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A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.

Background: Type II or III cryoglobulins are fairly prevalent in renal-transplant (RT) patients, and are often related to chronic hepatitis C virus (HCV) infection. However, they rarely result in graft dysfunction. They are sustained by proliferation of oligoclonal B-cells. Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have been achieved in HCV-positive immunocompetent patients with a human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (i.e., rituximab). Thus, this provides the rationale to use rituximab for cryoglobulin-related graft dysfunction in RT patients., Methods: Three RT patients, of whom one was HCV-positive, developed renal-function impairment long after transplantation, as well as de novo nephrotic syndrome (n=2) and severe hypertension (n=2). This latter case was related to type III cryoglobulinemia and was associated with membranoproliferative glomerulonephritis. In addition to their baseline standard immunosuppression, the patients were given weekly rituximab infusions of 375 mg/m (two infusions in patient and four infusions for the other two cases)., Results: This treatment resulted in a dramatic improvement in renal parameters, particularly in a sustained remittence of nephrotic syndrome, a sustained clearance of cryoglobulins in two cases, but also in severe infectious complications in two cases., Conclusion: We conclude that rituximab therapy is highly effective in cryoglobulin-related renal dysfunction in RT patients; however, due to chronic immunosuppression, this is at the expense of infectious complications.

Background: The aim of our study was to identify the independent factors that might predict anemia at 6 (M6) and 12 (M12) months posttransplantation., Methods: Postrenal transplant anemia (PTA) was defined as having a hemoglobin (Hb) level below 13 g/dl for men and below 12 g/dL for women. In this study, we included all the recipients who received a renal transplant in 2001 at our department, and for whom the graft was still functioning 1 year later (n=92)., Results: Anemia was observed in 78%, 35.5% and 25% of patients at day (D)0 and at M6 and M12, respectively. Iron deficiency was found in 14% of patients at D0 and in 13% of patients at M12. A total of 59.8% of patients had received at least one blood transfusion in the postoperative period, whereas 41.3% of patients had received recombinant erythropoietin (rEpo) therapy within the first months posttransplantation. In multivariate analysis, the independent predictive factors of anemia at M6 were Epo level at D0, initial nephropathy (polycystic kidney disease vs. others), posttransplantation rEpo therapy, hematocrit at M3, platelets at D7, and sirolimus therapy. The independent predictive factors of anemia at M12 were Epo level at D0, platelets at D7, delayed graft function (DGF), creatinine clearance at M12, serum creatinine at M12, and Hb level at M6., Conclusions: The prevalence of PTA was 25% at M12. DGF, renal function at M12, and anemia at M6 were independent risk factors for still having anemia at M12.

Background: Sequential anti-thymocyte globulins (ATG)/cyclosporine immunosuppression has two main advantages: delayed introduction of the nephrotoxic drug cyclosporine and prevention of acute rejection. Basiliximab, a recently developed chimeric monoclonal antibody that selectively depletes the minor subpopulation of activated T lymphocytes, has been shown to reduce the incidence of acute rejection when used with cyclosporine introduced on day 1., Methods: This open, randomized, multicenter study was undertaken to compare the safety and efficacy of ATG versus basiliximab induction therapy (IT) with delayed introduction of cyclosporine for microemulsion (Neoral) in 105 low immunologic risk renal-transplant patients receiving mycophenolate mofetil and steroids., Results: One-year patient and graft survival rates were 98.1% and 94.2%, respectively, in the basiliximab group (n = 52), and 98.1% and 96.2% in the ATG group (n = 53). The incidence of biopsy-confirmed acute rejection was comparable (basiliximab 9.6%, ATG 9.4%), as were key parameters of renal function, notably serum creatinine levels, time-to-nadir serum creatinine, and the number of patients requiring posttransplantation dialysis (basiliximab 28.8%, ATG 30.2%). However, significantly fewer patients in the basiliximab group experienced cytomegalovirus (CMV) infection, leukopenia, and thrombocytopenia, and this without any significant difference in any other key safety parameters (including the incidences of serum sickness, fever, lymphoma, and infections in general)., Conclusions: Both ATG and basiliximab, when used for IT in a sequential protocol, are equally effective in terms of graft and patient survival as well as at preventing acute rejection. However, basiliximab is associated with a lower incidence of certain key adverse events, namely CMV infection, leukopenia, and thrombocytopenia.

Background: The results of the transplantation of marginal donor kidneys remain controversial. This study aimed to investigate the impact of donor risk factors as predictors of kidney-graft outcome., Methods: Allograft failure risk factors were studied in 7,209 cadaveric kidney-transplant recipients reporting to the Etablissement français des Greffes (EfG) from 1996 to 2000, of which 544 (7.6%) were from donors aged over 60. Both univariate and multivariate analysis were used to assess the effect of donor risk factors and were stratified according to recipient age., Results: Overall graft survival was 91.1% (95% confidence interval [CI] 90.5-91.8) at 1 year, 88.6% (95% CI 87.8-89.4) at 2 years, and 85.6% (95% CI 84.6-86.6) at 3 years posttransplant. Univariate analysis of risk factors showed a significant reduction of graft survival in recipients transplanted with kidneys coming from donors older than 60 years, donors with a history of hypertension, a cerebrovascular cause of death, and a preharvesting serum creatinine greater than 150 micromol/L. Multivariate analysis revealed significantly higher failure rate associated with cerebrovascular cause of death (RR=1.2, P=0.02), history of hypertension (RR=1.2, P=0.04), and elevated serum creatinine (RR=1.3, P=0.03), whereas donor age greater than 60 years was not found as an independent risk factor., Conclusions: Our results suggest that cerebrovascular cause of death, history of hypertension, and elevated creatinine are significant independent donor risk factors for graft survival, whereas donor age is a statistically significant, but dependent, risk factor. This result is important for the design of allocation and transplantation strategies for kidneys procured in elderly donors.

Background: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients., Methods: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day., Results: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction)., Conclusion: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

Background and Methods: A cross-sectional study of multifaceted male sexual function in 323 consecutive kidney transplant recipients was conducted by mail by means of the validated International Index of Erectile Function (IIEF). All five IIEF domains (IIEF-5), i.e., erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction, were scored for each responder. IIEF-5 scoring that conformed to the National Institutes of Health definition of erectile dysfunction (ED) was computed for all patients sexually active within the past 4 weeks., Results: Two hundred and seventy-one patients replied. Compared to the controls used for IIEF psychometric validation, kidney transplant recipients gave lower erectile function (P<0.01) and intercourse satisfaction (P<0.05) scores, despite their being younger. ED, according to the IIEF-5 method, was demonstrated in 55.7% of the sexually active patients (n=212). Age, time on dialysis, and iterative transplants were significantly and negatively related to erectile dysfunction., Conclusion: IIEF proved to be a valuable means of unveiling highly prevalent erectile dysfunction in male kidney transplant recipients. The negative impact of the time on dialysis was emphasized in the results.

Background: Mycophenolate mofetil (MMF) is a potent immunosuppressive agent and might inhibit chronic rejection, at least in primates. The prevalence of chronic hepatitis C virus (HCV) infection is high in renal transplant (RT) patients. To date, it has not been demonstrated whether MMF has any effect upon HCV viremia., Methods: Fourteen long-term HCV(+) RT patients with chronic allograft dysfunction whose maintenance immunosuppression was based on cyclosporine, were given MMF therapy either in place of azathioprine (n=11) or in addition to baseline therapy (n=3). HCV viremia levels were measured by the Amplicor HCV-Monitor RT-PCR assay (Roche Diagnostic Systems) on two separate occasions before the introduction of MMF, and 1 year after changing to MMF or at the last follow-up visit., Results: MMF therapy was associated with a significant rise in HCV viremia, i.e., 5.8+/-0.5 vs. 5.2+/-0.7 log copies/ml (P=0.01), although there were no significant changes in liver enzymes. The increase in HCV viremia was not related to HCV genotypes either. At the patient level, HCV RNA concentrations changed in only seven patients (group B), i.e. >1 log copies/ml, whereas it remained stable in the others (group A). Before conversion, the only significant difference between group A and B was the level of HCV RNA, i.e., 5.5+/-0.4 log copies/ml in group A and 4.9+/-0.7 log copies/ml in group B (P=0.05)., Conclusion: Our study suggests that MMF should be used with caution in stable HCV RT patients whose maintenance immunosuppressive therapy is based on cyclosporine, at least in the case of patients with a low HCV RNA titer.

Background: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus., Methods: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine., Results: At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus., Conclusions: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Background: The hepatitis G virus (HGV) has been recently cloned. Studies in immunocompetent patients have shown that HGV superinfection in hepatitis C virus (HCV)-positive patients does not affect (i) clinical presentation, HCV RNA level, or response to interferon-alpha therapy; or (ii) the histopathologic severity and characteristics of chronic hepatitis. No data are currently available on the impact of HGV infection on liver histology of renal transplant (RT) patients although the reported prevalence of serum HGV RNA in this population is high, ranging from 14% to 55%., Patients and Methods: We determined the prevalence of HGV infection in 103 HCV-positive RT patients for whom HGV RNA was retrospectively determined by reverse transcription-polymerase chain reaction before, at the time of, and after transplantation (last follow-up). We evaluated the impact of HGV on liver function tests, liver histology (by means of the Knodell score), and renal parameters such as the prevalence of acute rejection and renal function., Results: A total of 29 (28%) of the HCV-positive RT patients had a positive HGV RNA (group 1). The mean duration of HGV infection was at least 119+/-64 months (range: 18-240 months). Group 1 patients were compared to the 74 HGV RNA-negative/HCV-positive RT patients (group 2). Liver histology showed a significantly lower degree of fibrosis in group 1 (0.4+/-0.5) than in group 2 (1+/-1.2; P=0.02); two patients from group 2 but none from group 1 had overt cirrhosis. Conversely, the extent of hepatic inflammation and hepatocellular destruction was not statistically different between the two groups. The number of patients who experienced at least one acute rejection episode was significantly higher in group 1 (69%) than in group 2 (42%; P=0.01). However, the multivariate analysis did not identify the presence of HGV RNA at the time of renal transplantation as an independent factor of acute rejection; conversely, (i) the occurrence of cytomegalovirus infection or disease and (ii) the duration of HCV infection significantly increased the likelihood of having acute rejection., Conclusions: This study shows that: (i) HGV infection was often present when the patients seroconverted for HCV, (ii) HGV RNA-positive/HCV-positive RT patients experienced acute rejection more frequently than HGV RNA-negative/HCV-positive RT patients, and (iii) HGV infection seems to have no detrimental effect upon liver enzymes or liver histology in HCV-positive RT patients.

Background: The aim of this pilot study was to evaluate the efficacy and the safety of lamivudine therapy in hepatitis B virus (HBV)-positive/DNA-positive renal transplant recipients., Methods: Six HBV DNA-positive cadaveric renal transplant recipients ranging in age from 49+/-6 years were administered lamivudine, at 100 mg/day for a period of at least 6 months, on a compassionate-use basis. Lamivudine is the (-) enantiomer of 3'-thiacytidine, which is known to be a potent inhibitor of HBV replication. All of the patients but one were on cyclosporine-based immunosuppression., Results: The mean serum creatinine was 134+/-44 micromol/L. The mean duration of HBV infection was 230+/-54 months (156-288). All of the patients but one had high serum alanine aminotransferase levels (122+/-52 IU/L; range, 45-243). Histological evaluation showed the presence of either chronic active hepatitis (n=4) or cirrhosis (n=2). All of the patients but one were hepatitis B e antigen negative/hepatitis B e antibody positive, but none were coinfected with either hepatitis C virus or hepatitis D virus., Conclusions: Lamivudine therapy was associated with (i) a normalization of alanine aminotransferase levels in four of five patients when these levels were increased at the beginning (n=5); (ii) a rapid disappearance of HBV DNA from the serum (detected by hybridization) in all of the patients; (iii) the negativity of HBV DNA by polymerase chain reaction in four patients; and (iv) no change in renal function and in proteinuria when present (one patient). Finally, no adverse effects were noted. When lamivudine therapy was stopped for four patients after 6 months, it was associated with a biochemical and virological relapse within the weeks that followed. Lamivudine therapy was therefore resumed for these patients.

Adhesion molecules are involved in several steps in the immune response: leukocyte adhesion to the endothelium, transendothelial migration, cooperation between immunocompetent cells, and cytotoxicity. Leukocyte function-associated antigen-1 plays a central role among adhesion molecules. In a multicenter randomized open trial, we compared a monoclonal antibody directed against the alpha chain of LFA-1 (Oduli-momab; IMTIX/Pasteur Mérieux Sérums et Vaccins) with rabbit antithymocyte globulin (rATG; IMTIX/Pasteur Mérieux Sérums et Vaccins), as part of a quadruple sequential protocol in 101 patients receiving a first kidney transplant. Clinical tolerance of anti-LFA-1 mAb was better than that of rATG. Short-term rejection rates (< 15 days) were not significantly different (15% and 16% for anti-LFA-1 mAb and rATG, respectively). However, 11% of the anti-LFA-1 mAb patients experienced rejection during the first 10 days of the treatment course compared with none of the patients treated with rATG. The incidence and severity of acute rejection in the first 3 months was not significantly different between groups. Of the LFA-1 and rATG patients, 96% and 92% of the grafts, respectively, were functioning at 12 months. The incidence and severity of infection, whatever the origin, were comparable in both groups. In addition, it was observed that fewer patients required posttransplantation dialysis in the anti-LFA-1 mAb group (19%, vs. 35% for rATG), although the difference was not statistically significant. Altogether, the beneficial action of this monoclonal antibody on short-term renal function recovery makes it a useful tool in the management of renal patients undergoing kidney transplantation.

Chronic hepatitis C is a common cause of viral liver disease in kidney transplant (KT) recipients. To assess the efficacy and safety of therapy with interferon alpha we conducted a prospective study where 14 cadaveric KT recipients with chronic hepatitis C received recombinant interferon alpha-2b (IFNa) 3 million units three times weekly (scheduled) for 6 months (group A). 14 KT recipients with chronic hepatitis C were not treated and served as controls for the study period (group B). All the patients in both groups had had stable renal function for at least one year. All patients in both groups had a positive HCV viremia at the beginning of the study. Patients of group A were treated for 142 +/- 34.8 days (range 65-168); elevated serum aminotransferase (ALT) levels decreased rapidly and significantly from 100.3 +/- 48.9 to 37.7 +/- 13.9 IU/L (P = 0.001); 10 patients (77%) were "responders," whereas the others experienced a decrease in ALT values but without reaching the normal ranges. With a mean follow-up of twelve months after discontinuation of IFNa therapy, 8 responders--i.e., 80%--relapsed within 1-20 weeks. Only 4 patients had no detectable HCV viremia at the end of the IFNa; two of them already have abnormal values of ALT. Moreover HCV viremia was present in all patients one month after the cessation of IFNa treatment. Side effects of IFNa (fatigue, anorexia, weight loss) were frequent, and 3 patients decided to drop out of the treatment. The hematological tolerance was good although there was a significant decrease in hemoglobin (11.9 +/- 1.7 vs. 13.4 +/- 1.7 g/dl; P = 0.0044). In group B, serum ALT levels did not significantly decrease (84.2 +/- 47.6 vs. 105.2 +/- 68.8 IU/L). At the end of the study period serum ALT levels were significantly lower in group A than in group B (37.7 +/- 13.9 vs. 84.2 +/- 47.6 IU/L, P = 0.013). The major concern in group A was the occurrence of 5 renal failures. Kidney transplant biopsies showed edema, no significant tubulitis, scarcely scattered interstitial inflammatory cellular infiltration, and mesangial thickening. Four patients received methylprednisolone pulses but renal function improved in only two cases. We were not able to discover predictive factors of renal failure. We conclude that IFNa therapy is effective in controlling disease activity--i.e., reducing amino-transferase levels in KT patients with chronic hepatitis C, although relapse and detection of HCV RNA after the cessation of treatment were observed, respectively, in 80% and 100% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

In 45 patients who received kidney transplants, both homologous and heterologous human antiglobulins (anti-Ig) and HLA cytotoxic antibodies have been studied before and after transplantation and in some cases after nephrectomy. A similar study has been performed in a control group of 1,019 healthy blood donors and in 130 patients with acute or chronic glomerulonephritis. After transplantation, homologous anti-IgG were found in 60% of the patients, as compared with 3.5% in the healthy blood donors and 21% in patients with various forms of glomerulonephritis. This difference is particularly striking in sera obtained prior to nephrectomy; the presence of anti-IgG and cytotoxic antibodies in the same patient being significantly associated with early transplant failure. Anti-IgA were found in 75% of the patients with transplants and in 37% of the patients with glomerulonephritis. There was no relationship between the anti-IgA and the outcome of the graft. On the other hand, heterologous anti-Ig were unchanged in the three groups investigated. The mechanism of formation of the anti-IgG is not clear. They are probably antibodies against antigenic structures of the patient's own antibodies, previously combined with a soluble antigen or an antigen on the transplant that has undergone molecular transformation in the course of this reaction. Their pathogenic role, although not demonstrated, can be strongly suspected, and, in a practical way, screening for the anti-Ig in kidney transplant recipients could be of value as a prognostic test.