris) and Federico II University (Naples), looking for patients who have received "intensive IST" in combination with eculizumab. Amongst a total of 145 PNH patients seen between 2007 and 2016, we have identified 6 patients who have received intensive IST during eculizumab treatment ; thus, roughly the prevalence of severe BMF associated with hemolysis is around 5%. All the 6 patients have been initially classified as AA/PNH syndrome at time of eculizumab starting, but did not require specific treatment before; they were all on eculizumab treatment at the standard dose of 900 mg fortnightly, with adequate control of intravascular hemolysis. Five of the patients fulfilled the criteria of severe AA, the latter had very severe isolated neutropenia, and was diagnosed with an immune-mediated agranulocytosis. Since no patient had a HLA-matched related donor for BMT, all the patients received intensive IST according to different institutional regimens; eculizumab was not discontinued to minimize the risk of rebound intravascular hemolysis and thrombotic complications. Three patients (2 AA and 1 agranulocytosis) received standard IST with horse-antithymocyte globulin (h-ATG, 40 mg/kg for 4 consecutive days) combined cyclosporine A (CsA). The 3 other AA patients received alemtuzumab (3-10-30-30 mg subcutaneously in 4 consecutive days) and CsA within the prospective trial NCT00895739; one of these patients a few months later also received a second IST course with rabbit-ATG (3.5 mg/kg for 5 consecutive days) and CsA. All the patients completed the scheduled treatment without any side effect, including infusion-related reactions. Lymphocyte depletion was observed in all patients irrespective of sustained therapeutic complement blockade, with lymphocyte count dropping <100/μL in all cases and lasting for several days (or even months in the case of alemtuzumab). All patients remained on eculizumab treatment, even if one AA patient required an increase of the dose up to 1200 mg because of pharmacokinetic breakthrough; in 2 patients 50% hemolytic complement (CH50) was systematically monitored during the treatment course, without showing any significant change from status at pre-IST treatment. All the patients were available for response assessment at 6 months; globally, 3 out of 6 showed a hematological response. The agranulocytosis patient achieved a partial response (PR) requiring G-CSF chronic treatment. Among the 5 AA patients, we observed 2 CR (1 with h-ATG and 1 with alemtuzumab) and 1 PR (after alemtuzumab); this latter was converted into a CR after a second IST course with r-ATG. One of the CR relapsed at 3 years showing clonal evolution toward a myelodysplastic syndrome, and finally died. All the other patients are alive, keeping their hematological response; of the 3 non-responders, 1 was rescued with an unrelated transplantation, and 2 remain on eculizumab treatment (one has developed thromboembolic complications).This is the first systematic description of the management of severe BMF in PNH patients on anti-complement treatment; we first observed that this rare challenging condition may pertain to about 5% of PNH patients. Then we demonstrated that intensive IST, based on either polyclonal or monoclonal anti-lymphocyte antibodies can be safely delivered even in concomitance of eculizumab. Pharmacological lymphocyte depletion was achieved irrespective of terminal complement inhibition. Clinical efficacy was in the expected range as in broader AA populations, with an overall reponse rate of 50%. Based on these data, intensive IST delivered on top of eculizumab should be considered in PNH patients who develop severe AA during eculizumab treatment lacking a low-risk bone marrow transplant procedure. DisclosuresPeffault de Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Risitano:Alnylam: Research Funding; Novartis: Research Funding; Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Rapharma: Research Funding.

The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant

The Registry of the International Society for Heart and Lung Transplantation: Nineteenth Pediatric Heart Transplantation Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant

Intestinal and multivisceral transplantation.

Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run.

Induction treatment with monoclonal antibodies for heart transplantation

Individualization of induction therapy for heart transplantation (HT) is needed, given that only patients at significant risk for fatal rejection seem to present a favorable risk-benefit ratio. The question whether monoclonal interleukin 2 antagonists or antilymphocyte antibodies should be recommended remains unanswered. As most studies suggest that they have similar efficacy in preventing acute rejection, other variables related to safety or management costs should be taken into account. The cytokine release syndrome, associated with the use of OKT3, complicates management of HT patient. The experience in our center with 2 consecutive cohorts, treated with basiliximab (BAS) and OKT3, respectively, suggests that the use of BAS is associated, in addition to similar immunosuppressive efficacy and better safety profile than OKT3, with simpler patient management during the initial hospital stay, which could be associated with a reduction in posttransplant costs. Because few centers continue to use OKT3 as induction therapy in HT, more studies comparing cost-effectiveness of BAS vs polyclonal antilymphocyte antibodies (ATG) are needed.

Long-Term Outcome on Kidney Retransplantation: A Review of 100 Cases From a Single Center

Renal transplantation has become an effective form of treatment for end-stage renal failure. Unfortunately, as a consequence of immunological and nonimmunological pathogenic mechanisms, chronic allograft nephropathy is responsible for the loss of a large proportion of kidney grafts after several years and return to dialysis. We have reported herein our 24 years of experience with second kidney transplantations. Of 1302 kidney transplantations between January 1983 and June 2007 performed in our transplantation center, 100 were second transplantations. Kidney retransplantation was performed in 74 men and 26 women of overall mean age of 35.4 ± 12.6 years. Cadaveric donor grafts were transplanted in 92 patients, whereas the remaining 8 were living-related donor kidneys. At 1, 5, and 10 years after kidney transplantation, patient survival rates were 100%, 96%, and 92%, respectively, whereas graft survival rates were 85%, 72%, and 53%, respectively. Immunosuppressive therapy included induction therapy with polyclonal anti-lymphocyte antibodies (ALG/ATG) or (starting from 1999) monoclonal anti CD 25 antibody. Our results demonstrated good outcomes for kidney retransplantations with allocation based on anti- HLA antibody identification together with induction immunosuppression.

Editorial Comment: An Old Drug Just Keeps Getting Better: New Mechanisms of Action Suggest New Therapeutic Targets

Editorial Comment: An Old Drug Just Keeps Getting Better: New Mechanisms of Action Suggest New Therapeutic Targets

Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6‐Month Course of Steroids

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)-free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus- and CsA-treated patients (60 +/- 27 vs. 57 +/- 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy-proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 +/- 19 vs. 60 +/- 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus-treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI-free regimen using sirolimus-MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.

Essay: History of transplantation

Over the past 50 years organ transplantation has become established worldwide with ever-improving results, conferring immense benefi t to hundreds of thousands of patients. The general principles of the surgical procedures and organ preservation have been accepted for all organ transplants, but the biology of graft rejection is still only partly understood. The discovery of natural acquired immunological tolerance and experimental methods of producing tolerance by Billingham, Brent, and Medawar raised the hopes of clinicians that there might be a way of inducing in the recipient at the time of organ grafting a state of temporary immunological plasticity similar to the stage that occurs in fetal development. In 1959 mercaptopurine, which is used in the treatment of leukaemia, was shown by Schwarz and Damechek to prevent antibody formation in rabbits challenged with foreign protein. They called this observation drug-induced immunological tolerance. Studies in the UK on kidney-grafted animals treated with mercaptopurine produced a moderate extension of graft survival and led to a practical clinical regimen of treatment with the mercaptopurine analogue azathioprine plus corticosteroids. At 1 year, graft function was around 50%. Kidney transplantation remained confi ned to about ten centres worldwide, and the procedure was viewed with suspicion because of the poor overall results. Then, in the late 1970s, Borel and colleagues discovered the immunosuppressive properties of the fungal cyclic peptide ciclosporin, which prolonged survival of skin grafts in mice. Further studies of this drug in the UK showed prolonged survival of cardiac allografts in rats and pigs and renal transplants in dogs. When ciclosporin was fi rst used in people, based on the dose given to animals, it was severely nephrotoxic. After a worrying learning curve of dose adjustments, ciclosporin was shown to improve the 1-year survival of kidney grafts to around 80%, and for the fi rst time surgeons became confi dent in transplanting the liver and heart with ciclosporin immunosuppression. Ciclosporin was a watershed in the development of transplantation. Instead of a treatment limited to a handful of centres worldwide, transplantation became a muchvalued form of therapy spreading to more than a thousand centres. The kidney was the organ most commonly transplanted, but increasingly good results were obtained with heart, liver, and, eventually, lungs and pancreas. One method of minimising the nephrotoxicity of ciclosporin was to combine this drug with azathioprine and corticosteroids so that the total immunosuppressive activity would be additive, but the individual side-eff ects of the diff erent agents would be less. Gradually, the “halflife” of organ transplants improved. Many new immunosuppressive agents have been investigated experimentally, and several have been introduced into the clinic, including polyclonal and monoclonal antilymphocyte antibodies. There has been an unfortunate tendency to add more and more potent immunosuppressive agents to therapy with concomitant over-immunosuppression. Bone-marrow transplantation has also advanced through new regimens of non-ablative transplantation with mixed chimaerism, initially planned to retain the graft-againstleukaemia eff ect but also used in an important series of clinical experiments in patients subsequently given kidney transplants, in whom tolerance occurred despite the disappearance of the donor chimaeric state in the blood. Besides their expense, conventional drug regimens can cause great hardship to patients and non-compliance is common. Some patients with liver transplants stopped taking their drugs and performed a clinical experiment demonstrating immunological tolerance, surviving many years with good liver function despite the absence of any maintenance immunosuppression. Other patients were not so lucky, and this weaning of maintenance immunosuppression is far more likely to be successful with liver than with kidney transplants, which is consistent with experimental demonstration of liver tolerance without any drugs after orthotopic liver transplantation in pigs and rodents. Lancet 2006; 368: S51–S52

Long-Term Results of Monoclonal Anti-Il2-Receptor Antibody Versus Polyclonal Antilymphocyte Antibodies as Induction Therapy in Renal Transplantation

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin ( n = 50) versus anti-IL-2R monoclonal antibody ( n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

Immunosuppression use in renal transplantation from Asian transplant centers: A preliminary report from the Asian Transplant Registry

Since the first renal transplant (RTx) in 1956 in Asia in Japan, over 100,000 RTx have been performed in over 300 centers across the region. A survey was conducted to evaluate immunosuppression (IS) use among Asian RTx. Briefly, directors of RTx centers were surveyed regarding IS use for RTx performed at their centers in 2001 for (1) induction therapy, (2) maintenance IS therapy at hospital discharge, (3) antirejection treatment (REJ) to 1 year post-RTx, and (4) maintenance IS therapy to 1 year post-RTx. Categories and types of IS included in the survey were polyclonal antilymphocyte antibodies (PAB), OKT3, IL2 receptor antibodies (IL2RAb), corticosteroids (CS), cyclosporine (CyA), tacrolimus (Tac), azathioprine (Aza), mycophenolate mofetil (MMF), Mizoribine (Miz), Sirolimus (Sir), and other agents. Though only 17 RTx centers in Asia responded to the survey, a wide variation in IS use was demonstrated. In the 334 living and 85 cadavericRTx among whom actual usage was reported, induction therapy was used in only 18.4% of Asian RTx (14.1%, IL2RAb; 4.3%, PAB), in contrast to the 59.3% reported as using induction IS among RTx from the UNOS database in the same year. For maintenance therapy at hospital discharge, 87.1% of Asian RTx received CyA-based IS while only 12.4% received Tac-based therapy. This is in contrast to the 55.3% use of Tac for new RTx in the United States. Generic CyA has widespread use in Asia with over 29.9% on CyA using generic versus the Neoral formulation. Azathioprine is still the predominant antimetabolite in use in Asian RTx, with MMF being used in only 33.6% of patients, in contrast to its 77% usage in the United States. Usage of Tac and MMF for maintenance therapy was significantly higher among cadavericRTx ( P < .005). Corticosteroids were used in 51.1% of REJ episodes while PAB or OKT3 were used in 31.9% and 17% of REJ episodes, respectively. As these results may be skewed due to participation of few centers in the survey, greater participation will ensure more accurate evaluation of immunosuppression use in Asia for de novo RTx.

Reduced dose Thymoglobulin, tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes.

Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas-kidney transplants. Thymoglobulin (TMG), a polyclonal rabbit-derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1-yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate. Eighteen pancreas after kidney and four pancreas transplants alone were performed between January 1998 and October 2000 at McGill University. Induction therapy with TMG at a starting dose of 1.5 mg/kg/d was started 12 h post-operatively. The daily dose of TMG was held if the total leukocyte count was <2,500/mm3 or if the lymphocyte count was <100/mm3. Maintenance therapy was initiated with steroids (tapered to 20 mg prednisone orally once a day) tacrolimus (2 mg twice a day), and mofetil mycophenolate (1 g daily). Patients received three to seven doses of TMG over the first seven post-operative days at a dose of 0.85 +/- 0.27 mg/kg/d (mean +/- SD). The mean follow-up was 1.28 +/- 0.14 yr. The 1-yr patient and graft survival was 100% (22 of 22) and 96% (21 of 22), respectively. The 1 yr acute rejection rate was 27.3% (six of 22). Five of the six rejections responded to steroid boluses. One was refractory to steroids and TMG resulting in graft loss. Presumed rejections were diagnosed on the basis of decreasing urine amylase and/or hyperglycemia. Monitoring the total leukocyte and lymphocyte count resulted in a 43% reduction in the amount of TMG used compared with the recommended dosing. Despite the reduced amounts, patient and graft survival were excellent with acute rejection rates comparing favorably to other published series.

Initial experience of combined immunosuppressive induction therapy with polyclonal antithymocyte antibody, FK 506 (tacrolimus), and prednisolone in clinical liver transplantation

LIVER TRANSPLANTATION has become an accepted treatment modality for end-stage liver diseases such as chronic hepatitis C, posthepatitis, primary biliary, ethyl-toxic cirrhosis, primary sclerosing cholangitis, fulminant hepatic failure, Budd-Chiari syndrome, polycystic liver disease, and biliary atresia in infants. Results of liver transplantation improved dramatically with the introduction of the immunosuppressant cylosporine. Recently, newer immunosuppressive drugs such as polyclonal antilymphocyte antibodies (eg, ATG, ALG), tacrolimus (FK506), and mycophenolate mofetil (MMF) have been introduced to the field of human organ transplantation. Specifically, these drugs aim to confer satisfactory immunosuppression with fewer side effects. More selective regimes are anticipated with such drugs, together with a reduction in frequency and severity of rejection. Tacrolimus is being used more often as an alternative or replacement for induction, maintenance, and “rescue” therapy in acute graft rejection following liver transplantation. Currently, the ideal choice of immunosuppression induction in liver transplantation remains controversial. Although many multiand single-center trials have been conducted, questions remain unanswered. Such questions relate to the optimal time point of immunosuppression induction (before, during, after transplantation), and the choice of combination of immunosuppressive drugs, as well as their route of administration. At our institution, we have employed a novel combined regime for immunosuppression induction of polyglonal antithymocyte antibody (ATG), tacrolimus, and prednisolone in a prospective follow-up study in human orthotopic liver transplantation (OLT). We report our preliminary experience in 14 consecutive patients with a follow-up period of up to 19 months.

THE KIDNEY IN LIVER TRANSPLANTATION

Early recognition and determination of the cause of renal failure in patients with ESLD can be difficult because of the potential interplay among various factors and the wide array of differential diagnoses. A systematic approach, however, assists clinicians to identify common and potentially reversible causes of ARF. It is crucial to distinguish patients with functional renal failure, such as HRS, from those with advanced irreversible renal disease. Isolated liver transplantation is the treatment of choice for the former, and CLKT may be a therapeutic option for the latter. Because of the ever-increasing shortage of donor organs, CLKT must be used judiciously. Kidney biopsy may resolve diagnostic dilemmas. Management of renal complications post-OLT remains a challenge for the physician caring for transplant patients. Modification of nephrotoxic immunosuppressive regimens to avoid postoperative ARF/CRI has met with variable results. Azathioprine has been used in place of cyclosporine. Therapy with polyclonal antilymphocyte preparations or anti-OKT3 monoclonal antibodies (Orthoclone) should be reserved for patients with delayed graft function and for the treatment of acute rejection. The routine use of these agents as prophylactic therapy is not recommended. Data on the impact of renal insufficiency on patient and allograft outcome are inconsistent. Nonetheless, the authors' literature review suggests that renal failure associated with sepsis and, except for patients with HRS, renal failure requiring dialysis are the most consistent features associated with a worse outcome. The need for preoperative or postoperative dialysis has no adverse effect on survival in patients with HRS. On long-term follow-up, despite a greater percentage of patients reaching ESRD in patients with HRS compared with their non-HRS counterparts, the overall outcome in patients with HRS following OLT is favorable. In patients with HRS requiring prolonged dialysis (i.e., greater than 4 weeks), however, irreversible renal failure may develop, necessitating CLKT. Ideally, timely referral of patients for OLT may avoid this complication and obviate the need for double organ transplantation.

Opportunistic pulmonary infection after renal transplantation

INFECTIOUS complications in kidney transplant recipients are associated with significant morbidity and mortality. The risk of infection is based on two main factors: recent or past exposure to infectious agents, and the patient’s level of immunosuppression. Bacterial infections usually occur in the first month following transplantation, and technical issues related to the procedure can play an important etiologic role. Most febrile illness that occurs in kidney recipients between 1 and 6 months posttransplantation is caused by cytomegalovirus (CMV) and other opportunistic agents. The regimen and level of immunosuppression are important in the pathogenesis of these infectious complications. Kidney recipients whose grafts have come from cadavers tend to develop more frequent and severe infectious complications than living-donor kidney recipients due to the increased level of immunosuppression that is usually needed in the former group. Also, recipients of cadaveric kidneys who receive induction antilymphocyte globulin (ATG) preparations have higher infection rates than those who do not receive this treatment. Further, research has shown that patients who receive azathioprine as their primary immunosuppressive agent have a higher rate of infection than patients on cyclosporine-based regimens. Beyond 6 months, in patients with well-functioning allografts who are on stable maintenance immunosuppression the pattern of infection is similar to that in the general population. Another significant finding is that transplant recipients often develope infection that simultaneously involves several causal agents. This underlines the importance of considering concomitant infection in patients who do not respond to the initial line of treatment. While the incidence of tuberculosis (TB) after kidney transplantation in highly industrialized countries is low, the figure for developing regions is significantly higher. Mycobacterial disease should be considered in any patient with fever of unknown etiology. Most cases of Mycobacterium tuberculosis infection in kidney transplant recipients are due to reactivation of latent TB lesions. Important risk factors for reactivation include nonwhite race, history of active TB, presence of a marked abnormality on a chest radiograph, exposure to a person with a confirmed case of TB, and skin test positivity. In transplant patients, the clinical presentation of tuberculosis may be atypical, and extrapulmonary and miliary tuberculosis is seen more frequently than in the normal population. With regard to fungal infection, in kidney transplant recipients these most commonly present as prolonged fever that does not respond to antibiotic therapy. These infections are associated with very high mortality. The most common fungal infections reported in first series from developing countries were candidiasis, aspergillosis, and cryptococcosis. Several factors influence the development of symptomatic CMV infection after kidney transplantation, but most important are the CMV serologic statuses of the donor and recipient. Symptomatic CMV infection can be primary, can occur due to reactivation of latent infection, or can arise secondary to superinfection. The most severe form is usually observed when a CMV-seronegative recipient receives a graft from a CMV-seropositive donor. Host cell–mediated immunity and the type and level of immunosuppressive therapy influence the development of symptomatic CMV infections. Polyclonal and monoclonal antilymphocyte antibody treatments have the highest CMVpromoting effect, and represent the most important factor in the development of CMV infections after kidney transplantation. Nocardia is a filamentous gram-negative soil organism that can cause pneumonia. This infection also frequently disseminates to the brain and results in abscess formation. The overall mortality associated with nocardiosis in kidney transplant recipients is 25%, but this figure jumps to 44% in patients who have central nervous system involvement.

New scoring system identifies kidney outcome with radiation therapy in acute renal allograft rejection

Purpose: To evaluate the role of radiation therapy for acute refractory renal rejection after failure of medical intervention, and to identify risk factors that influence graft survival following radiation therapy. Methods: Between June 1989 and December 1995, 53 renal transplant recipients (34 men and 19 women) were treated with localized radiation therapy for acute renal allograft rejection. Graft rejection was defined as an increase in serum creatinine with histologic evidence of rejection on renal biopsy. Ninety-one percent were cadaveric transplant recipients. The majority of patients who experienced acute graft rejection initially received corticosteroid therapy, except for 25% who were referred for radiation therapy and steroids for the first rejection. In more recent years, patients with moderate or severe steroid-resistant or recurrent rejection received OKT3, a polyclonal antilymphocyte antibody (ATGAM), tacrolimus (FK506), or mycophenolate mofetil (MMF). Patients who failed to respond to medical treatment were then referred for radiation therapy. Ultrasound was performed for kidney localization. Treatment consisted of a dose of 600 cGy given in 3 or 4 fractions using 6 MV photons, delivered AP or AP/PA. Results: The overall actuarial graft survival from the initiation of RT was 83% at 1 month, 60% at 1 year, and 36% at 5 years. The median follow-up from the date of transplant to the last follow-up was 22 months. The median time from the date of transplant to the initiation of radiotherapy was 3 months, and the median time from the initiation of radiotherapy to the last follow-up was 10 months. Variables evaluated were as follows: human leukocyte antigen matching on HLA-A, HLA-B, and HLA-DR, the transplant panel-reactive antibodies (PRA) at transplantation, number of acute rejection episodes, interval from the date of the transplant to the first rejection, serum creatinine levels at the time of the first radiation treatment, number of transplants, and concomitant immunosuppressive therapy. Independent factors examined by Cox regression modeling were: gender ( p = 0.005), creatinine levels ( p = 0.000), HLA-DR ( p = 0.05), PRA-Maximum >70% ( p = 0.014). Each factor was scored using integral coefficients to generate four different groups. The Kaplan-Meier survival analyzed by group produces an interpretable separation of the risk factors for graft loss. Conclusions: The outcome in patients treated with radiation therapy for acute renal graft rejection can be predicted by a novel scoring system. Patients with scores of three or less are able to achieve 100% renal graft salvage, while patients who have scores of 12 or higher are not able to be salvaged with the current radiation therapy regimen. Future studies should be directed toward identifying more effective treatment for patients who have a high score based on our criteria. The scoring system should be utilized to identify patients at risk who could benefit from radiation therapy. Further study with a randomized trial utilizing this scoring system is needed to confirm the validity of the scoring system in predicting graft survival and the efficacy of radiation in patients who receive radiation therapy for acute graft rejection.

Current use of polyclonal antilymphocyte antibody preparations

OLYCLONAL antilymphocyte agents have been widely used since the 1960s for induction therapy as well as for the treatment of allograft rejection in clinical organ transplantation. In addition to their role as induction agents, polyclonal antibodies are used in many centers in order to delay administration of nephrotoxic interleukin-2 (IL-2)‐ based agents such as cyclosporine (CyA) or tacrolimus until allograft function is established. Recent efforts have focused on selective use of polyclonal antibodies for recipient populations deemed to be at higher immunologic risk for allograft rejection. Many different preparations have been developed, using a range of hosts (primarily horse, rabbit, and goat) for the generation of antibody to either resting or stimulated lymphocytes or thymocytes. For many years, it was difficult to discern whether the use of polyclonal antilymphocyte agents in kidney transplantation was associated with a significant immunologic advantage. Recently, however, several large database analyses have demonstrated that polyclonal induction is associated with a significant increase in graft survival and a decreased risk of rejection in patients receiving kidney transplants. 1‐3 A large multicenter study of the use of polyclonal agents in the treatment of rejection demonstrated excellent reversal rates and low recurrence rates. 4 Outside of kidney transplantation, a number of series have documented favorable results using polyclonal antibodies in the treatment of liver, 5,6 pancreas, 7 and heart transplant recipients. 8 In specific patient populations, polyclonal antilymphocyte antibody preparations have been shown to be of particular benefit. This is especially true for pediatric renal transplant patients, who have been shown to derive immunologic benefit as well as a decreased incidence of allograft thrombosis when polyclonal agents are included as part of their immunosuppressive regimen, 9,10 and for recipients of repeat transplants. 11