Showing papers in "Clinical Transplantation in 2003"

Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management.

Abstract: Each year, 55 000 organ transplants are performed worldwide. Cumulatively, the number of living organ recipients is now estimated to be over 300 000. Most of these transplant recipients will remain on immunosuppressive drugs for the remainder of their lives to prevent rejection episodes. Controlled doses of these drugs are required to prevent over-medication, which may leave the patient susceptible to opportunistic infection and drug toxicity effects, or under-dosing, which may lead to shortened graft survival because of rejection episodes. This paper describes the result of a multicenter study conducted at the Universities of Pittsburgh, Alabama and Maryland to evaluate an in vitro assay (CylexTM Immune Cell Function Assay) for the measurement of global immune response in transplant patients receiving immunosuppressive therapy. The assay uses a whole blood sample to maintain the presence of the drug during incubation. Following overnight incubation of blood with phytohemagglutinin (PHA), CD4 cells are selected using paramagnetic particles coated with a monoclonal antibody to the CD4 epitope. The CD4-positive cells are targeted as major immunosuppressive drugs are designed to specifically inhibit T-cell activation which has been implicated in rejection. The data generated at these three sites were submitted in support of an Food and Drug Association (FDA) application for the use of this assay in the detection of cell-mediated immunity in an immunosuppressed population. The assay was cleared by the FDA on April 2, 2002. This cross-sectional study was designed to establish ranges for reactivity of this bioassay in the assessment of functional immunity for an individual solid organ recipient at any point in time.

Gastroesophageal reflux disease in lung transplant recipients.

Abstract: Background: Chronic allograft dysfunction after lung transplantation contributes to poor long-term survival. A link between gastric aspiration and post-transplant lung dysfunction has been suggested, but little is known about the significance of gastroesophageal reflux disease (GERD) after lung transplantation. Methods: A retrospective study was performed to determine the prevalence of GERD in lung transplant recipients. Patients who underwent lung transplantation at Duke University, survived at least 6 months and had post-transplant 24-h pH studies were included in the analysis. Antireflux medications were discontinued prior to the pH study. Demographic data, pH study date and results, FEV1 at the time of the pH study, confirmed acute rejection episodes, and current medications were collected. The FEV1 ratio was calculated at the time of pH study (current FEV1/best post-transplant FEV1). Results: Forty-three patients met entry criteria. Studies were performed at a median of 558 d post-transplant. Thirty of forty-three (69.8%) patients tested had abnormal total acid contact times (normal: <5%). The mean acid contact times for all patients were 10% total, 11.8% upright and 7.9% supine. A negative correlation was found between total or upright acid reflux and FEV1 ratio at the time of studies (−0.341 and −0.419; p = 0.025 and p = 0.005, respectively). The effect of acid reflux on FEV1 ratio remained significant after multivariable analysis. Conclusions: There is a high prevalence of GERD among selected lung transplant recipients who had pH studies performed and its presence is associated with worse pulmonary function. Future studies are needed to assess whether GERD contributes to the pathogenesis of bronchiolitis obliterans syndrome (BOS).

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

Abstract: Background: Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circum- stances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated. Methods: In this study, a cohort of 721 kidney transplant recipients who received immunosuppression using MMF in conjunction with cyclosporine and prednisone and OKT3 (n ¼ 425) or Simulect (n ¼ 296) induction were evaluated. Clinical outcomes were compared and contrasted between patients with and without MMF dose changes within the first year post- transplantation. Results: The majority of patients (70.3%, n ¼ 507) had at least one dose change within the first post-transplant year. Compared with the 214 patients who did not have a dose change, these patients had a much higher incidence of acute rejection within the first post-transplant year (23.3% vs. 3.7%, p < 0.001). This resulted in a significantly decreased 3-yr death-censored graft survival (76.3% vs. 88.3%, p ¼ 0.003). The incidence of acute rejec- tion for patients who had a dose change was highest if the dose change occurred within the first post-transplant month (34.4%). The incidence of acute rejection for the dose change patients was influenced by recipient ethnicity (African-American vs. Caucasian) and the type of induction agent used (OKT3 vs. Simulect). Conclusion: Altering the dose of MMF within the first post-transplant year correlated with a significantly worse clinical outcome in this cohort of renal transplant recipients. These data suggest that avoidance of MMF dose changes within the first year after renal transplantation would result in improved graft survival.

Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systematic review.

Abstract: Objective: To identify and prioritize key areas for further research in kidney preservation systems. Materials and methods: We conducted a systematic review and meta-analysis of the effectiveness of machine perfusion and cold storage techniques in reducing delayed graft function (DGF) and improving graft survival in recipients of kidneys from beating and non-heart-beating donors. Literature quantifying the link between DGF and graft survival was used to evaluate the potential long-term impact of machine perfusion and cold storage systems. Cox proportional hazards modelling was used to predict graft survival and graft years gained over 10 yr. Monte Carlo sensitivity analysis was conducted to evaluate stochastic uncertainties within the model. Results: Machine perfusion leads to a relative risk of DGF of approximately 80% (67%, 96%) compared with cold storage, although the evidence base is limited in quality and study size. Direct evidence on graft survival at 1 yr demonstrates no statistically significant difference between machine perfusion and cold storage. Predictions based upon quantifying the link between DGF and graft survival suggest potential improvements of between 0 and 6% at 10 yr. Discussion: Studies of high methodological quality and sufficient size are required to determine whether machine preservation leads to reduce rates of DGF. Predicted impact on graft survival implies that direct evidence would require a large population followed up over a long period of time. Registry database analysis supported by validation of the link between DGF and graft survival may be preferable and more feasible than randomized controlled trials.

Extended criteria for organ acceptance. Strategies for achieving organ safety and for increasing organ pool.

Abstract: The terms extended donor or expanded donor mean changes in donor acceptability criteria. In almost all cases, the negative connotations of these terms cannot be justified. Factors considered to affect donor or organ acceptability have changed with time, after showing that they did not negatively affect graft or patient survival per se or when the adequate measures had been adopted. There is no age limit to be an organ donor. Kidney and liver transplantation from donors older than 65 years can have excellent graft and patient actuarial survival and graft function. Using these donors can be from an epidemiological point of view the most important factor to esablish the final number of cadaveric liver and kidney transplantations. Organs with broad structural parenchyma lesion with preserved functional reserve and organs with reversible functional impairment can be safely transplanted. Bacterial and fungal donor infection with the adequate antibiotic treatment of donor and/or recipient prevents infection in the latter. The organs, including the liver, from donors with infection by the hepatitis B and C viruses can be safely transplanted to recipients with infection by the same viruses, respectively. Poisoned donors and non-heart-beating donors, grafts from transplant recipients, reuse of grafts, domino transplant and splitting of one liver for two recipients can be an important and safe source of organs for transplantation.

Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome.

Abstract: Background: Cerebrovascular and cardiovascular diseases are the most important causes of increased morbidity and mortality in patients with end-stage renal disease. Stroke has been widely reported in chronic dialysis patients, but there is scarce information about stroke in renal transplant recipients (RTR), although cerebrovascular events are the most common and potentially life-threatening neurological complications in them. Our aim is to analyze the prevalence, risk factors, etiopathogenia, clinical aspects and outcome of stroke in RTR. Methods: We analyzed 403 patients who received one or more renal grafts between 1979 and 2000: group A = patients who had stroke (n = 19); group B = those who did not (n = 384). Medical records and pertinent data were compiled. The risk of stroke was studied using univariate and multivariate Cox regression models. Results: prevalence of stroke in RTR was 7.97% at 10 yr. Time elapsed between renal transplantation (RT) and stroke: 49.3 months. Possible risk factors based on the univariate analyses were: diabetic nephropathy (DN) (p 40 yr (OR = 3.3; p = 0.019) were predictive risk factors for stroke. For group A, hypertension was present in all patients, 68.4% had hyperlipidemia and 42.1% reported previous stroke. Cerebral hemorrhage occurred in seven of 19 (36.84%) of the stroke patients, but no subarachnoid hemorrhage occurred in them. Seven of 12 ischemic strokes were atherotrombotic. Considering all strokes, basal ganglia was the predominant localization. The outcome was poor, as nearly half of the patients died in the 3 months following stroke. Conclusions: Prevalence of stroke in our RTR population was 7.97%. Cerebral hemorrhage appears to be more prevalent in RTR than in general population. More than that, the cerebral hemorrhage rate we found is higher than that reported elsewhere in RTR. The main predictors of stroke were DN, PVD and age. No patient with interstitial nephropathy suffered stroke. Mortality is high in RTR with stroke.

Humanized anti‐CD20 monoclonal antibody (Rituximab) treatment for post‐transplant lymphoproliferative disorder*

Abstract: Introduction: Post-transplant lymphoproliferative disorders (PTLD) is a consequence of Epstein–Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes The treatment of PTLD includes reduction/withdrawal of immunosuppression and chemotherapy This study reports our center experience with humanized monoclonal antibody against CD-20 (Rituximab) for the treatment of PTLD Material and methods: Eight cases of PTLD after solid organ transplantation [six kidney, one kidney/pancreas (KP) and one liver] occurred between September 1998 and October 2001 The mean time between transplant and the diagnosis of PTLD was 573 months (range 3 months to 10 yr) Five patients underwent cadaveric transplant, five males and six were Caucasians with mean age of 48 yr (range 20–67 yr) Results: The clinical presentation was as follows: lymphadenopathy-5, gastrointestinal bleeding-2 and tonsillar enlargement-1 The diagnosis was made by a lymph node biopsy in five, a gastric ulcer biopsy in two and a tonsillar biopsy in one case Six of them had polymorphous, two had monoclonal B-cell lymphoma, and all were positive for CD-20 Six were related to EBV, documented by latent membrane protein (LMP) or Epstein–Barr encoded RNA (EBER) staining Immunosuppression at the time of PTLD diagnosis consisted of tacrolimus in six cases and cyclosporine A (CsA) in two with mycophenolate mofetil (MMF) and azathioprine-3 each and sirolimus-1 Rituximab was administered at a dose of 375 mg/m2 once a week for 4 wk There were no side effects seen with this therapy Immunosuppression was reduced in all patients Complete remission was observed in seven cases (one required two courses) One patient who did not respond received chemotherapy Patients were followed for a mean period of 225 months (range 10–45 months post-PTLD diagnosis At the last follow-up all eight patients were alive, seven with a functioning graft and one on maintenance dialysis Three of these patients had been in remission for more than 25 yr Conclusion: Rituximab is an effective agent in the treatment of PTLD without the morbidity characteristic of chemotherapy Chemotherapy should be reserved only for those refractory to Rituximab therapy

Transplant recipients’ conceptions of three key phenomena in transplantation: the organ donation, the organ donor, and the organ transplant

Abstract: Thirty-five heart and kidney transplant patients were interviewed on five separate occasions during the first 2 yr after transplantation. The aim was to explore their experiences of phenomena that distinguish the transplantation from other kinds of medical treatment. The selection of informants was designed to permit comparisons between recipients with heart and kidney transplants and with living and necro-transplants. The qualitative analysis of the informants' reactions was focused on three themes; nine categories emerged. The first theme concerned general aspects of the donation and the donor and was differentiated in four categories: joy and sorrow, gratefulness and indebtedness, guilt, and inequity. The second theme related to the donor as a unique individual and included three categories: recognition and identification with the donor, influences of the donor, and relationship to the living donor. The third theme pertained to incorporation of the transplant and included two categories related to the naturalness of having a transplant, and the benevolent transplant. The informants' reactions were discussed in terms of primary and secondary processes. All informants were in an emotionally charged situation after transplantation and warded off anxiety-provoking impulses, most intensively during the first 6 months. Avoidance, suppression, and denial were the most common defence mechanisms, all of which seemed to be supported by the medical context. Other, more constructive strategies are suggested. The recipients' own interpretations of causes to possible personality changes are discussed. There were few differences between heart and necro-kidney patients concerning the reactions to the donation, the donor, and the transplant; the dividing line was more prominent between recipients with living and necro-transplants.

Hyperparathyroidism and long-term bone loss after renal transplantation.

Abstract: : Background: While early bone loss after renal transplantation (RT) is well described, factors affecting the long-term fate of bone have received less attention. Methods: Whole body (WB), lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) was measured using dual energy X-ray absorptionometry in 126 stable RT patients and repeated in 114 survivors after 3 yr. Percentage change per year (%/yr) was correlated to clinical and biochemical markers of bone metabolism. Results: Low bone mass was a marker of increased mortality (FN 80% 2.2%/yr). Percent change was WB −0.7 ± 1.5 (p 9 mg/d: −1.9 (p 175 ng/L: −1.9 (p 150 ng/L: −1.5 (p 275 U/L: −1.6 (p 75 μg/L: −1.6 (p < 0.05)]. Marginal detrimental effects of uremia, hypoalbuminemia and hyperphosphatemia were noted. Thiazide treatment seemed to protect against, and furosemide to exacerbate, bone loss, but this may have been related to associated uremia. Patients treated with vitamin D gained bone, while untreated patients with low initial 1,25-dihydroxyvitamin D lost bone [FN%−2.1 (p < 0.05)]. The prevalence of PTH (52%) and hypercalcemia (22%) remained unchanged. There was no effect of sex hormone levels, calcium and phosphate excretion, or serum calcium. Conclusion: While LS BMD stabilizes after RT, there is a continuing loss of WB and FN BMD. The major causes of bone loss are steroid therapy and continuing PTH, with no tendency towards spontaneous resolution. Increased vitamin D and calcium therapy should be considered for this patient group, and more aggressive therapy, e.g. parathyroidectomy given for patients with resistant PTH of >150 ng/L.

Predictive factors for early mortality following liver transplantation

Abstract: Aims: To retrospectively review our liver transplant performance to identify factors that influenced early outcomes and to prospectively test their validity in predicting outcomes. Methods: Clinical records from 190 patients with liver transplants (LT; n = 200) performed between 1991 and 1997 were reviewed and the data evaluated by univariate and multivariate analyses regarding clinical outcome. The prognostic model thus obtained was prospectively evaluated in 55 patients undergoing transplant between 1999 and 2000. Results: Main indication for transplant was post-necrotic cirrhosis (61%), mostly HCV(+). The majority of patients were Child-Pugh C status (46%). Post-operative mortality at 3 months was 15.3%. Risk factors predicting death were: Child-Pugh C status (OR 1.3), pre-LT renal insufficiency (OR 5.8), malnutrition (OR 2.9) and technically complex surgery requiring cross-clamping with or without bypass (OR 4.9). None of the donor factors was significant. Prospectively applied to predict outcome in the 55 patients, the model had a sensitivity of 80% and a specificity of 88.8% with a higher-than-anticipated accuracy with a positive predictive value of 61.5% and a negative predictive value of 95.3%. Conclusions: Pre-LT renal insufficiency is the most significant risk factor for early mortality and suggests that LT should be performed before evidence of irreversible renal insufficiency becomes manifest.

Detection of simultaneous β-herpesvirus infections in clinical syndromes due to defined cytomegalovirus infection

Abstract: Human herpesvirus (HHV)-6 and HHV-7 are increasingly being recognized as emerging pathogens among transplant recipients. Using quantitative polymerase chain reaction assays, we demonstrate the presence of HHV-6 and/or HHV-7 in 18 of 20 episodes of clinically presumed or microbiologically confirmed cytomegalovirus (CMV) infection. Seventeen (89%) of 19 microbiologically confirmed cytomegalovirus (CMV)-infected patients had concomitant HHV-6 variant B (47%) and/or HHV-7 (63%) infection. The degree of HHV-6 coinfection was significantly correlated with hyperbilirubinemia while HHV-7 coinfection demonstrated a non-significant trend toward cytopenias. In one of the 20 episodes described herein, the 'viral syndrome' was due solely to HHV-7 infection; clinical and virological response was observed during intravenous ganciclovir therapy in this patient. While this study emphasizes the significance of HHV-6 and/or HHV-7 coinfection during episodes of CMV infection, it significantly highlights the novel observation of the causal role of HHV-7 (in the absence of HHV-6 and CMV) in a clinical illness presumed to be caused CMV. Thus, HHV-7 (and HHV-6) should be considered as a pathogen (or copathogen) in the viral syndromes following organ transplantation.

Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy.

Abstract: Background: Two hundred and forty cadaveric renal transplant recipients given anti-thymocyte globulin (Thymoglobulin®) as induction immunotherapy were followed up prospectively to review safety and efficacy. Methods: The median number of infusions was 10 [2–21] with a cumulative dose of 8.8 mg/kg [2.0–23.2 mg/kg]. During the fortnight following transplantation, 231 patients (96%) received a calcineurin inhibitor; all patients were given steroids and azathioprine or mycophenolate mofetil. At 1 yr, 60% of patients were on tripletherapy, 38% on bitherapy, and 2% on monotherapy; 20% had discontinued steroids. Results: Tolerance was excellent with no cases of anaphylaxis. The commonest adverse event was fever (55%). Eighteen patients developed serum sickness on median day 11 [10–14]. Seven patients had thrombocytopenia; six patients had severe neutropenia. All of these adverse events recovered spontaneously. The overall incidence of delayed graft function was 24%. At 1 yr patient and graft survival were 98 and 95%, respectively, and creatinine was 135 ± 43 μmol/L. Clinically suspected and biopsy-proven acute rejection were observed in 65 patients (27%) and 34 patients (14%), respectively. There were 62 non-cytomegalovirus (CMV) infections (two fatal) and 81 episodes of CMV infections. Eight malignancies were reported; two possibly related to immunosuppression. Conclusions: These results demonstrate that anti-thymocyte globulin has a safety profile with good tolerability and excellent efficacy.

Prediction of 3-yr cadaveric graft survival based on pre-transplant variables in a large national dataset.

Abstract: Pre- and post-transplant predictive factors of graft survival for optimal and expanded criteria grafts have been studied in the past. The goal of our study was to evaluate the recent large set of United Network of Organ Sharing records (1990-1998) to generate a prediction algorithm of 3-yr graft survival based on pre-transplant variables alone. The dataset of patients with end-stage renal disease and cadaveric kidney or kidney-pancreas transplantation (1990-1998) used in the study consisted of 37,407 records. Logistic regression (LM) and a tree-based model (TBM) were used to identify predictors of 3-yr allograft survival and to generate prediction algorithm. Donor and recipient demographic characteristics (age, race, and gender) and body mass index showed non-linear, while human leukocyte antigen match showed strong linear relationships with 3-yr graft survival. Prediction of the probability of graft survival from the model, achieved a good match with the observed survival of the separate dataset, with a correlation of r = 0.998 for LM and r = 0.984 for TBM. The positive predictive value (PV) of allograft survival with LM and TBM was 76.0% and the negative PV was 63 and 53.8% for LM and TBM, respectively. Both LM and the TBM can potentially be used in clinical practice for long-term prediction of kidney allograft survival based on pre-transplant variables.

Radiofrequency ablation causes 'thermal fixation' of hepatocellular carcinoma: a post-liver transplant histopathologic study.

Abstract: Radiofrequency ablation (RFA) is increasingly used to treat hepatocellular carcinoma (HCC) in patients awaiting a liver transplant. Despite its increasing use, detailed histologic information is scarce regarding the nature of RFA-treated lesions. We identified four chronic hepatitis C patients who had RFA of their HCC before their liver transplant. For these four patients, we conducted a detailed histopathologic analysis of the treated lesions in their explanted livers. The five lesions included immediate (4 d) and long-term (14 months) post-RFA specimens. Of the five lesions, four were completely ablated. The one incompletely ablated lesion was also treated with chemoembolization. In the acute post-RFA period, a zone of interstitial hemorrhage occurred at the outer boundary of the lesion. Differing from classic tissue necrosis, the treated lesions all showed 'thermal fixation', with preserved tissue architecture and microscopic cellular detail. The cellular staining characteristics faded with time, but the treated tissue became brittle, resisted tissue breakdown, and generated a minimal wound healing response. At the periphery of the lesion, the fibrous septae of the cirrhotic liver and vascular structures appeared to demarcate or limit progression of the ablation front. A narrow hypocellular fibrous boundary with a focal 'foreign body' giant cell-type reaction developed around the edge of the ablation zone. Thus, RFA can produce immediate and complete thermal fixation of select lesions with an appropriate liver margin and can provide a satisfactory treatment option for select HCC patients before a liver transplant.

The first report from the patient outcomes registry for transplant effects on life (PORTEL): differences in side-effects and quality of life by organ type, time since transplant and immunosuppressive regimens

Abstract: Hathaway D, Winsett R, Prendergast M, Subaiya I. The first report from the patient outcomes registry for transplant effects on life (PORTEL): differences in side-effects and quality of life by organ type, time since transplant and immunosuppressive regimens. Clin Transplant 2003: 17: 183-194. a Blackwell Munksgaard, 2003 Abstract: Background: Post-transplant patient quality of life (QOL) is affected by a number of different factors. A nationwide patient registry has been established to evaluate QOL and determine the effects of transplant and immunosuppressive regimens on patient outcomes. Methods: Patients were contacted directly at national meetings, through transplant centers, and patient support groups and invited to participate in the registry. All transplant patients aged 16 and over were eligible to enroll. Patients completed a 100-item self-administered questionnaire consisting of questions about patient demographics, organ functioning, and other post- transplant outcomes. General QOL was measured by the Short form - 12 (SF-12). The Memphis Survey, an instrument developed and psychometri- cally validated at the University of Tennessee, was administered to patients to evaluate side-effects associated with immunosuppression. Data were analyzed from the first 722 patients who entered the registry. Side-effect profile and QOL outcomes were evaluated by organ type, time since transplant and immunosuppressive regimen. Multiple regression analyses were conducted to determine predictors of post-transplant QOL. Results: When outcomes were analyzed by organ type, there were no dif- ferences in SF-12 or total weighted Memphis scores. Analysis by time since transplant demonstrated that side-effects in the mobility domain increased with patient age and time since transplant. Analysis by immunosuppressive regimen focused on cyclosporine and tacrolimus-based regimens congruent with similar classifications reported in previous studies (Pirsch JD et al. Transplantation 1997: 63: 977, Shield CF III et al. Transplantation 1997: 64: 1738). When analyzed by regimen, there were no differences between the groups in terms of patients reporting good to excellent organ function, treatment for rejection, infection, and over-immunosuppression. Statisti- cally significant differences were observed when side-effect profile was analyzed by immunosuppressive regimen. Patients on cyclosporine-based regimens reported greater overall side-effect severity and more problems with mobility and life roles. Cyclosporine patients also reported more problems in the miscellaneous subscale, including high blood pressure, enlarged gums and hair growth, but less trouble with trembling hands. Multiple stepwise regression models identified several side-effect subscales as having profound effects on mental and physical QOL.

Survival benefit of kidney and liver transplantation for obese patients on the waiting list.

Abstract: As in the general population of the United States, obesity has become a significant problem in transplantation. Patient survival after deceased donor kidney transplantation is significantly lower among obese recipients (body mass index [BMI] > or = 30 kg/m2) than among non-obese recipients. Survival also appears to be decreased among obese liver transplant recipients. Based on these findings, some authors have argued against kidney or liver transplantation in the morbidly obese. However, the survival benefit for patients listed for and receiving either a kidney or liver transplant is not well understood. To determine if a significant survival benefit exists for obese patients after transplantation versus those on the waiting list, we studied a retrospective cohort of patients identified in the Scientific Registry of Transplant Recipients database. Adjusted, time-dependent Cox regression models were used to evaluate the relative risk (RR) of death after transplantation compared with waiting list mortality for either kidney or liver transplantation. These results demonstrate that kidney transplantation offers a significant survival benefit and is the preferred therapy for most obese dialysis patients. Although liver transplant recipients with a BMI > or = 35 kg/m2 had an increased RR for mortality compared with other recipients with a lower BMI, all groups, regardless of BMI, demonstrated a significant transplant benefit. These data suggest obesity should not be a contraindication for transplantation.

Outcome of transplantation using kidneys from controlled (Maastricht category 3) non-heart-beating donors.

Abstract: Background: Many renal transplant centres are reluctant to use kidneys from non-heart-beating (NHB) donors because of the high incidence of primary non-function and delayed graft function reported in the literature. Here, we report our favourable experience of using kidneys from Maastricht category 3 donors (controlled NHB donors). Materials and methods: From January 1996 to June 2002, 42 renal transplants using kidneys from 25 controlled NHB donors were undertaken at our centre. The rates of primary non-function, delayed graft function (DGF), rejection and long-term graft and patient survival were compared with those of 84 recipients of grafts from heart-beating (HB donors) transplanted contemporaneously. Results: Primary non-function did not occur in recipients of grafts from NHB donors but was seen in two grafts from HB donors. DGF occurred in 21 of 42 (50%) kidneys from NHB donors and 14 of 84 (17%) kidneys from HBD donars (p < 0.001). The acute rejection rates in the two groups were similar (33% for grafts from NHB donors vs. 40% from HB donors). By 1 month after transplantation, there was no significant difference in serum creatinine concentration between the two groups. Over a median follow-up period of 32 months (range 2–75 months), the actuarial graft survival rates at 1, 3 and 5 yr after transplantation were 84, 80 and 74% for recipients of kidneys from NHB donors, compared with 89, 85 and 80% for kidneys from HB donors. Conclusion: Controlled NHB donors are a valuable and under-used source of kidneys for renal transplantation. The outcome for recipients of kidney allografts from category 3 NHB donors is similar to that seen in recipients of grafts from conventional HB cadaveric donors.

First human double hand transplantation: efficacy of a conventional immunosuppressive protocol.

Abstract: Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33-yr-old man suffering from a traumatic amputation of both hands in 1996. Five HLA-A, -B, and -DR mismatches were present with the donor; T and B cell cross-match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti-HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side-effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft-versus-host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.

Individualized T cell monitored administration of ATG versus OKT3 in steroid‐resistant kidney graft rejection

Abstract: Acute steroid-resistant rejection episodes are recommended to be treated with set doses of anti-thymocyte globulin (ATG) or anti-CD3 monoclonal antibody (OKT3). Individualized T cell monitoring has been proposed as a tool for dose finding. A randomized study comparing the efficacy and safety of ATG (n = 27) with OKT3 (n = 28) in the treatment of biopsy verified acute steroid-resistant rejection (ASRR) when both drugs were administered on the basis of daily individualized T cell measurements. A drop to below 50 cells/mm3 CD2+ T cells was considered adequate and used to guide the dose of ATG/OKT3. Demographic, clinical and histopathological severities of rejections were equal in the two groups. During the 10 days of T cell monitoring and antibody treatment, 13 patients were in need of dialysis (ATG = 7/OKT3 = 6). Two grafts did not respond to antibody treatment and were lost due to rejection (ATG = 1/OKT3 = 1). There were 26 biopsy verified re-rejections (ATG = 12/OKT3 = 14) within the first 3 months following antibody treatment. Mean serum creatinine (micromol/L) was similar in the two groups (ATG/OKT3: before rejection 157 +/- 72/151 +/- 88, at start of antibody treatment 308 +/- 125/330 +/- 94, end of antibody treatment 254 +/- 122/246 +/- 144 and at follow-up after a mean of 32 months 166 +/- 55 (n = 24)/164 +/- 57(n = 23)). To keep the T cell count below 50 cells/mm3, average dose ATG given was 354 +/- 151 mg (2.3 administrations, range 1-4) and average OKT3 was 32.5 +/- 6.8 mg in 10 doses. In conclusion, individualized T cell monitored administration of ATG and OKT3 is safe and seems as effective as a standard set dose in treatment of ASRR. Tailoring the dose for each individual patient lowers the cost.

Deduction of the fraction of immunologic and non-immunologic failure in cadaver donor transplants.

Abstract: We utilized the UNOS Registry graft survival records to determine the fraction of graft failures attributable to immunological or non-immunological factors. Ten-year graft survival of HLA-identical sibling donor grafts was 77% excluding deaths, diabetics, Black recipients, recipients older than age 50, and those who required post-transplant dialysis. With similar exclusions, 10 year graft survival from living HLA-mismatched donors was 66%. To account for the overall 60% graft failures at 10 years for all cadaver donors, we deduced that 38% of the failures were due to immunological reactions against non-HLA factors as seen in HLA-identical sibling grafts; 18% of failures were due to HLA factors, as seen in mismatched living donor grafts; and the remainder of 43% was attributable to non-immunological factors.

The effect of calcineurin inhibitors on endothelial function in renal transplant recipients.

Abstract: Endothelial dysfunction is of vital importance, as it may cause ischemia and dysfunction in various organs. Despite, this problem has been well documented in patients with end-stage renal disease (ESRD), there is not enough data considering this issue following renal transplantation. One of the potential causes of endothelial dysfunction in renal transplant recipients may be administration of calcineurin inhibitors. The aim of this study is to evaluate the effects of two different calcineurin inhibitors [cyclosporin A (CsA) and tacrolimus (FK506)] on endothelial function in renal transplant patients. Forty-four renal transplant recipients [22 on FK506 (group I) and 22 on CsA (group II)] were studied. Endothelial functions of the brachial artery were evaluated by using high resolution vascular ultrasound. Endothelium-dependent and -independent vasodilations were assessed by establishing reactive hyperemia and using sublingual nitroglycerine (NTG), respectively. Results are presented as percentage change from baseline values. Significant endothelial dysfunction was noted in renal transplant patients treated with CsA. While endothelium-dependent vasodilation was 12.1 +/- 5.1% in group I and it was 6.5 +/- 3.7% in group II (p 0.05). Post-transplant course of renal transplant recipients is complicated by endothelial dysfunction. This problem is more prominent in patients on CsA therapy, which can predispose these patients to more frequent cardiac complications.

Renal transplant recipient attitudes toward steroid use and steroid withdrawal

Abstract: Although steroid avoidance and withdrawal in renal transplant recipients (RTR) are actively being evaluated by physicians, the attitudes of recipients toward steroid use have not been systematically studied in the modern era. We conducted a confidential written survey of single-organ adult RTR pertaining to prednisone-related side-effects. Recipients were asked which drug they felt maximized graft life, which drug they wished to avoid if graft life was unaffected, and which drug they had most compliant with. They also rated 16 common immunosuppressive-related side-effects on a Likert scale with 1 meaning complete disagreement and 10 complete agreement with their own prednisone-attributed experience. A comparison of responses based on RTR demographic characteristics was made by ANOVA or chi-square analysis with Bonferroni correction. The questionnaire was completed by 223 recipients, of whom 93% were primary recipients, 57% were cadaveric organ recipients, and 69% were white people, 7% black people, and 23% Asian people. Age at transplant, age at survey and time since transplant were 41.5 +/- 11, 47.5 +/- 11 and 6.0 +/- 5 yr, respectively. For the entire group, overall side-effect profile for prednisone was rated as 6.1 +/- 3 on the Likert scale, while efficacy was rated as 7.3 +/- 3. If offered monotherapy, 67% preferred a calcineurin-inhibitor (CI), 23% mycophenolate mofetil (MMF)/azathioprine (AZA), and 10% prednisone. When asked which drug they would like to discontinue, 19% chose CI, 16% MMF/AZA, and 65% prednisone. Most recipients felt that CI was the most efficacious drug (80%), followed by MMF/AZA (12%), and prednisone (8%). The side-effects reported as most common were unacceptable weight gain (5.8 +/- 3) and bone/joint disease (5.3 +/- 3). The least common side-effects were blood disorders (2.2 +/- 2) and cancer (2.3 +/- 2). Black people were more likely than non-black people to report developing diabetes (p = 0.02), blood disorders (p = 0.003) and headaches (p = 0.003) as a result of prednisone use. Males reported more liver damage (p = 0.01) while females reported more body fat (p = 0.01) and fluid retention (p = 0.006). RTR >5 yr post-transplant reported more infections (p = 0.008), skin/hair problems (p = 0.02), gastrointestinal irritation (p = 0.02), and bone disease (p = 0.02) compared with RTR <1 yr. Donor source and recipient age did not determine any responses. If given a 'risk-free' choice, the majority of recipients prefer withdrawal of steroids over other agents. Demographic data may be used to predict prednisone-related side-effects and guide steroid use in this population. Study designs related to steroid withdrawal should account for patient preferences in this context.

The use of an anti-CD25 monoclonal antibody and mycophenolate mofetil enables the use of a low-dose tacrolimus and early withdrawal of steroids in renal transplant recipients

Abstract: : Background: Reducing calcineurin-inhibitor-induced nephrotoxicity and simultaneously avoiding long-term steroid related side-effects is a desirable goal in renal transplantation. We examined the hypothesis that using anti-CD25 monoclonal antibody induction and mycophenolate mofetil (MMF) would allow the lowering of target pre-dose blood concentrations of tacrolimus immediately after transplantation and subsequently stopping steroids at 5 months. Methods: Eighty-two kidney recipients were enrolled in a single-center study comparing two tacrolimus-based protocols. Group I (n = 41) patients received a standard-dose tacrolimus (blood concentration 10–15 ng/mL) with MMF and a standard dose corticosteroid. Group II (n = 41) patients were treated with a low-dose tacrolimus (blood concentration 5–10 ng/mL) and MMF, a low-dose corticosteroid (stopped after 5 months) and induction with daclizumab. Results: Patient (95.1 versus 100%) and graft survival (92.6 versus 97.5%) at 1 yr were not different between groups. Patients of group II experienced significantly less acute rejections than group I (17.1 versus 41.4% p = 0.03). Delayed graft function occurred less often in group II (5 versus 12% p = 0.43). Graft function at 1 yr was significantly better in group II (serum creatinine 1.49 versus 1.69 mg/dL and creatinine clearance 59.6 versus 49 mL/min; p < 0.05). Corticosteroids could be stopped after 5 months in 82.9% of group II patients. Conclusion: A regimen consisting of anti-CD25 monoclonal antibody induction and MMF allows the safe and efficient use of low-target pre-dose trough concentrations of tacrolimus and enables the early discontinuation of steroids. Preliminary results indicate a better 1-yr graft function compared to a normal-dose tacrolimus regimen.

Acute pancreatitis following kidney transplantation - role of viral infections.

Abstract: Acute pancreatitis following renal transplantation is an unusual complication that carries a high mortality. Over the last 10 yr, five of 185 patients at our center developed acute pancreatitis. All had live related donors and were on conventional triple drug immunosuppression. Pancreatitis was classified according to the computed tomography scan based on Atlanta Classification. All five patients who developed acute pancreatitis had evidence of symptomatic or serologically active viral infection (chicken pox in two, cytomegalovirus infection in two, hepatitis E virus in one) and no patient without viral infection developed pancreatitis. Overall, 45 patients developed symptomatic or serologically active viral infection. There was a significant association between viral infection and pancreatitis (chi-square test, p < 0.001). Three patients with severe acute pancreatitis died while both patients with mild pancreatitis survived. An active search for viral infections should be made in all patients with acute pancreatitis. Specific antiviral measures may help reduce the mortality of acute pancreatitis in these patients. Consideration must be given to varicella immunization in patients with renal failure.

Neuropsychologic side‐effects of tacrolimus in pediatric renal transplantation

Abstract: Calcineurin inhibition with tacrolimus has been used after renal transplantation (RTPL) as rescue therapy for insufficient immunological control or if cyclosporin A (CSA) toxicity occurred. Neurologic side-effects occur but are rare in children, usually presenting as tremor; however, serious complications, e.g. the posterior leukoencephalopathy syndrome are also documented. Twenty children (10 girls) were switched to tacrolimus: 11 (55%) for immunological reasons (n = 9: steroid-resistant rejection; n = 2: recurrent rejections) and nine for CSA side-effects. Tacrolimus was started at a median of 8 wk (range 10 d to 8.7 yr) after RTPL and was continued for a median of 2.5 yr (range 5 wk to 4.6 yr). Renal function significantly improved over a period of 12 months following conversion to tacrolimus (glomerular filtration rate 56 +/- 19 vs. 66 +/- 16 mL/min/1.73 m2; p < 0.03; n = 13). Fifteen of 20 (75%) patients tolerated tacrolimus well. The most frequent side-effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms with weight loss, amenorrhea, depression and school problems to severe insomnia and to aggressive and anxious behavior in one child. Only the latter child was exposed to toxic tacrolimus blood levels. All side-effects were fully reversible after discontinuation of tacrolimus. In conclusion, tacrolimus had a beneficial effect on renal function and was well tolerated in the majority of pediatric patients. However, neuropsychologic and behavioral side-effects are important and maybe underrecognized in children.

Pre-transplant Th1 and post-transplant Th2 cytokine patterns are associated with early acute rejection in renal transplant recipients.

Abstract: In this retrospective study, we tried to define pre- and post-transplant immunological parameters that identify patients at risk for early acute rejection. Lymphocyte subpopulations and plasma levels of cytokines and neopterin were determined pre- and post-transplant in 32 renal transplant recipients with biopsy-proven early acute graft rejection. Recipients without early acute rejection served as controls. High pre-transplant interferon-gamma (IFN-gamma) plasma levels (p = 0.006), consistently high levels of neopterin early post-transplant (p = 0.008), a post-transplant switch from a Th1 to a Th2 cytokine pattern with decreasing IFN-gamma (p = 0.02), low CD8+ lymphocyte counts (p = 0.006) and consistently high CD19+ B lymphocyte counts were associated with acute rejection. Our data suggest that patients with a pre-transplant Th1 and an early post-transplant Th2 cytokine pattern are pre-disposed for early acute rejection.

Morphological and biochemical effects of immunosuppressive drugs in a capillary tube assay for endothelial dysfunction.

Abstract: Immunosuppressive drugs common in clinical transplantation are known to have untoward effects on the vascular system. The effects of some drugs, notably cyclosporin A (CyA), have been studied on the vascular system, whilethose of others have not. In the vascular system, endothelial cells are the predominant cell type exposed to intravascular concentrations of immunosuppressive drugs. We therefore studied the effects of drugs common in clinical transplantation on endothelial cells in a capillary tube assay. The endothelial cells in the capillary tubes are morphologically more similar to those in the microvasculature than endothelial cells in monolayers. We studied the kinetics and extent of capillary tube formation and prostacyclin (PGI 2 ) and endothelin-1 (ET-1) release from the in vitro capillaries to determine the morphological and biochemical effects of five immunosuppressive agents on endothelial function. We found a significant difference in the morphological and biochemical effects of the two common calcineurin inhibitors, CyA and tacrolimus (FK506) on capillary morphology in vitro. The former had a pronounced injurious effect on the morphology of the in vitro capillaries, while the latter did not. CyA also significantly increased ET-1 release by the capillaries, but FK506 did not. Mycophenolate mofetil (MMF) was the only other agent that had a moderately injurious effect on the morphology of the in vitro capillaries. Sirolimus (rapamycin) and dexamethasone. similar to FK506, had no effect on the capillary morphology. All these agents, except dexamethasone. increased PGI 2 release. Our data suggest that CyA adversely affects the morphology of the microvasculature and that this is mediated, at least partly, by an increased ET-1 release by endothelial cells exposed to CyA. These findings describe a novel effect of CyA and MMF on endothelial cells that could be relevant to understanding the mechanisms of immunosuppressive drug-mediated endothelial injury in clinical transplantation.

A pilot protocol of a calcineurin-inhibitor free regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function.

Abstract: Background: The worsening shortage of cadaver donor kidneys has prompted use of expanded or marginal donor kidneys (MDK), i.e. older age or donor history of hypertension or diabetes. MDK may be especially susceptible to calcineurin-inhibitor (CI) mediated vasoconstriction and nephrotoxicity. Similarly, early use of CI in patients with delayed graft function may prolong ischaemic injury. We developed a CI-free protocol of antibody induction, sirolimus, mycophenolate mofetil, and prednisone in recipients with MDK or DGF. Methods: Adult renal transplant recipients who received MDK or had DGF were treated with a CI-free protocol consisting of antibody induction (basiliximab or thymoglobulin), sirolimus, mycophenolate mofetil, and prednisone. Serial biopsies were performed for persistent DGF. Patients were followed prospectively with the primary endpoints being patient and graft survival, biopsy-proven acute rejection, and sirolimus-related toxicity. Results: Nineteen recipients were treated. Mean follow-up was 294 days. Actuarial 6- and 12-month patient survival was 100% and 100% and graft survival was 93% and 93%, respectively. The only graft loss was due to primary non-function (PNF). The incidence of AR was 16%. Mean serum creatinine at last follow-up was 1.6 mg/dL. Sirolimus-related toxicity included lymphocele (1), wound infection (2), thrombocytopenia (1) and interstitial pneumonitis (1). Conclusion: A CI-free protocol with antibody induction and sirolimus results in low rates of AR and PNF and excellent early patient and graft survival in patients with MDK and DGF. CI-free protocols may allow expansion of the kidney donor pool by encouraging utilization of MDK at high risk for DGF or CI-mediated nephrotoxicity.

Technique of bile duct reconstruction and management of biliary complications in right lobe living donor liver transplantation.

Abstract: From December 1999 to January 2002, 50 right lobe living donor liver transplantations were performed. The donor operations included an intraoperative cholangiography to elicit variations in bile duct anatomy. The biliary reconstruction was done whenever possible as an end-to-end microanastomosis of the donor right hepatic duct with the recipient's bile duct. As a result of the early segmental branching of the donor biliary tree, two segment bile ducts had to be anastomosed in 20 patients and three segment bile ducts in three patients. In 12 patients, a Roux-en-Y hepaticojejunostomy was performed. All anastomoses were drained externally. We observed two leakages at the resection surface which could be treated successfully by an external drainage. Six leaks occurred at the site of end-to-end biliary anastomoses. Twice the problem could be conservatively solved placing a stent percutaneously. In two patients a hepaticojejunostomy was performed after a bile duct necrosis. In two patients with an anastomotic leak, occurring 3 d, respectively, 3 month after the original transplantation, the bile duct could be directly reconstructed over a T-tube. Two anastomotic stenoses were observed, one in combination with a leak treated by percutaneous stent implantation and the second, 3 month after transplantation which was treated surgically. Biliary reconstruction after living donor liver transplantation requires microsurgical techniques and can be performed as a direct end-to-end anastomosis in most cases. Biliary complications were treated by percutaneous drainage or surgical revision in all cases.

Steroid-free immunosuppression during and after liver transplantation--a 3-yr follow-up report.

Abstract: Background/aims: Steroids are traditionally used in liver transplantation as a part of a triple or quadruple immunosuppressive regimen. Steroids act non-specifically and cause multiple side-effects. Most liver transplantation centers reduce the dosage of steroids and eventually withdraw them after various time intervals. A few steroid-free trials have been recently conducted after liver transplantation but long-term data are not yet available. In addition, in these trials steroids were usually given during surgery. We report the long-term (median = 40 months) follow-up data of a prospective pilot study designed to determine whether liver transplantation could be performed with no steroids at all (neither during nor after surgery). Methods: Twenty-one consecutive liver transplantations in 20 adult patients between August 1998 and July 1999 were prospectively included in an ab initio steroid-free immunosuppressive protocol. Mean age was 54 yr (40–67 yr). Tacrolimus (through levels, 8–10 ng/mL) and azathioprine (1–2 mg/kg) were started after liver transplantation. Patients were not given steroids during or after liver transplantation except in the event of rejection or in case of tacrolimus or azathioprine toxicity requiring significant dose reduction and/or withdrawal. Results: There has been no case of primary graft dysfunction or non-function. Eleven of 21 liver transplantations (52%) received no steroids throughout the whole study. Rejection developed in five of 21 liver transplantations (23.5%). These rejections responded to standard i.v. steroids (plus ATG in one patient), followed by an oral steroid taper stopped 3 months after rejection. Steroids were transiently given in six liver transplantations for non-immune reasons: two with tacrolimus-induced neurotoxicity, three cases where azathioprine was discontinued, and one for an allergic reaction; four of these six patients are off steroids at last follow-up. The 3-yr graft and patient survival is 95 and 100%, respectively. Conclusions: Steroids are not necessary in more than 50% of liver transplantations. Steroids were transiently needed to treat acute rejection in 23.5% liver transplantations and for toxicity of calcineurin inhibitors or azathioprine or other reason in 28%. Of the patients who received steroids, the majority (70%) was eventually taken off steroids. This prospective single-center pilot study shows that liver transplantation without steroids is feasible and yields no penalty in terms of acute and chronic rejection, immune graft loss, graft function, patient and graft survival.