Use of rituximab as an induction therapy in anti-glomerular basement-membrane disease.

BACKGROUND: Anti-glomerular basement-membrane (anti-GBM) disease (or Goodpasture disease) is characterized by severe kidney and lung involvement. Prognoses have improved with treatments that combine plasma exchange and immunosuppressive drugs. However, patients with severe renal involvement can have poor renal outcomes and cyclophosphamide can cause significant complications. Anti-GBM antibodies have a direct pathogenic effect on the disease: thus, therapeutics that can decrease their production, such as rituximab, could be a good alternative. METHODS: The medical files of five patients that had received rituximab as a first-line therapy (instead of cyclophosphamide), plus plasma exchange and steroids, were reviewed. All patients had severe disease manifestations. RESULTS: Four patients required dialysis at diagnosis and remained dialysis-dependent over the mean follow-up of 15 months. Three patients had pulmonary involvement, but recovered even though mechanical ventilation was required. Anti-GBM antibodies became rapidly undetectable in all patients. One infectious and two hematological complications were observed. CONCLUSIONS: We report the outcomes of five patients with Goodpasture disease and treated with rituximab as a first-line treatment. This strategy was effective at treating pulmonary manifestations and was associated with a good biological response with no major serious adverse events. However, renal outcomes were not significantly improved.

Intravenous Immunoglobulins in the Prevention of Rejection of a Second or Third Kidney Graft.

BACKGROUND: Intravenous immunoglobulin (IVIg) reduces acute rejection episodes in kidney transplantation, but adverse events (AEs) are common. The aim of this study was to assess whether human IVIg enhances immunosuppressive effects without increasing AEs in the prevention of acute kidney graft rejection. METHODS: Patients receiving a second or third kidney graft were treated with standard immunosuppressant therapy with (n = 18) or without (n = 10) IVIg. The primary efficacy endpoint was biopsy-proven acute rejection (BPAR) rate at 3 months, and secondary endpoints included acute rejection rate at 12 months, intensity of rejection, and patient survival. RESULTS: Patients in the experimental arm received 3 infusions of IVIg. The BPAR rate decreased with IVIg versus standard immunosuppression alone over 12 months of follow-up. Experimental versus control rates of survival without BPAR were 94% versus 63% and 82% versus 63% at 3 and 12 months. The intensity of the acute rejection episodes (BANFF 97 grade) was similar between groups. One patient from each group died during the 12-month follow-up period. Treatment-emergent AEs were reported in 100% and 94.4% of the control and experimental arms. Most AEs were considered unrelated or unlikely to be related to treatment. CONCLUSIONS: This study supports the efficacy and safety of IVIg in highly sensitized transplant patients for improving transplant rates and reducing graft rejection episodes.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.

Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial.

This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.

Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study.

One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n=99) or no CS (-CS; n=98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the -CS group (5-year follow-up, p=0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p=0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p=0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p=0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in -CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.

Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study.

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42­48%) versus tacrolimus groups (15­38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15­34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients.

Although large retrospective studies have identified the presence of donor-specific antibodies (DSAs) to be a risk factor for rejection and impaired survival after liver transplantation, the long-term predicted pathogenic potential of individual DSAs after liver transplantation remains unclear. We investigated the incidence, prevalence and consequences of DSAs in maintenance liver transplant (LT) recipients. Two hundred sixty-seven LT recipients, who had undergone transplantation at least 6 months previously and had been screened for DSAs at least twice using single-antigen bead technology, were included and tested annually for the presence of DSAs. At a median of 51 months (min-max: 6-220) after an LT, 13% of patients had DSAs. At a median of 36.5 months (min-max: 2-45) after the first screening, 9% of patients have developed de novo DSAs. The sole predictive factor for the emergence of de novo DSAs was retransplantation (OR 3.75; 95% CI 1.28-11.05, p = 0.025). Five out of 21 patients with de novo DSAs (23.8%) developed an antibody-mediated rejection. Fibrosis score was higher among patients with DSAs. In conclusion, monitoring for the development of DSAs in maintenance LT patients is useful in case of graft dysfunction and to identify patients with a high risk of developing liver fibrosis.

Long-term exposure to belatacept in recipients of extended criteria donor kidneys.

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study.

The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of belatacept or cyclosporine A (CsA). The 5-year results of the long-term extension (LTE) cohort are reported. A total of 456 (68.5% of intent-to-treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of belatacept MI, belatacept LI and CsA patients, respectively; graft loss occurred in 0% belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero belatacept MI, one belatacept LI and one CsA. Rates for infections and malignancies for Months 36-60 were generally similar across belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m(2) ) at Month 60 was 74 for belatacept MI, 76 for belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in belatacept-treated patients in the early posttransplant period was sustained through 5 years.

Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial.

Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.

Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients.

The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was ∼21 mL/min/1.73 m(2) higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m(2) /year (MI) and +1.2 mL/min/1.73 m(2) /year (LI) versus a decline of -2.0 mL/min/1.73 m(2) /year (cyclosporine). One cyclosporine-treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept-treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine-treated patients, despite an early increased occurrence of acute rejection and PTLD.

Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation.

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Viral infections after kidney transplantation.

Chronic immunosuppression, required to maintain allograft function postorgan transplant, predisposes transplant patients to a variety of viral infections. These can occur at every stage of post-transplantation. Some infections, however, such as cytomegalovirus (CMV), Epstein Barr virus (EBV), or BK virus (BKV), tend to occur within months after transplantation. CMV infections can be easily prevented by prophylaxis therapy whereas EVB or BKV infections can be prevented by lowering (when possible) immunosuppression. Some viral infections can result in posttransplant lymphoproliferative disorders (EBV), Kaposi sarcoma (human herpes simplex virus type 8), or skin and/or cervical cancers (papillomavirus). Other viral infections, such as those due to influenza or para influenzae viruses, respiratory syncytial virus, or West nile fever virus, are mostly acquired through environmental spread. Thanks to modern laboratory technique, and a formidable antiviral armamentarium, viral infections in organ transplant patients i) can be easily detected at early stages, and ii) can be efficiently treated.

JC virus DNA in the peripheral blood of renal transplant patients: a 1-year prospective follow-up in France.

There is little information on JC virus (JCV) infection in renal transplant patients. A long-term prospective follow-up study was conducted to assess the incidence of JCV DNA in the blood of 103 adult renal transplant patients enrolled prospectively between 1 January and 31 December 2006. Patients were monitored until April 2008. JCV DNA was quantified by a real-time polymerase chain reaction in whole blood samples collected regularly for at least 1 year post-transplant. JCV was detected in seven patients (6.8%) (31/1,487 whole blood samples) at a median time of 139 days post-transplant. The median JC virus load of the first positive DNA blood sample was 3.4 log(10) copies/ml (1.9-5.7 log(10) copies/ml). Induction therapy were either anti-CD25 monoclonal antibodies (n = 5) or antithymocyte globulins (n = 2). Post-transplant immunosuppressive treatment included steroids with tacrolimus/mycophenolate mofetil (MMF) (n = 2), or ciclosporin/MMF (n = 1), or belatacept/MMF (n = 4). Two patients were also treated with rituximab. All seven patients infected with JCV had other viral infections(s): BK virus (3), Epstein-Barr virus (2), Cytomegalovirus (1) or both BK virus and Epstein-Barr virus (1). Three patients had BKV-associated nephropathy and decoy cells shedding. JCV infection was not associated with acute rejection episodes or nephropathy, regardless of the virus load. No patient developed progressive multifocal leukoencephalopathy during follow-up. Thus the incidence of JCV infection in renal transplant patients was low and not associated with any specific clinical manifestations. JCV replication must still be diagnosed and differentiated from BK virus infection because of its non-aggressive course.

[Pneumocystis jiroveci infection associated with organizing pneumonia in a kidney transplant patient]. / Infection à Pneumocystis jiroveci associée à une pneumopathie organisée chez une patiente transplantée rénale.

The authors report the association of organizing pneumonia (OP) and a Pneumocystis jiroveci infection in a woman who benefited from a kidney transplant 13 years before and was under corticoids, cyclosporine and mycophenolate mofetil. The diagnosis was based on progressive dyspnoea with fever with an alteration in the general state associated with diffuse micronodular pneumopathy suggesting bronchiolitis. The conformation was obtained by the analysis of the alveolar bronchial washings and the histological examination of the distal biopsies revealing endo-alveolar vegetant fibromas. Transbronchial biopsies may be used for the diagnosis and thereby, avoid an invasive surgical pulmonary biopsy. The aetiology of OP may be related to the immunosuppressant treatment or infection by Pneumocystis jiroveci. The evolution in this case was favourable with trimethoprime and sulfamethoxazole associated with a transient increase in the corticoid treatment. This association is rarely described in patients undergoing solid organ transplants.

High dose epoetin beta in the first weeks following renal transplantation and delayed graft function: Results of the Neo-PDGF Study.

Erythropoietin promotes nephroprotection in animal models of ischemia-reperfusion injury. Neorecormon and Prevention of Delayed Graft Function (Neo-PDGF) is a French open-label multicenter randomized study to evaluate the effect of high doses of epoetin beta (EPO-beta) during the first 2 weeks of renal transplantation on renal function in patients at risk for delayed graft function (DGF). One hundred and four patients were included in the study. Patients randomized in treatment group (A) received four injections of EPO-beta (30.000 UI each), given before surgery and at 12 h, 7 days and 14 days posttransplantation. Patients randomized in control group (B) did not receive EPO-beta. Immunosuppression included induction with basiliximab and maintenance therapy with steroids, mycophenolate mofetil and tacrolimus. At 1 month posttransplant, the estimated glomerular filtration rate (MDRD formula) was 42.5 +/- 19.0 mL/min in the EPO-beta group and 44.0 +/- 16.3 mL/min in the control group (p = ns). The frequency of DGF was similar in both groups (32% vs. 38.8%; p = ns). No difference in the incidence of serious adverse events was observed. (ClinicalTrials.gov number, NCT00815867.).