Nephrology literature watch

Citation: Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010;21: 1587–1596. Analysis: Belatacept is a co-stimulation blocker that binds CD80/CD86 on antigen-presenting cells preventing T-cell activation, a new class of therapeutic agents in transplantation immunosuppression that differs from existing immunosuppressive agents. It is a recombinant soluble fusion protein consisting of the extracellular domain of human CTLA-4 and a fragment (hinge–CH2–CH3 domains) of a modified Fc domain of human IgG1. It is given intravenously.1 The primary aim of the current study was to assess the safety and tolerability of long-term belatacept administration in kidney transplant patients. The secondary aim was to assess the efficacy of belatacept as a long-term maintenance immunosuppressant. Pharmacokinetic and pharmacodynamic properties of the belatacept and anti-belatacept antibody generation were also investigated. The current study extends the observations reported from a randomized multicenter Phase 2 clinical study of 218 patients conducted in the U.S., Canada, and Europe that demonstrated non-inferiority of belatacept for safety and efficacy (allograft preservation) with better preservation of the glomerular filtration rate (GFR) at 12 months when compared with cyclosporine (CsA).2 In the original study, patients were randomly assigned in equal numbers of three groups to receive a more intensive or less intensive regimen of belatacept, or CsA. All patients received induction therapy with basiliximab and adjuvant therapy with mycophenolate mofetil and corticosteroids for 12 months after transplant. This paper by Vincenti and colleagues reports on the results of the extension of the first randomized clinical trials to assess long-term safety and efficacy of belatacept over 5 years compared with conventional therapy with CsA. The data cutoff date occurred 6 years and 7 months after the initiation of the original trial. One-hundred twentyeight patients consented to continue in the extension trial and were kept on the original maintenance treatment arms: CsA or belatacept (5 mg/kg at 4- or 8-week intervals); 56 belacept recipients received 4-week dosing, and 46 received 8-week dosing; 78 of 102 patients receiving belatacept and 16 of 26 receiving CsA completed the 5 year extension of the trial. Renal function was stable in belatacept patients with average calculated GFR was 75.8 ml/min per 1.73 m2 at 12 months and 77.2 ml/min per 1.73 m2 at 60 months post-transplantation. GFR was similar for patients on either 4- or 8-week belatacept dosing. In the CsA group, GFR decreased significantly from 74.4 ml/min per 1.73 m2 at 12 months to 59.3 ml/min per 1.73 m2 at 60 months post-transplantation. Incidences of graft loss or death were low. There were 6 cases of biopsyproven acute rejection (BPAR) in the belatacept group (2 cases in 4-week dosing during year 2, and 4 cases in 8-week dosing in years 2, 3, 4, and 5). In the CsA extension arm there were no BPAR cases, however, 3 cases were treated for acute rejection (AR) on the basis of clinical findings. Overall, BPAR was uncommon in the years following the initial RCT and no BPAR cases in the belatacept group led to graft loss. At 60 months post-transplant, 86% of patients in the belatacept group and 89% in the CsA group required antihypertensives, and 52% of the belatacept group and 72% of the CsA required lipid-lowering agents. Serious infections were seen in 16% of the belatacept group and 27% in the CsA group. Cytomegalovirus (CMV) and BK polyomavirus infection were rare in both groups. The frequencies for CMV infection were 1% in the belatacept and 4% in the CsA group. Two percent of the belatacept recipients but no CsA recipients developed BK polyomavirus infection. During the extension of the original RCT, no patient in the belatacept group but 1 patient in the CsA group developed post-transplantation lymphoproliferative disorder (PTLD). Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic studies from a subset of belatacept study subjects showed consistent exposure to belatacept over time. Safety and efficacy were similar between the 4- and 8-week dosing groups, except for a higher incidence of AR with the 8- week dosing schedule. Mean half-life of belatacept was 8 days with a predictable decline in the levels over time and little inter-patient variability. Two belatacept-treated patients developed neutralizing antibodies. CD86 receptor saturation was higher in the 4-week schedule than the 8-week schedule patients (74% versus 56%). Validity and threats to validity: This study is an extension of open label RCT, prospectively randomized (with masked allocation) multicenter clinical study in which bias and threats to validity were addressed by the randomization procedure, masked allocation and masked adjudication of outcomes. The patients, however, who entered the long-term extension trial were selfselected and were generally those who did particularly well during the RCT phase of the study prior to entrance into the long-term extension study. The average GFR of the study subjects continuing into the extended phase trial at the time of extension study entrance was higher than that observed in patients who did not enter the long-term extension phase; 75.8 versus 69.5 ml/min per 1.73 m2 for belatacept and 74.4 versus 67.4 ml/min per 1.73 m2 for CsA. In addition, a higher percentage of belatacept recipients remained in the long-term extension trial (76% versus 62% for CsA). Both of these potentially introduce a selection bias into the study and may have distorted the results of the extension phase trial. The limitation of the study also includes small sample size and relatively “short” duration of follow-up (5 years). This follow-up period is not long enough to observe the full longterm effects of belatacept on the occurrence of chronic allograft nephropathy. Another potential limitation is that this study used CsA rather than tacrolimus as the primary calcineurin inhibitor for comparison to belatacept where the latter is now the preferred calcineurin inhibitor in many centers. Clinical bottom line: Belatacept may be an alternative to calcineurin inhibitors because of the observed superior preservation renal function, and possible improvement of long-term outcomes. Calcineurin inhibitors are associated with non-immunologic untoward side effects including worsening of hypertension, diabetes, and dyslipidemia that can negatively impact on cardiovascular morbidity and allograft function where these untoward side effects might be avoided with the use of belatacept. On the downside, belatacept requires intravenous administration which may be difficult long-term in many ESRD patients. The current long-term extension trial demonstrated high patient adherence with intravenous belatacept, providing stable renal function, predictable pharmacokinetics, in addition to similar efficacy and safety to CsA over 5 years.3, 4 These extend the findings reported after shorter periods of followup in the Phase 3 studies.These Phase 3 studies (the BENEFIT Study3 and the BENEFIT-EXT Study)4 have shown similar results, namely, that belataceptbased regimens sustained better renal function, similar patient/graft survival, and improved cardiovascular and metabolic risk profiles at 2 years when compared with CsA. Additionally, belatacept (BENEFIT-EXT Study) appears to be safe and effective for ECD kidney transplant recipients. Citation: Franz S, Regeniter A, Hopfer H, Mihatsch M, Dickenmann M. Tubular toxicity in sirolimus- and cyclosporinebased transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis. 2010;55:335–343. Analysis: Cyclosporine has been a mainstay of immunosuppressive therapy for more than 30 years, but the side effects of renal vasoconstriction, increased risk of cardiovascular disease and malignancies, and chronic allograft nephropathy have prompted the continuing search for better alternatives.5 Sirolimus, which acts at a later step in the T-cell signaling pathway, has been promoted over the last decade as both a calcineurin sparing agent6 and as an alternative for the prevention of acute and chronic rejections.7 Recently, however, several studies have focused on the tubular toxicity of sirolimus, particularly with respect to the development of delayed graft function and proteinuria.8, 9 In this randomized, prospective trial by Franz and colleagues, a sirolimus-based regimen for incident transplant patients was compared to that of a more traditional cyclosporine regimen. The study enrolled 127 patients, excluding high and low risk patients, who were all treated with mycophenolate mofetil and prednisone and randomized to receive either cyclosporine or sirolimus. Patients were followed for 6 months and comparisons were made with respect to overall kidney function, patient and graft survival, number of rejection episodes, and for biomarkers of glomerular and tubular injury. The results demonstrate no difference in kidney function or graft survival, but do show greater tubular and glomerular damage in the sirolimus group. Validity and threats to validity: Strengths of the study include masked randomization, prospective allocation, predefined inclusion and exclusion criteria, and clinically important predefined primary and secondary outcomes. There was nearly complete follow-up with 2 patients being lost to death and 2 to primary non-functioning grafts. While specifics of how the randomization was carried out (block randomization, stratification, etc.) are not detailed in this paper, the baseline characteristics of both groups are similar. The data was rigorously analyzed, and the tables indicate that the analysis was performed by intention-to-treat. Several factors, however, must be considered when interpreting the results. First, nearly half of the sirolimus arm and one-quarter of the cyclosporine arm patients were withdrawn from the protocol before the 6-month follow-up. Such high numbers lost to follow-up and possible unknown secondary interventions/protocol deviations, introduce a significant degree of uncertainty into the findings and reduce the strength of any conclusions arising from this study about hard outcomes. Also, while the total number of rejections was similar between the groups, 18 patients were withdrawn from the sirolimus group due to severe or repeated rejections, versus only 10 patients in the cyclosporine arm. A per-protocol analysis may be beneficial in this situation to help determine whether the increased markers of glomerular and tubular dysfunction were related to the higher number of severe rejections in the sirolimus subjects or to direct toxicity from sirolimus. It is likely that the differential drop-out rate will have distorted the results but if so, the direction of distortion is likely to have demonstrated a more favorable outcome with sirolimus than truly exists. An unfavorable outcome for the subjects on sirolimus was demonstrated so the expected distortion will most likely act to lessen the magnitude of the adverse effects and reduced the power of this study to demonstrate important patient centered adverse clinical outcomes. Additionally, markers of injury declined in both groups over time. While the ratios were unchanged between the groups, there was a steady decline over the 6-month period. Whether the difference in tubular injury markers would remain significant or whether patientcentered outcomes such as mortality and graft survival would be differentially affected after a longer follow-up period is unaddressed by this study. Clinical bottom line: While the current study demonstrates that markers of tubular and glomerular injury are worse in patients on sirolimus, this intention-to-treat analysis may produce significantly skewed results because of the differential and high drop-out rate and protocol deviations, particularly in the sirolimus arm of the study where protocol deviations occurred in nearly 50% of the patients. An additional potentially important observation reported from this study is the high rate of severe rejection episodes (29% in the sirolimus group), a rate much higher than previously reported.7, 10 This study does add concern to the growing evidence of potential tubulotoxic or proteinuric effects of sirolimus, but at this point, the data are insufficient to address whether the evidence of tubular injury translates into additional adverse long-term patient-centered outcomes. Citation: Van Leeuwen MT, Webster AC, McCredie MR, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ. 2010;340:c570. Analysis: Van Leeuwen and colleagues exploit two robust, independently assembled, relatively complete and linkable registries (the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry (Australian participants) and the Australian National Cancer Statistics Clearing House registry) to estimate the risk of various types of cancer during immunosuppression for renal transplantation and after immunosuppression is discontinued for those individuals who have a failed transplant and return to dialysis. The authors use the time of return to dialysis as a means of estimating the date of discontinuation of immunosuppression therapies. In this study, the authors confirm the previously reported observation that risk for a broad range of cancers is increased with immunosuppression, including those that are, in part, thought to be related to concurrent viral infections including Kaposi's sarcoma, non-Hodgkins lymphoma and anogenital cancers. The novel finding from this study is the observation that cancer risk compared to age- and gender-matched healthy individuals in the general population changes for certain types of cancer when immunosuppression is discontinued—that the cancer risk for certain types of cancers is rapidly reversible once immunosuppression is discontinued. This finding is particularly evident for Kaposi's sarcoma, non-Hodgkin's lymphoma, melanoma, and lip cancers. For cancers that are more strongly associated with ESRD such as kidney, urinary tract and thyroid cancers and for lung cancer, leukemia, no such reversibility is seen in individuals who return to dialysis off of immunosuppression medications. In this epidemiologic analysis, colon, breast and prostate cancer risks were not increased in patients with transplantation or those in the on dialysis when compared with the general population. Validity and threats to validity: This study reports on cancer risk in transplant recipients and the changes in cancer risk when immunuosuppression is discontinued. A robust way of evaluating this question is to measure cancer risk in a prospective cohort. The ANZDATA registry represents such a prospective cohort. Data regarding transplant type and duration and the data of return to dialysis are prospectively recorded and the data is complete for the population (except for the very small number of individuals who migrate from Australia). In this study, individuals were censored from the data when they died, where death from a non-cancerous cause represents a competing outcome for the development of cancer. A composite outcome, cancer or death was not evaluated and therefore, competing outcomes might have distorted somewhat the risk profiles. Only cancers occurring more than 3 months after change in immunosuppression status were included in an attempt to evaluate cancers likely to have been influenced by treatment status. Outcomes (i.e., cancer diagnosis) were obtained from the national cancer registry, where data were collected prospectively on a national level and independently of transplant status. It is unlikely that there was a significant rate of misclassification of individuals included in the registry related to transplant status. It is uncertain, however, if any individuals with cancer were not captured in this registry where this ascertainment of outcomes might be different depending on transplant status. It is likely that nearly everyone with a functioning transplant was identified if and when they developed a cancer. The added surveillance for cancer in patients followed in a transplant specialty clinic might have resulted in the identification of cancers at an earlier stage. It is also possible that individuals with a failed transplant back on dialysis might choose not to have suspicious symptoms evaluated thereby leading to an under diagnosis of cancers in individuals on dialysis. The influence of any potential ascertainment bias on the results can not be determined. It seems unlikely that this bias was large given that not all cancer risks changed similarly with changes in immunosuppression status. It seems reasonable to equate dialysis or functioning transplant with immunosuppression therapy status especially if the customary practice in Australia is to discontinue immunosuppressive medications promptly upon resumption of chronic dialysis therapy. It is also possible that some patients were not taken off of their immunosuppression medications promptly on the return to dialysis and this would represent a potential, albeit likely small, misclassification of exposure bias. The study was underpowered to evaluate risk for certain rare types of malignancies and either a larger prospective cohort study of longer duration or a carefully crafted case-control study, nested within a much larger cohort, will be required to evaluate for any incremental risk for rare or uncommon cancers. Clinical bottom line: This study supports the view that the excess risk observed for certain cancers amongst individuals on immunusuppression therapy after renal transplantation can be reversed rapidly with cessation of the immunosuppressive medications. For certain other types of cancers, however, changes in immunosuppression medication status does not seem to alter risk. These findings may provide clinicians and patients with a better understanding of cancer risk and the contribution from immunosuppresion therapy to this risk, a clearer appreciation that this risk is rapidly reversible for some but not all cancers, and a better understanding of whether judicious changes in therapy might alter risk for some patients. This study provides support for the strategy of relatively promptly discontinuing immunosuppression therapy once an individual's kidney transplant fails and they are required to return to dialysis.

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