Transplant nephrectomy after graft failure: is it so risky? Impact on morbidity, mortality and alloimmunization.

PURPOSE: To determine the impact of transplant nephrectomy on morbidity and mortality and HLA immunization. METHODS: All patients who underwent transplant nephrectomy in our centre between 2000 and 2016 were included in this study. A total of 2822 renal transplantations and 180 transplant nephrectomies were performed during this period. RESULTS: The indications for transplant nephrectomy were graft intolerance syndrome: 47.2%, sepsis: 22.2%, vascular thrombosis: 15.5%, tumour: 8.3% and other 6.8%. Transplant nephrectomies were performed via an intracapsular approach in 61.7% of cases. The blood transfusion rate was 50%, the morbidity rate was 38% and the mortality rate was 3%. Transplant nephrectomies more than 12 months after renal transplant failure were associated with more complications (p = 0.006). Transfusions in the context of transplant nephrectomy had no significant impact on alloimmunization. CONCLUSION: The risk of bleeding, and therefore of transfusion, constitutes the major challenge of this surgery in patients eligible for retransplantation. Even if transfusions in this context of transplant nephrectomy had no significant impact on alloimmunization, this high-risk surgery, whenever possible, must be performed electively in a well-prepared patient.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

De novo kidney graft tumors: results from a multicentric retrospective national study.

De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients.

Sotrastaurin, a novel protein-kinase-C inhibitor, blocks early T-cell activation. In this 12-month, Phase II study, de novo renal-transplant patients were randomized to sotrastaurin (200 mg b.i.d.) + standard-exposure tacrolimus (SET) or reduced-exposure tacrolimus (RET) (SET: n = 76; RET: n = 66), or control (SET + mycophenolic acid [MPA, 720 mg b.i.d.]; n = 74). In both sotrastaurin groups, patients were converted from tacrolimus to MPA after Month 3, achieving calcineurin inhibitor-free immunosuppression. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up). The key secondary endpoint was glomerular filtration rate (GFR). Composite efficacy failure rates were: 4.1%, 5.4% and 1.5% at Month 3 (preconversion) and 7.8%, 44.8% and 34.1% at study end in the control, sotrastaurin + SET and sotrastaurin + RET groups, respectively; these results led to premature study discontinuation. Median GFR at Month 6 was: 57.0, 53.0 and 60.0 mL/min/1.73 m(2), respectively. Study-drug discontinuations due to adverse events occurred in 16.2%, 18.4% and 12.1%, respectively. Leukopenia and neutropenia occurred more frequently preconversion in control versus sotrastaurin groups: 13.7%, 5.6%, and 4.6%; and 11.1%, 4.3% and 3.1%, respectively. The initial sotrastaurin + tacrolimus regimen was efficacious and well tolerated but the postconversion sotrastaurin + MPA regimen showed inadequate efficacy. Longer-term evaluation of sotrastaurin + tacrolimus is warranted.

Chronic lymphocytic leukemia: a hazardous condition before kidney transplantation.

Long-term survival of patients with chronic lymphocytic leukemia (CLL) is over 10 years, and such patients are thus potential kidney recipients in the case of superimposed end-stage renal disease. However, the renal and patient outcome in this condition is unknown. We report the charts of four patients with CLL who were engrafted in France with a deceased-donor kidney and underwent routine triple immunosuppressive therapy. The results show that these patients developed severe infectious episodes (fatal in one case) and tumoral complications including rapid progression of CLL in two cases. Moreover, the graft may be infiltrated and damaged by monoclonal B cells: one patient lost his graft 14 months after transplantation. Various therapeutic options (modifications of the immunosuppressive regimen, anti-CD20 antibodies, irradiation of the graft) showed little (if any) efficacy. Therefore, we believe that CLL is a too hazardous condition to envisage solid organ transplantation with a routine immunosuppressive regimen, and we propose a more appropriate approach.

[Viruses involved in allograft recipients'cutaneous carcinomas]. / Virus impliqués dans les carcinomes cutanés des greffés rénaux.

BACKGROUND: Cutaneous carcinomas are frequent in renal allograft recipients. Their treatment can be difficult especially in cases of multiple carcinomas. The aim of this study was to determine whether human papillomavirus are more frequent in patients group with multiple cutaneous carcinomas and whether other viruses such as Epstein-Barr virus, cytomegalovirus, and herpes simplex might be associated in this kind of tumour. PATIENTS AND METHODS: Forty-three patients were included. Twenty-two had a single carcinoma (group 1) and 21 had multiple cutaneous carcinomas (group 2). Histologic analysis and in situ hybridization were used to search for Epstein-Barr virus, human papillomavirus, herpes simplex virus and cytomegalovirus latency genes. RESULTS: In both groups, epidermoid carcinomas were more frequent than basal cell carcinomas and delay between graft and first carcinoma was similar (5 years). In situ hybridization was more often positive in group 2 (41/50) than in group 1 (13/22). Human papillomavirus DNA was detected more frequently in the group with multiple carcinomas (26/50) than in the group with a single carcinoma (6/22). Moreover, cytomegalovirus was more frequent in group 2. CONCLUSION: This study shows a higher prevalence of human papillomavirus DNA in the carcinomas of the multiple carcinoma population. Moreover, for the first time, cytomegalovirus DNA was detected in carcinomas of renal allograft recipients with a higher frequency in the patients with multiple carcinomas.

Clinical features and contribution of virological findings to the management of Kaposi sarcoma in organ-allograft recipients.

OBJECTIVES: To describe the clinical features of Kaposi sarcoma (KS) in organ-allograft recipients and to determine the contribution of human herpesvirus 8 (HHV-8) investigations to the management of KS. DESIGN, SETTING, AND PATIENTS: We examined 20 organ-allograft recipients with KS at Pitié-Salpêtrière Hospital, Paris, France, between November 1, 1991, and May 31, 1999. METHODS: We detected HHV-8 antibodies using an indirect immunofluorescence assay and the HHV-8 DNA genome using nonnested polymerase chain reaction with KS-associated herpesvirus 330(233) primers in peripheral blood mononuclear cells collected at transplantation and KS diagnosis. We detected the HHV-8 genome in involved and uninvolved tissue specimens and in 10 patients' serum samples collected 1 month before the first manifestation of KS. We determined the HHV-8 double-strand DNA sequence and subtypes of open reading frame 26. INTERVENTION: Management of KS consisted of progressively tapering immunosuppressive therapy regardless of KS dissemination. Associated infections were treated when possible. Chemotherapy was prescribed only when a functional disability persisted, and polychemotherapy was prescribed for life-threatening disease. MAIN OUTCOME MEASURES: Percentage of recipients with KS remission and stabilization, organ-graft survival, and death rates. RESULTS: Remission of KS was obtained in 9 (45%) of the 20 patients independently of disease dissemination, with a mean follow-up of 35 months. The kidney graft survived in 12 (67%) of the 18 patients. Only 1 patient (5%) died of KS progression. All allograft recipients had anti-HHV-8 antibodies before transplantation. We detected HHV-8 DNA in all involved tissue samples but not in serum samples 1 month before KS onset. The most prevalent subtype was HHV-8 C (9 [53%] of 17 patients) and was not associated with extradermatological extension of KS compared with subtypes A and B'. CONCLUSIONS: Virological investigations of HHV-8 contribute poorly to KS management. Prospective studies are needed to determine the role of HHV-8 virological investigations and to identify associated cofactors so as to prevent KS in organ-allograft recipients.

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.

Interaction of anti-HLA antibodies with pig xenoantigens.

BACKGROUND: Many patients with renal failure are condemned to long-term dialysis with little prospect of transplantation because they are highly sensitized with immunoglobulin G (IgG) directed against class I human leukocyte antigens (HLA) of virtually all donors. Xenotransplantation could represent an attractive solution providing their alloantibodies (alloAb) do not recognize porcine motifs. Hitherto there has been no in vivo demonstration of any cross-reactivity and the objective of this work was to investigate this problem using a technique of extracorporeal pig kidney perfusion as a model of clinical xenografting. METHODS: Pig kidneys were perfused ex vivo with plasma from both a group of highly sensitized patients and healthy individuals. Sequential plasma samples were analyzed for the titer of anti-Galalpha1-3Gal antibody (Ab) (major natural xenoreactive Ab) by enzyme-linked immunosorbent assay and anti-HLA class I Ab against a cell panel. At the end of perfusion, kidneys were perfused with a citric acid buffer to elute bound Ab. RESULTS: Galalpha1-3Gal Ab were shown to decrease rapidly in the plasma (in less than 10 min) and then reached a plateau. A fractional decrease in anti-HLA Ab was also found in some of the perfused plasma samples. Anti-Gal Ab were readily detected in all citric acid perfusates and anti-HLA Ab in 8 of 10. The HLA specificities of eluted Ab were mainly concordant with the originally designated specificities for each patient. CONCLUSION: Anti-HLA class I Ab presumably cross-react with pig class I homologues. However, some plasma samples did not cross-react, suggesting that negatively cross-matched pig kidneys could be identified in the pig population for xenotransplantation in these patients. Further studies are required to precisely describe these cross-reactivities and to understand their functional significance in xenotransplantation.

Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens.

BACKGROUND: Long-term administration of cyclosporin carries a risk of renal toxicity, and immunosuppressants are associated with an increased rate of malignant disorders. We undertook an open randomised study of the risks and benefits of two long-term maintenance regimens of cyclosporin in kidney-allograft recipients. The primary endpoint was graft function; secondary endpoints were survival and occurrence of cancer and rejection. METHODS: 231 recipients of a first allograft with at most one previous rejection episode were randomised 1 year after transplantation. Most were receiving cyclosporin and azathioprine. One group received cyclosporin doses adjusted to yield trough blood concentrations of 75-125 ng/mL (low-dose group); the second received doses that yielded trough concentrations of 150-250 ng/mL (normal-dose group). Analysis was by intention to treat. FINDINGS: At 66 months' follow-up, the low-dose and normal-dose groups were similar in mean serum creatinine (182 [SD 160] vs 184 [157] micromol/L; p=0.9) and mean creatinine clearance (47.5 [25.1] vs 45.3 (22.5] mL/min; p=0.6). Nine of 116 patients in the low-dose group and one of 115 in the normal-dose group had symptoms of rejection (p<0.02). There was no difference between the low-dose and normal-dose groups in survival (95 vs 92%; p=0.7) or graft survival (89 vs 82%; p=0.17) at 6 years. 60 patients developed cancers, 37 in the normal-dose group and 23 in the low-dose group (p<0.034); 66% were skin cancers (26 vs 17; p<0.05). INTERPRETATION: We found no evidence that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival. The low-dose regimen was associated with fewer malignant disorders but more frequent rejection. The design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.

Decreased cytotoxic activity of natural killer cells in kidney allograft recipients treated with human HLA-derived peptide.

Peptides derived from a conserved region (aa 75-84) of HLA class I, overlapping the supertypic HLA-BW4/BW6 antigen region, have been shown to exhibit nonallele restricted immunosuppressive properties in rats and mice, prolonging survival of major histocompatibility complex-mismatched allografts. Furthermore, HLA-B7 peptides inhibit alloreactive cytotoxic cells, and both HLA-B7 and HLA-B2702 peptides inhibit natural killer (NK) cytotoxicity in vivo. In this article, we report on a randomized, controlled study of the safety and pharmacokinetics of HLA-B2702-derived peptide in human recipients of a first kidney allograft. Escalating doses of HLA-B2702 were compared with doses of placebo controls. No toxicity and no immunization against the peptide were noted. Although the study was not designed as an efficacy trial, patients who received the high-dose protocol (7 mg/kg) did experience more rejection episodes, but this was not statistically significant when compared with control patients. Interestingly, in human recipients, as previously observed in rodents, administration of the peptide was associated with a statistically significant decrease in the cytotoxicity of NK cells against K562 targets (P<0.001). As these peptides correspond to a region of the HLA class I molecule that interacts with the newly described NK receptors for class I, their mode of action through interaction with such receptors is discussed. As a peptide of the same sequence from HLA-B7 blocks both NK and alloreactive T cell cytotoxicity, it is possible that, in humans too, both types of cytotoxic cells are affected by this peptide. The biological significance of these observations should be confirmed in future controlled studies with a larger patient population.

Frequency of mucosal HPV DNA detection (types 6/11, 16/18, 31/35/51) in skin lesions of renal transplant patients.

Human papillomaviruses (HPV) probably play a role in the development of skin cancer in renal transplant recipients. Since some mucosal HPV are strongly related to cervical cancer, we compared the frequency of HPV DNA detection (mucosal types 6/11, 16/18, and 31/33/51) in skin cancer of renal transplant recipients (21 lesions) with that in normal subjects without immunodeficiency (21 lesions) and studied the frequency of these same HPV in benign lesions of renal transplant recipients (34 lesions) and normal subjects (30 lesions). An in situ hybridization technique employing cold biotin probes was used. HPV DNA was not significantly (P = 0.095) more frequent in malignant skin cancer in renal transplant recipients (42.9%) than in normal subjects (19.04%), but was significantly more frequent in benign lesions in renal transplant recipients (32.4%) than in controls (10%; P < 0.05). These results on a limited number of skin lesions do not allow one to confirm the predominant role of mucosal HPV in the development of skin cancer in renal transplant recipients. HPV interaction with other factors related to the immunosuppressive state may play a role.

[Post-transplantation of Hodgkin's disease. Clinico-pathologic study of 3 cases]. / Maladie de Hodgkin après transplantation d'organè. Etude anatomoclinique de 3 observations.

As a frequent complication of immunosuppression, lymphoproliferative disorders affect approximately 2 % of allorgan transplant recipients. Most of them are EBV-associated-B-cell-lymphoproliferations. Other types of non Hodgkin's lymphomas and Hodgkin's disease, as observed in general population, have only rarely been reported in this group of patients. We report three cases of Hodgkin's disease, which were diagnosed in two renal transplant recipients and one heart transplant patient. They were associated with Epstein-Barr virus, as demonstrated by immunohistochemistry and in situ hybridization. EBV is frequently associated with Hodgkin's disease in the general population, and always implicated in AIDS-related Hodgkin's disease. However in transplant patients the rarity of Hodgkin's disease argues against a direct oncogenic role of this virus.

Hodgkin's disease after transplantation.

Hodgkin's disease (HD) has seldom been reported after transplantation. Epstein-Barr virus (EBV) is present in about 50% of Reed-Sternberg cells in HD developing in immunocompetent individuals, but is more frequently found in HD of acquired immune deficiency syndrome patients. We report 7 cases of HD that occurred in transplant recipients. Clinical and pathological data and studies of EBV reveal specific features of HD after transplantation. Six patients received kidney transplants and 1 patient received combined kidney and pancreas transplantation. Immunosuppressive therapy consisted of cyclosporine, steroids, azathioprine, and antilymphocyte globulins. One patient received, in addition, anti-CD3 mAb therapy and an EBV+ B cell lymphoma developed. Retrospective EBV serological data from patients were collected. Tumors were classified according to pathology. EBV studies were conducted by immunohistochemical methods with monoclonal antibodies to EBV-latent membrane protein (LMP) or EBV-nuclear antigen 2 (EBNA2), and by in situ hybridization for latent nuclear EBV-early RNAs (EBERs). The mean lapse of time between transplantation and HD was 49 months. Six patients presented with enlarged lymph nodes and 1 patient presented with liver involvement. HD was classified as IA in 2 patients, IIA in 3 patients, IIIB in 1 patient, and IVB in 1 patient. Four patients had primary EBV infection after graft, before HD, and the others reactivated latent EBV infection. Histological subtypes were mixed cellularity in 6 cases and lymphocytic depletion in 1 case. Latent EBV infection was detected with EBERs in all tumors. Reed-Sternberg cells expressed LMP, and were negative for EBNA2 expression. Six patients were treated: 2 patients at stage I received radiotherapy, and relapsed within 1 year with a more advanced stage of HD; chemotherapy was indicated as primary therapy in 5 patients, and as salvage therapy in 2 patients; it was associated with radiotherapy in 4 patients. Immunosuppressive therapy was reduced in all patients. Four patients were alive and in complete remission 18, 25, 31, and 67 months after chemotherapy, with a functioning graft in 3 patients. Two patients died of infection. Mixed cellularity is the most frequent histological subtype observed in HD occurring in transplant patients. EBV is present in all Reed-Sternberg cells. Posttransplant HD shows similarities with human immunodeficiency virus-associated HD. These facts argue for a role of EBV infection and immunosuppression in the progression of HD after transplantation.

Single-center analysis of 468 first cadaveric kidney allografts with a uniform ATG-CsA sequential therapy.

Progress in clinical management and sophistication of immunological treatment of kidney allografts depend upon continuous reassessment of the risk factors related to pre- and post-graft information according to the therapeutical strategies used. We studied predictive factors of long-term graft survival (up to 9 years) and of kidney graft function at one year after surgery in a single-center population of 468 first cadaveric kidney recipients treated with a uniform immunosuppression induction regimen of anti-thymocyte globulin, followed by cyclosporine A. The statistical analysis showed that long-term graft survival was highly correlated with the occurrence of one or more acute cellular rejections and with the timing of these episodes. In addition, this uniformly treated series of patients confirmed the potential importance of gender matching. The magnitude of anti-HLA immunization and delayed graft function were also strongly linked to low graft survival rates. We found no significant influence of HLA matching, with serological HLA typing, on graft loss. The quality of graft function at one year was found to be a strong prognostic factor of long-term graft survival. In addition, the impact of pre- and post-graft parameters were studied in terms of prediction of one-year graft function. A stepwise multivariate analysis showed that graft function at one year was a multivariate phenomenon strongly correlated with a history of acute rejection episodes and with donor and recipient age. However, these 3 factors could account for only 15% of the graft function deterioration, the remaining 85% might be explained in part by chronic cyclosporine toxicity and/or chronic rejection.

Renal transplantation from cadaver donors over 60 years old.

The influence of donor age on the short- and long-term outcome of cadaveric kidney transplantation was analyzed at our institution. During a 6-year period, 34 and 806 patients underwent kidney transplantation from cadaver donors over or less than age 60, respectively. Graft and patient survivals were compared throughout follow-up and herewith reported. In addition, main medical and surgical complications among recipients of elderly cadaver donors are detailed.

Cadaveric renal transplantation after 60 years of age. A single center experience.

We report the outcome of 121 cadaveric renal transplants performed in our institution between September 1985 and April 1992 in 117 patients, aged 60-71 years (mean 63 years) at the time of transplantation. Compared to 640 patients 20-59 years of age transplanted during the same study period, a nonstatistically significant difference was observed in the 5-year actuarial patient (80% and 90%, respectively, in recipients over and under 60 years of age) and transplant (80% and 72%, respectively, in recipients over and under 60 years of age) survival rates. However, elderly patients had significantly lower survival than recipients 20-29 years of age (P < 0.009). Fourteen patients died (all but one with a functioning graft) due to cardiovascular diseases (5%; 42.8% of total deaths), infections (3%; 28.6% of total deaths), and gastrointestinal complications (3%; 28.6% of total deaths). Younger patients showed a similar and nonsignificantly different incidence of cardiovascular- (35%) and infectious-(30%) related deaths. The incidence of acute rejection episodes and cytomegalovirus (CMV) infectious episodes was 27% and 24%, respectively, during the 1st post-transplant year. Ongoing acute rejection and CMV infectious episodes were significantly higher in patients who died than in those still alive (P < 0.002 and P < 0.02, respectively). Cyclosporin maintenance therapy was well tolerated in all patients but one, and 64% of the patients could be maintained without steroids. These data indicate that cadaveric renal transplantation is a safe and effective procedure in the management of chronic renal failure of selected patients 60 years of age or older.

Prevention of acute rejection episodes with an anti-interleukin 2 receptor monoclonal antibody. II. Results after a second kidney transplantation.

The focus of progress in transplantation immunosuppression is to achieve more specific immunosuppression with monoclonal antibodies. We have already shown that the efficacy of 33B3.1, a rat monoclonal Ig2A directed against the human IL-2 receptor, was similar to that of rabbit antithymocyte globulin in the prevention of acute rejection in first kidney transplants. A similar comparative analysis has been made in 40-sec renal transplants. ATG (1 mg/kg/day) or 33B3.1 (10 mg/day) was administered during the first 10 days postgrafting in association with corticosteroids and azathioprine. Cyclosporine was introduced on day 9 and azathioprine/CsA constituted the patient's maintenance treatment after day 45. Rejection treatment consisted of equine antilymphocyte globulin in both cases and of steroid boluses when patients were under Cyclosporine. One patient in each group died. Graft survival was 90%, 85%, and 79% in the ATG group (n = 20) and 100%, 89%, and 89% in the 33B3.1 group (n = 20) at 3, 12, and 24 months, respectively. Of the ATG group patients, 45% and 40% in the 33B3.1 group had at least one rejection episode, half the episodes in the MoAb cohort occurring under 33B3.1, vs. none in the ATG group. Transplant function was similar in both groups. Viral infections appeared to be more frequent with ATG (60%) than with 33B3.1 (12%), with CMV accounting for half of these in the ATG group, and none in the MoAb group. Tolerance of both agents was good. Of the 33B3.1 recipients, 70% developed anti-33B3.1 antibodies. From these data, we conclude that this anti-IL-2 receptor MoAb seems less effective than rabbit ATG as induction treatment in second kidney transplant patients.

Prevention of acute rejection episodes with an anti-interleukin 2 receptor monoclonal antibody. I. Results after combined pancreas and kidney transplantation.

A prospective, randomized trial was conducted to evaluate the short-term and long-term effects of induction immunosuppression with the rat IgG 2a monoclonal antibody 33B3.1, directed against the human alpha chain of the interleukin 2-receptor, following primary, cadaveric, combined pancreas and kidney transplantation. Forty patients were randomly assigned to receive 10 mg/day of 33B3.1 (n = 20) or 1.5 mg/kg/day of rabbit antithymocyte globulin (n = 20) for the first 10 postoperative days. Azathioprine, low-dose corticosteroids, and cyclosporine were given in association with either 33B3.1 or ATG. All 40 patients received the entire 10-day bioreagent course and no episode of rejection was observed during this period. Although the incidence of rejection did not significantly differ within the first, second, and third postoperative months (ten 33B3.1 and 6 ATG patients experienced, respectively, 10 and 6 rejection episodes within the first 3 months), the total number of 33B3.1 patients experiencing rejection throughout the follow-up was significantly higher than that of ATG (13 versus 6; P < 0.02). Immunological graft failure accounted for 2 pancreas and 2 kidney losses in the 33B3.1 group versus 1 in the ATG one (P = ns). The total number of infectious episodes was similar in both groups (21 versus 23). Two malignancies were observed in the ATG group (1 responsible for patient's death). One 33B3.1 patient died because of infectious pneumonia and 3 ATG patients died because of 2 cardiovascular diseases and 1 cancer. All patients had functioning grafts at the time of death. The 3-month and 36-month patient, pancreas, and kidney actuarial survival rates were, respectively, 100, 65, and 100%, and 95, 50, and 82% in the 33B3.1 group and 95, 80, and 90%, and 80, 70, and 80% in the ATG one (P = ns). These data suggest that, although a significantly higher rejection episode incidence was observed in patients treated with 33B3.1 monoclonal antibody as compared with ATG, similar long-term results can be obtained following primary cadaveric combined pancreas/kidney transplantation.