Josep M. Grinyó

A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT‐EXT Study)

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long‐term outcomes versus CNIs. BENEFIT‐EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial—EXTended criteria donors) is a 3‐year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4–7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept‐based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine‐treated patients.

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

Background. The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resulted in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. Methods. Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2R&agr;), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 months and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy endpoint was biopsy-proven rejection during the first 6 months posttransplant. Results. Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 &mgr;mol/L (95%, confidence interval [CI], 100.7 to 125.3 &mgr;mol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 &mgr;mol/L (95% CI, 135.0 to 173.0 &mgr;mol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2R&agr; saturation. Conclusions. This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2R&agr; blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.

Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss

Chronic allograft nephropathy (CAN) in protocol biopsies is associated with graft loss while the association between subclinical rejection (SCR) and outcome has yielded contradictory results. We analyze the predictive value of SCR and/or CAN in protocol biopsies on death‐censored graft survival. Since 1988, a protocol biopsy was done during the first 6 months in stable grafts with serum creatinine <300 μmol/L and proteinuria <1 g/day. Biopsies were evaluated according to Banff criteria. Borderline changes and acute rejection were grouped as SCR. CAN was defined as presence of interstitial fibrosis and tubular atrophy. Mean follow‐up was 91 ± 46 months. Sufficient tissue was obtained in 435 transplants. Biopsies were classified as normal (n = 186), SCR (n = 74), CAN (n = 110) and SCR with CAN (n = 65). Presence of SCR with CAN was associated with old donors, percentage of panel reactive antibodies and presence of acute rejection before protocol biopsy. Cox regression analysis showed that SCR with CAN (relative risk [RR]: 1.86, 95% confidence interval [CI]: 1.11–3.12; p = 0.02) and hepatitis C virus (RR: 2.27, 95% CI: 1.38–3.75; p = 0.01) were independent predictors of graft survival. In protocol biopsies, the detrimental effect of interstitial fibrosis/tubular atrophy on long‐term graft survival is modulated by SCR.

A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients

In a randomized, open‐label, multicenter study, de novo renal transplant patients received no steroids (n = 112), steroids to day 7 (n = 115), or standard steroids (n = 109) with cyclosporine microemulsion (CsA‐ME), enteric‐coated mycophenolate sodium (EC‐MPS) and basiliximab. The primary objective, to demonstrate noninferiority of 12‐month GFR in the steroid‐free or steroid‐withdrawal groups versus standard steroids, was not met in the intent‐to‐treat population. However, investigational groups were not inferior to standard steroids in the observed‐case analysis. Median 12‐month GFR was not significantly different in the steroid‐free or steroid‐withdrawal groups (58.6 mL/min/1.73 m2 and 59.1 mL/min/1.73 m2) versus standard steroids (60.8 mL/min/1.73 m2). The 12‐month incidence of biopsy‐proven acute rejection (BPAR), graft loss or death was 36.0% in the steroid‐free group (p = 0.007 vs. standard steroids), 29.6% with steroid withdrawal (N.S.) and 19.3% with standard steroids. BPAR was significantly less frequent with standard steroids than either of the other two regimens. Reduced de novo use of antidiabetic and lipid‐lowering medication, triglycerides and weight gain were observed in one or both steroid‐minimization group versus standard steroids. For standard‐risk renal transplant patients receiving CsA‐ME, EC‐MPS and basiliximab, steroid withdrawal by the end of week 1 achieves similar 1‐year renal function to a standard‐steroids regimen, and may be more desirable than complete steroid avoidance.

Early cyclosporine withdrawal from a sirolimus‐based regimen results in better renal allograft survival and renal function at 48 months after transplantation

We report the 48‐month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)‐CsA‐steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL‐CsA‐ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215). SRL‐ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL‐ST. Differences in the incidences of biopsy‐proven acute rejection after randomization (6.5% vs. 10.2%, SRL‐CsA‐ST versus SRL‐ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL‐CsA‐ST‐treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL‐ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL‐CsA‐ST regimen rapidly improves renal function and ultimately results in better graft survival.

Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low‐dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low‐doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow‐up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow‐up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow‐up, renal function remained stable (mean change: −0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low‐dose tacrolimus arm continued to have the highest GFR (68.6 ± 23.8 ml/min vs. 65.9 ± 26.2 ml/min in the standard‐dose cyclosporine, 64.0 ± 23.1 ml/min in the low‐dose cyclosporine and 65.3 ± 26.2 ml/min in the low‐dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair‐wise tests). The MMF and low‐dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low‐dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Mammalian Target of Rapamycin Pathway Blockade Slows Progression of Diabetic Kidney Disease in Rats

Recent data suggest that the phosphatidylinositol 3-kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway is important in diabetic nephropathy. The effect of mTOR blockade by sirolimus (SRL) in diabetic kidney disease in rats was investigated. Diabetes was induced by streptozotocin in male Sprague-Dawley rats. Sixteen weeks later, diabetic animals were divided into the following groups: diabetes (D; n = 8), diabetes + SRL at 1 mg/kg per d, SRL trough level 2.3 +/- 0.25 ng/ml (D+SRL; n = 7); and diabetes + normoglycemia maintained by insulin implants (D+NG; n = 5). There was an age-matched nondiabetic group (ND; n = 6). All animals were followed for 4 wk. The D group showed glomerular hypertrophy (mean glomerular volume 5.0 +/- 0.4 in D versus 3.3 +/- 0.2 10(6) mu(3) in ND; P < 0.05) without renal hyperplasia (calculated by reverse transcription-PCR of proliferative cell nuclear antigen) and albuminuria (29 +/- 4 in D versus 1.4 +/- 1.5 mg/24 h in ND; P < 0.05). Both D+NG and D+SRL groups had a significant reduction of albuminuria, although glomerular hypertrophy was still present. SRL treatment did not modify the number of infiltrating renal ED1(+) cells. Diabetic animals had greater expression of p-Akt and mTOR, unlike ND rats. NG and SRL treatment reduced p-Akt and normalized mTOR. It is interesting that D+SRL was associated with a significant reduction of renal TGF-beta1 and glomerular connective tissue growth factor. SRL treatment reduced glomerular alpha-smooth muscle actin overexpression and reduced significantly the mesangial matrix accumulation that is characteristic of diabetic nephropathy. In conclusion, mTOR blockade by low-dose SRL has a beneficial effect in diabetic kidney disease, suggesting that the mTOR pathway has an important pathogenic role in diabetic nephropathy.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended‐criteria donor (ECD) kidneys have poorer long‐term outcomes compared to standard‐criteria donor kidney recipients. We report 3‐year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty‐three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept‐treated versus cyclosporine‐treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine‐treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept‐treated patients (27–30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept‐treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Hepatitis C Virus Infection and de Novo Glomerular Lesions in Renal Allografts

In the present study we examine whether hepatitis C virus (HCV) infection status influences glomerular pathologic findings in renal allografts and its effect on graft outcome. Renal allograft biopsies performed between January 1991 and June 1999 were considered. Exclusion criteria were insufficient sample, unknown HCV serological status at time of biopsy and final diagnosis of acute rejection. Light microscopy and immunofluorescence studies were performed on all biopsies. According to a predefined protocol, electron microscopy was carried out. Of 138 eligible renal allograft biopsies, 42 fulfilled at least one exclusion criterion. Of 96 biopsies selected for the study, 44 (45.8%) were from HCV‐positive and 52 from HCV‐negative recipients. Renal biopsy was performed 74 ± 55 and 60 ± 39 months after transplantation in HCV‐positive and HCV‐negative groups, respectively (p = 0.12). Of 44 HCV‐positive biopsies, 20 (45.4%) showed membranoproliferative glomerulonephritis (MPGN) (16 type I and 4 type III). Conversely, in HCV‐negative biopsies there were only three cases of MPGN (2 type I and 1 type III). De novo membranous GN (MGN) was diagnosed in 8/44 (18.2%) HCV‐positive and in 4/52 (7.7%) HCV‐negative cases. The prevalence of chronic transplant glomerulopathy was similar in HCV‐positive and HCV‐negative groups (11.4% and 11.5%, respectively). The prognosis of de novo GN (either MPGN or MGN) was worse in HCV‐positive than in HCV‐negative recipients (relative risk 4.89; 95% confidence interval, 1.15–20.69; p = 0.03). By multivariate analysis, HCV‐positive serology infection was the only independent predictor of graft loss (relative risk 2.64; 95% confidence interval, 1.35–5.17; p = 0.005). In diagnostic renal allograft biopsies the presence of de novo immune‐mediated glomerulonephritis, especially type I MPGN, is strongly associated with HCV infection and results in accelerated loss of the graft.

The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.

Safety and efficacy of two sirolimus (SRL)‐based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher‐than‐expected biopsy‐confirmed acute rejections (BCARs), was sponsor‐terminated; therefore, Group 2 two‐year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One‐ and 2‐year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1‐ and 2‐year modified intent‐to‐treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One‐year post hoc analysis of new‐onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between‐group malignancy rates were similar. The SRL‐based regimens were not associated with improved outcomes for kidney transplantation patients.