Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study.

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Long-term glomerular filtration rate in liver allograft recipients according to the type of calcineurin inhibitors.

The calcineurin inhibitors (CNI) cyclosporine micro emulsion (CyA-ME) and tacrolimus (Tac) both display renal and vascular toxicities. We undertook a single-center retrospective study among 149 surviving liver transplant recipients. The primary outcome was kidney function over 10 years posttransplant, evaluating the glomerular filtration rate (GFR) by the abbreviated Modification of Diet in Renal Disease formula with subsequent Kidney Disease Outcomes Quality Initiative staging. The secondary outcomes included correlations between CNI trough levels (C0), GFR, and items of cardiovascular toxicity. At 1 and 5 years, the mean GFRs were 74.2 and 76.9 mL/min/1.73 m(2) under Tac versus 62.8 and 66.0 mL/min/1.73 m(2) under CyA-ME (P < .001). The mean value in favor of Tac was + 10 mL/min/1.73 m(2). Distribution of GFR stages showed more Tac patients at stage 1 or 2 and more at stage 4 or 5 under CyA-ME. There was no significant correlation between CNI-C0 and GFR. Switches between CNI or to mycophenolate mofetil did not show any significant GFR improvement. Patients under CyA-ME displayed significantly higher blood pressures with 3 requiring dialysis versus none under Tac. In conclusion, we observed that liver transplant patients under Tac maintained significantly better renal function with less progression to dialysis as compared with CyA-ME, indicating a lower renal and vascular (lower BP) toxicity.

Differential effect of cyclosporine and mycophenolic acid on the human regulatory T cells and TH-17 cells balance.

BACKGROUND: Beyond the usual TH1/TH2 polarization, a reciprocal pathway between FoxP3+ regulatory T cells (Tregs) and interleukin (IL)-17-secreting effector T cells (TH-17) has recently been identified. We have investigated the effects of two immunosuppressive drugs, cyclosporine (CsA) and mycophenolic acid (MPA) on the development of Treg/TH-17 cell responses. METHODS: We compared the influence of CsA and MPA on the transcription levels of FOXP3 (Treg marker) and IL17 (TH-17 marker) in activated human peripheral blood mononuclear cells (PBMC). RESULTS: After 48 hours of activation, IL17 transcription was rapidly induced, remaining stable over 96 hours, whereas only a transient increase in FOXP3 was noted, suggesting that the Treg/TH-17 cell balance was tipped toward TH-17 during PBMC activation. The addition of either CsA or MPA did not affect the level of transcription of FOXP3. MPA but not CsA was found to significantly inhibit IL17 expression by activated PBMC. This effect of MPA seemed to result from its capacity to hamper (1) the production of IL1beta by monocytes and (2) the expression of TIM-1 by CD4+ T cells, two key signals involved in human TH-17 differentiation. CONCLUSION: Through a preferential inhibition of IL17, MPA might favorably influence the Treg/TH- 17 balance. Our results suggest that the immunosuppressive drugs used in the clinic may differentially influence lymphocyte polarization, including the newly identified TH-17 pathway.

Significant risk factors for occurrence of cancer after renal transplantation: a single center cohort study of 1265 cases.

Occurrence of cancer after renal transplantation remains a major problem, and the second cause of death. We performed a retrospective analysis of first cancer, first skin cancer, and first organ cancer (including posttransplant lymphoproliferative disease [PTLD]) among 1265 cases from 1979 to 2006. The occurrence of cancer was clearly a time-dependent event justifiying the use of Kaplan-Meier survival and Cox regression methods. The 10-year cumulative incidences of first cancer, first skin cancer, and first organ cancer were 24.6%, 14.5%, and 14.5%, respectively. Recipient age was a major, independent risk factor for the 3 endpoints with a 6% increased relative risk for each year increment (P < .0001). Female gender was also a major, independent risk factor, but only for skin cancer (P = .0002). We could not demonstrate any difference between the immunosuppressive drugs used for induction or maintenance therapy, especially between antithymocyte globulin (ATG) vs anti-CD25, cyclosporine vs tacrolimus, and azathioprine vs mycophenolate mofetil. Large cohorts are needed with strict stratifications for recipient age and gender to detect any difference, if any, among the drugs.

A trial comparing local pain after subcutaneous injection of epoetin-beta versus darbepoetin-alpha in healthy volunteers.

BACKGROUND: The aim of this study was to compare local pain experienced with subcutaneous (s.c.) injection of epoetin-beta vs. darbepoetin-alpha. METHODS: 40 healthy volunteers were enrolled into this single-blind, crossover study. After receiving an injection of placebo, individuals were randomized to receive s.c. injections of epoetin-beta 6,000 IU (0.3 ml) or darbepoetin-alpha 30 mg (0.3 ml), with a 1-week washout period between injections. Local pain was evaluated using a Visual Analog Scale (VAS) and a 6-item Verbal Rating Scale (VRS) immediately after (T0) and 1 h after injection (T1). RESULTS: The respective mean (standard deviation) and median (range) VAS values at T0 were 1.2 (1.7) and 0.5 (0.0 - 6.9) for epoetin-beta vs. 2.8 (2.4) and 1.9 (0.0 - 9.0) for darbepoetin-alpha (p < 0.0001). At T0, VRS scores demonstrated that 51% of individuals experienced no pain after epoetin- injection compared with 16% of those receiving darbepoetin-alpha. The percentage of individuals perceiving moderate or important pain was significantly greater with darbepoetin-alpha (38%) compared with epoetin-beta (5%, p = 0.0005) and placebo (14%). Pain evaluation at T1 showed no difference between treatment groups. Local tolerance was excellent except for a small hematoma with epoetin- at T1 and with darbepoetin-alpha at T0 which persisted at T1. CONCLUSION: In healthy volunteers, s.c. injection of epoetin-beta was significantly less painful than with darbepoetin-alpha and comparable with placebo. No significant pain was apparent at T1 in any group.

TNFA2 and d2 alleles of the tumor necrosis factor alpha gene polymorphism are associated with onset/occurrence of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) has a strong association with the major histocompatibility complex HLA B8DR3(17)DQ2 haplotype. The tumor necrosis factor (TNF)A gene is located within the major histocompatibility complex region on chromosome 6. We have studied the influence of two functional polymorphisms; the -308 (promoter region) and the TNFd microsatellites on initiation and/or progression of IMN. This was a case-control study comparing data from 100 Caucasians patients (67 male subjects; 67%) with IMN to 232 Caucasians local controls (171 male subjects; 74%). We have analyzed genotypes and alleles distributions and the role of these polymorphisms in disease progression towards end-stage renal failure or patient death. For -308 TNFA polymorphism, distribution of genotypes was significantly different between IMN and controls (chi(2)=16.25; P=0.0003): the A2 allele frequency was 28.0% in IMN vs 15.3% in controls (chi(2)=14.57; P=0.0001). For TNFd polymorphism, alleles distribution (from d1 to d7) was also significantly different between IMN and controls (chi(2)=56.74; P<0.0001) with both diminished d3 allele frequency (chi(2)=27.30; P<0.0001; Pc=0.001) and increased d2 allele frequency (chi(2)=29.95; P<0.0001; Pc=0.001) in IMN. We could not isolate any significant and independent influence of these different genotypes on IMN disease progression. The TNFA2 and TNFd2 alleles were strongly associated with occurrence/initiation of IMN and should be considered as susceptibility genes for this disease.

Tolerability of enteric-coated mycophenolate sodium to 1 year in combination with cyclosporine and corticosteroids in renal transplant recipients.

Enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil, but delays release of mycophenolic acid until it reaches the small intestine. De novo renal transplant patients taking part in a 12-month, multicenter, randomized study received cyclosporine microemulsion (CsA-ME, early or delayed to day 6), EC-MPS, steroids, and interleukin-2 antagonist induction. Tolerability data relating to EC-MPS are reported. Ninety-seven patients were randomized to early CsA-ME and 100 patients to delayed CsA-ME. Median daily dose of EC-MPS was 1440 mg at all time points throughout the 12-month period. The most frequently reported adverse events were constipation, anemia, urinary tract infection, abdominal pain, leukopenia, and cytomegalovirus infection; there were four malignancies. Fifty patients (24.6%) discontinued EC-MPS prematurely by 12 months, including 42 patients (84%) who discontinued owing to adverse events. No patient discontinued treatment because of gastrointestinal adverse events. Two-thirds of patients (137 [67.5%]) maintained full EC-MPS dose throughout the 12-month study and did not require any dose reduction or dose interruption. EC-MPS is well tolerated in de novo renal transplant recipients when administered in combination with CsA-ME and steroids, with low rates of dose reductions or interruptions. Gastrointestinal adverse events were responsible for dose reduction or interruption in only 5% of patients.

CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis.

The chemokine (CK) receptor 5 (CCR5) is necessary for two adjacent cysteines (CC)-CKs such as Regulated upon Activation Normal T cell Expressed and Secreted, a/o Macrophage Inflammatory Protein 1alpha/beta to mediate their inflammatory properties. The CCR5 gene polymorphism with 32-basepair deletion (d32) leads to receptor inactivation/dysfunction in homo/heterozygous individuals. We have evaluated its role in both initiation and/or progression of primary immunoglobulin A (IgA) nephropathy (IGAN) in a case-control study involving a prospective cohort of 318 IGAN patients and a matched group of 294 controls. Genotyping was performed by a two-specific primers single polymerase chain reaction technique: normal allele (nl) vs d32 allele. The d32 allele frequency was not different in patients (11.0%) vs controls (8.3%), indicating no significant influence on IGAN initiation. Genotype to clinical phenotype correlation demonstrated that progression to renal/patient death was associated with the d32 allele: 18.2% (12 out of 66 with d32) vs 8.3% (21 out of 252); chi(2)=6.73; P=0.017. The Kaplan-Meier survival without renal/patient death was worse in d32-positive patients (log-rank test; P=0.002). The Cox regression analyses confirmed that the nl/nl genotype was a significant and independent protective factor for progression to end-stage renal failure (ESRF)/dialysis: beta/standard error (s.e.)=-3.1; chi(2)=9.5; relative risk=0.31 (95% confidence interval 0.15-0.65); P=0.002. The d32-CCR5 polymorphism played a significant role in the progression of primary IGAN, with the nl/nl genotype being an independent protective factor for late progression towards ESRF/dialysis. These data raise question about the usefulness of systematic CCR5 genotyping in IGAN patients.

[Antibodies and immunomodulation]. / Anticorps et immunomodulation.

CURRENT SITUATION: When examining immunosuppressor induction one important question is to determine the efficacy of anti-CD25 antibodies or the new compound efalizumab compared with anti-lymphocyte globulins and anti-OKT3 agents known to be very effective but with important side effects. DACLIZUMAB: Recent work has shown that 2 injections at 1 mg/kg (one on day 1 the other between day 10 and day 14) completely block interleukin-2 receptor for more than 10 weeks in 98% of the recipients. Instead of the 5 injections every 15 days as indicated by the recommendations, this new protocol is easier to institute and less costly. The efficacy remains to be demonstrated. BASILIXIMAB: This chimeric monoclonal antibody has affinity for the IL-2 receptor. Balisiximab is administered in 2 doses at 20 mg, one on day 0 and the other one on day 4. A unique 40 mg dose on day 1 has a comparable efficacy. OTHER PROTOCOLS: Among the different induction molecules with promising properties, particular attention should be given to efalizumab. The antisense oligonucleotide (ICAM-1; ISIS 2302) appears to show relatively poor tolerance and no therapeutic efficacy. In association with plasmapheresis and intravenous immunoglobulins, it has been shown to be very effective when given to graft candidates with a positive cross match or after transplantation in case of acute rejection.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

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.

Comparison of ELISA method versus MEIA method for daily practice in the therapeutic monitoring of tacrolimus.

BACKGROUND: For the adequate management of transplant patients on tacrolimus therapy, it is important to obtain optimal blood concentrations. The purpose of this study was to determine the most appropriate method for daily practice of tacrolimus determination in whole blood. We compared enzyme-linked immunosorbent assay (ELISA) with microparticle enzyme immunoassay (MEIA), using European controls and blood samples from organ graft recipients treated with tacrolimus. Time, practicability and cost were considered also. METHODS: The assays were performed according to the procedures detailed in the product inserts. In five European controls and 40 blood samples from kidney and liver transplant patients, we determined the blood levels of tacrolimus by both MEIA and ELISA tests. RESULTS: MEIA gave more reliable results with the European controls (y=1.078x+0.092; r=0.996) than ELISA (y=0.956x+1.307; r=0.946). For the patient samples, the correlation between the two tests was 0.85 and the extreme range of values was +65% and -56% for ELISA vs MEIA. Although the manufacturer of the ELISA test used claims the best sensitivity and precision, in our experience the MEIA test was quicker and cheaper. CONCLUSIONS: MEIA provides a quick, reliable and easy-to-handle method for routine monitoring of tacrolimus blood levels.

Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis.

Experimental evidence suggests a role for obesity in the formation and progression of some glomerular lesions, but data for human glomerulonephritis are lacking. In a cohort of 162 incident patients with biopsy-proven immunoglobulin A (IgA) nephropathy, we assessed whether the presence of an elevated body mass index (BMI >/= 25 kg/m(2)) at the time of the first renal biopsy (RB1) correlated with clinical data at RB1 (24-hour proteinuria, arterial hypertension, and renal function), pathological data (global optical score [GOS] with detailed pathological indices), and clinical progression to both arterial hypertension and chronic renal failure (CRF). In both univariate and multivariate analyses, the presence of an elevated BMI at RB1 was significantly associated with the severity of pathological renal lesions (GOS and vascular, tubular, and interstitial indices). Hypertension-free survival was significantly less in overweight patients (P: < 0.0001) compared with those with normal weight. In a Cox regression analysis for hypertension-free survival including 24-hour proteinuria greater than 1 g, GOS, and metabolic parameters, only elevated BMI and GOS were independent factors for the development of arterial hypertension. CRF-free survival was also significantly less in patients with an excessive BMI. In a multivariate Cox regression analysis for CRF-free survival, hypertension, GOS, and BMI at RB1 were independent risk factors for CRF. In IgA nephropathy, excessive body weight and/or BMI are underestimated predictive factors for the development of arterial hypertension and, ultimately, CRF.

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.