H. J. Schlitt

Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss.

BACKGROUND Although most transplanted patients with underlying IgA nephropathy (IgAN) develop histological recurrence, its clinical relevance is considered low. METHODS We performed a single-center analysis of 61 renal transplant patients with IgAN. RESULTS Forty-four percent of the patients showed a stable graft function. Progressive graft dysfunction apparently due to recurrent IgAN occurred in 23% of the patients (16% required dialysis). Five patients were retransplanted, and three again developed dialysis-dependent renal failure apparently due to recurrent IgAN. In 20% of the patients, chronic transplant dysfunction was due to other reasons, whereas no reason was identified in 13% of the patients. Neither findings before transplantation, the ACE genotype, the type of immunosuppression, nor the course after transplantation predicted transplant dysfunction due to recurrent IgAN. Follow-up after transplantation was longer in the group with dysfunction due to recurrent disease than in the group with dysfunction due to chronic rejection or in the stable group. CONCLUSION Recurrent IgAN is a clinically relevant problem in renal transplant patients. Its importance may have been underestimated in the past due to inadequate lengths of follow-up.

Ex-vivo resection techniques in tissue-preserving surgery for liver malignancies

Abstract Some primary and secondary liver tumours are not absolutely irresectable, but cannot be resected using a conventional approach because of the limited warm ischaemia tolerance of the liver or poor accessibility of the tumour region. In such situations, the techniques of ex vivo liver surgery, pioneered by Rudolf Pichlmayr some 10 years ago, offer new chances for R0 resection. All the three different approaches, namely ”in situ”-, ”ante situm”-, and ”ex situ” resection, require the use of measures originally developed for transplantation, such as hypothermic liver perfusion and veno-venous bypass. They differ mainly in the extent to which major vessels are divided in order to achieve optimal mobility of the organ. The results show that radical resection can be achieved accomplished in many cases. If necessary, complex vascular reconstructions can be performed. Although perioperative morbidity and mortality are high, there are a number of long-term survivors. Tumour recurrence, however, remains the main problem over the long term. In conclusion, ex vivo liver surgery is an important extension of surgical treatment possibilities. However, the procedure is suitable only for a small number of carefully selected patients and should be reserved for use in specialised centres. Furthermore, in view of the fact that the results are not yet optimal, additive and adjuvant treatment modalities are needed.

Renal transplantation for patients with autoimmune diseases: single-center experience with 42 patients.

BACKGROUND In patients with autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE), end-stage renal disease develops in a high percentage of patients, and kidney transplantation has become a therapeutic option. However, only limited data about the prognosis and outcome after kidney transplantation are available. METHODS Long-term graft survival and graft function of renal transplant recipients with SLE, Wegeners granulomatosis, microscopic polyangiitis, Goodpastures syndrome, and Henoch-Schonlein purpura were evaluated in a single center. In addition, the incidence of renal and extrarenal relapses and the impact of the immunosuppressive therapy on the course of the autoimmune disease were studied. RESULTS Renal transplant recipients with autoimmune diseases such as vasculitis and SLE had a patient survival rate (94% after 5 years) and a graft survival rate (65% after 5 years) comparable to those of patients with other causes of end-stage renal disease (patient survival 88% and graft survival 71% after 5 years). Graft losses due to the underlying disease were rare. Extrarenal relapses occurred in three patients with Wegeners granulomatosis, one patient with microscopic polyangiitis, and three patients with SLE, but were less frequent compared with the period with chronic dialysis therapy. Autoantibody levels in patients with SLE, Wegeners granulomatosis, or microscopic polyangiitis did not seem to influence the outcome. CONCLUSIONS Renal transplantation should be offered to patients with autoimmune diseases. Follow-up should include the short-term control of renal and extrarenal disease activity.

Immunoprophylaxis with a monoclonal anti-IL-2 receptor antibody in liver transplant patients.

The immunosuppressive effect of a monoclonal antibody (moAb), BT563, directed to the alpha-chain of the IL-2R (CD25), was analyzed in a prospective nonrandomized trial and a prospective randomized trial. Primary objectives were evaluation of the incidence of acute rejections and infections; secondary objectives were safety and tolerability of the moAb. A total of 28 patients were enrolled (phase II) to receive 10 mg/day of BT563 (12 days) as immunoprophylaxis in combination with cyclosporine, azathioprine, and low-dose steroids. Subsequently 32 patients were randomly assigned (phase III) to receive BT563 (10 mg/day) for 12 days or ATG (5 mg/kg/day) for 7 days in addition to cyclosporine and low-dose steroids. No side effects of the BT563 treatment were noted. The actuarial survival was 82% at 12 months in the phase II trial and 92% at 12 months in both arms of the phase III trial. There was one acute rejection in the phase II trial. No acute rejections were noted in the BT arm of the phase III trial and 5 acute rejections were treated in the ATG arm. In the phase II trial 7 infectious episodes were observed, while one infection was seen in the BT arm and 7 in the ATG arm of the triple immunosuppression phase III trial. In all patients circulation of coated CD25+ lymphocytes was observed during BT563 treatment; there was no evidence of depletion or modulation of CD25+ cells. Mean serum levels of BT563 ranged from 1.6 to 7.6 microgram/ml throughout the therapy. An antimurine response was seen in 82% (phase II) and 100% (phase III) of the patients. Antirabbit antibodies were found in 56% of the patients treated with ATG. Analysis of the antimurine response specificity revealed in 56% blocking anti-isotypic antibodies and only in 3% of the patients an anti-idiotypic response. The data of the study presented suggest that therapy with an anti IL-2R moAb is at least equal to ATG application according to the incidence of acute rejections and infections.

Attitude of patients toward transplantation of xenogeneic organs

Abstract Background: The prospect of xenotransplantation has stimulated considerable hopes as well as major concerns. The question of whether or not patients accept xenografts is influenced not only by scientific facts but also by psychological factors. It was the aim of this study to analyze the attitudes of patients toward transplantation of xenogeneic organs and evaluate factors influencing these attitudes. Methods: To this end, attitudes toward xenogeneic compared with allogeneic organ grafts were evaluated by means of detailed questionnaires in 1049 patients in Germany, who either had received transplants (n=722) or were on the waiting list for various organ grafts (n=327). Answers were correlated to demographic data as well as to the physical and mental conditions of the patients. Results: The survey indicates that 77% of patients would accept xenografts while 7% would refuse them if results of xenotransplantation were comparable with those of allotransplantation. If xenotransplantation were associated with increased risks due to more intensive medication 58% would still basically accept xenografts. Acceptance of xenografts was significantly higher in patients who had received transplants and among males. Age, religion, waiting time, and type of organ were not found to influence acceptance rates. Xenografts were thought to be associated with considerable or severe emotional stress by 23% of patients, versus 3% for allografts. The pig was the preferred donor animal, and gene therapeutic manipulation for improvement of results would be accepted by 84%. Inadequate graft function/increased risk of rejection and risk of disease transmission were the major concerns for 60% and 52% of patients, respectively; emotional concerns were the major concerns for 24% and animal-rights concerns for 15%. Conclusions: These findings show that the potential acceptance rate of xenografts would be quite high, with a more positive attitude in transplanted patients than in waiting-list patients; there was no major difference in acceptance rate for various types of organs. Major concerns about xenotransplantation currently are functional inferiority and transmission of diseases.

Total hepatectomy and liver transplantation for metastatic neuroendocrine tumors of the pancreas - a single center experience with ten patients.

Abstract  Background: Metastatic neuroendocrine pancreatic tumors have a poor prognosis. We have studied retrospectively the efficacy of liver transplantation as ultimate therapy of otherwise untreatable symptomatic neuroendocrine hepatic metastases originating in the pancreas. Methods: We reviewed our experience of liver transplantation (LTx) for hepatic metastases of neuroendocrine pancreatic tumors in ten patients. The indication for liver grafting was seen in cases of irresectable metastases and when patients were suffering from otherwise untreatable tumor-associated symptoms due to massive hormonal release or large intra-abdominal tumor bulk. Results: In four patients, the primary tumors had been removed before LTx, in five patients simultaneously with LTx and in one case 46 months after grafting. There was no operative mortality. After hepatectomy and LTx, all patients had complete relief of symptoms and all preoperatively increased hormonal levels returned to normal. In nine of ten patients, the transplant procedure had the potential for cure, whereas, in one patient, the primary tumor had remained in situ at LTx and was removed 46 months later by an R2-resection. At present, nine patients are alive with a median follow-up of 33 months (range 13.5 months to 117 months). The one patient in whom the primary tumor was removed after transplantation died due to massive intra-abdominal tumor spread 68 months after LTx. Currently, two patients are without evidence of disease, but one of them after re-operation because of lymph-node metastases 8 months after transplantation. The longest disease-free survival is now more than 7 years. In seven of nine patients, tumor recurred between 1.5 months and 48 months after transplantation. Conclusions: Patients with otherwise untreatable symptomatic neuroendocrine hepatic metastases of pancreatic origin may benefit from total hepatectomy and liver transplantation with regard to symptomatic relief and long-term survival, despite frequent recurrence of disease. In some patients, liver transplantation may even offer the chance for cure.

Development of microchimerism in pediatric patients after living-related liver transplantation

Microchimerism has been suggested to play an important role in the long-term acceptance of allogeneic organ grafts by transplant patients and for the maintenance of a state of donor-specific low responsiveness. In order to elucidate the kinetics of the development of chimerism we have performed a follow-up analysis in 10 pediatric patients with living-related liver transplantation (LRLTx). Blood samples obtained during the first 6 months and at 18 months post-transplant and skin biopsies taken at one month were analysed for the presence of donor cells by PCR using donor-specific HLA-DRB1 primer pairs or primers for a Y chromosome-specific sequence. Furthermore 13 long-term patients more than 2 yr after LRLTx were studied at two different time points. In the follow-up studies donor cells could be demonstrated in the blood of all patients immediately after transplantation. After a gradual decline all patients became chimerism-negative for several weeks or months. At 6 months, however, in five of eight patients tested and at 18 months in six of nine patients donor cells had reappeared. This biphasic pattern in the development of chimerism is proposed to reflect the occurrence of different donor-derived cell populations in the recipient. The population giving rise to the first wave of chimerism probably represents matured cells with a limited lifespan which are released from the graft into the circulation of the recipient during the first weeks after transplantation. The population of cells occurring with the second wave of chimerism is likely to have been generated by donor-derived cells with stem cell potential located either in the graft or in the hematopoetic organs of the recipient after emigration from the graft. This model may be able to explain fluctuations in the incidence and degree of microchimerism described in other patient populations during the first year post-transplant. Of the 13 long-term patients, chimerism could be demonstrated in 11. In seven patients it was detected in both blood and skin, in three patients the results obtained for blood and skin were discordant. In one patient only blood was analysed. It is not clear whether the negative results really reflected the absence of chimerism or whether the number of donor cells was below the level of detectability.

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation

Mutations within the low density lipoprotein (LDL)‐receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL‐receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL‐apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL‐receptor gene. Clinical follow‐up for almost nine yr post‐transplantation revealed excellent liver function, normal liver enzymes, normal LDL‐cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL‐cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL‐receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.

Immunological effects of the anti-IL-2 receptor monoclonal antibody BT 563 in liver allografted patients

The immunological effects of therapeutic monoclonal antibodies (mAbs) depend upon their interaction with the target structure as well as the isotype of the mAb which is responsible for the binding to Fc receptors of accessory cells. The aim of the presented analysis was the evaluation of the in vivo immunosuppressive effect of BT 563, a mAb directed to the alpha-chain of the interleukin-2 receptor (IL-2R). Thirty-eight patients following liver transplantation were treated prophylactically for 12 days with 10 mg/day BT 563 (clinical phase II and III study). As baseline immunosuppression cyclosporin (CyA) and low dose steroids were administered. BT 563 levels, lymphocyte subpopulations, levels of soluble CD25 and Fc receptor polymorphism were evaluated and compared to the clinical outcome. Preoperatively in all patients a small subset of CD45R0+ cells expressed CD25 with detectable density. These cells were coated by BT 563. There was no evidence for depletion of IL-2R+ cells or modulation of the IL-2R. During therapy stable levels of the soluble IL-2R were measured in patient sera. Throughout the therapy high levels of unbound BT 563 were found in sera, suggesting that IL-2R newly expressed on cells activated by the allograft could also be inhibited by BT 563. No acute rejections were observed in these patients and no side effects of BT 563 were noted. There were only minor bacterial infections, while mycotic or viral infections did not appear. Administration of BT 563 together with CyA and low dose steroids to liver allografted patients represents a safe and effective protocol. Its action is likely to be mediated by turning off the pathway of signal transduction of the IL-2R in T-cells by the antibody while IL-2 gene transcription is simultaneously modified by CyA and steroids. The addition of all three immunosuppressive mechanisms is suggested to lead to a state of anergy during mAb application that is reversible at the end of antibody therapy but does not lead to rebound rejections. Analysis of the phenotype of CD25+ cells showed that they preferentially belonged to the CD45R0+ cell type. Thus we assume that BT 563 specifically turns off preactivated cells enabling rather selective and effective immunoprophylaxis in liver allografted patients.

INDIKATIONSSTELLUNG ZUR LEBERTRANSPLANTATION BEI SCHWERER KNOLLENBLATTERPILZVERGIFTUNG

Summary. The clinical course of 12 patients with mushroom poisoning was evaluated in order to define the parameters considered to be relevant to the indication for liver transplantation. Eight patients recovered under conservative therapy; one patient died due to pre-existing, concomitant cardiopulmonary disease. In three patients transplantations had to be performed because of severe liver failure. On admission, the transplanted patients had a decreased Quicks test score and factor V value (< 10 %). The peak of liver enzymes, serum bilirubin, serum creatinine, partial thromboplastin time and azotemia were not of any prognostic value. Main indications for liver transplantation were a very low initial Quicks test score and factor V value (both < 10 %) and their inadequate response under substitution therapy. The development of encephalopathy and renal failure were further parameters indicating poor prognosis.Zusammenfassung. Der Verlauf von 12 Patienten mit Knollenblätterpilzvergiftung wurde retrospektiv analysiert, um prognostische Kriterien für die Indikationsstellung zur Lebertransplantation herauszuarbeiten. Acht Patienten erholten sich unter konservativer Therapie, bei 3 Patienten war eine Lebertransplantation erforderlich; ein Patient starb bei Vorliegen schwerer Begleiterkrankungen unter konservativer Therapie. Die transplantierten Patienten wiesen initial einen Quick- und Faktor-V-Wert unter 10 % auf. Die Höhe der Transaminasen, des Serumbilirubins, des Serumkreatinins, eine Verlängerung der PTT sowie eine Azotämie hatten keinen sicheren prognostischen Wert. Für die Indikationsstellung zur Transplantation war der initiale Quick- und Faktor-V-Wert und deren inadäquater Anstieg unter Substitution entscheidend. Die Ausbildung einer Encephalopathie sowie ein progredientes Nierenversagen stellen zusätzliche prognostisch schlechte Parameter dar.Schlüsselwörter: Knollenblätterpilzvergiftung – Lebertransplantation – fulminantes Leberversagen.