Simon R. Knight

Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk: a meta-analysis

Introduction. The morbidity related to long-term steroid therapy has led to continued interest in withdrawal of steroids from immunosuppressant regimens after renal transplantation. A number of recent trials have provided long-term information regarding the risks and benefits of steroid avoidance or withdrawal (SAW). Methods. A literature search was performed using Ovid Medline, Embase, the Cochrane Library, and the Transplant Library. Randomized controlled trials comparing a maintenance steroid group with complete avoidance or withdrawal of steroids were selected. All studies were assessed for methodological quality. Trials were pooled by meta-analysis to provide summary effects (relative risk [RR] or weighted mean difference) with 95% confidence intervals (CI). Results. Thirty-four studies including 5637 patients met the inclusion criteria. SAW regimens significantly increased the risk of acute rejection (AR) over maintenance steroids (RR 1.56, CI 1.31–1.87, P<0.0001). No significant differences in corticosteroid resistant AR, patient survival, or graft survival were observed. Serum creatinine was increased and creatinine clearance was reduced with SAW. Cardiovascular risk factors including incidence of hypertension (RR 0.90, CI 0.85–0.94, P<0.0001), new onset diabetes (RR 0.64, CI 0.50–0.83, P=0.0006), and hypercholesterolemia (RR 0.76, CI 0.67–0.87, P<0.0001) were reduced significantly by SAW. Conclusion. Despite an increase in the risk of AR with SAW protocols, there is only a small effect on graft function with no measurable effect on graft or patient survival. There are significant benefits in cardiovascular risk profiles after SAW. SAW protocols would seem justified with current immunosuppressive protocols in low-risk recipients.

Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review.

Background. Mycophenolate mofetil (MMF) has increasingly replaced azathioprine (AZA) as the antimetabolite of choice in immunosuppressive protocols. Initial trials comparing MMF with AZA in patients receiving cyclosporine A sandimmune showed a clinical benefit in reducing the incidence of acute rejections. It has been questioned whether this benefit remains significant when using newer formulations of cyclosporine A (neoral) and tacrolimus. Methods. Literature searches were performed using the Transplant Library, Cochrane library, Medline, and Embase for all randomized controlled trials directly comparing MMF with AZA in renal transplant recipients. Trials were assessed for quality using the Jadad scoring system. Trials were pooled using meta-analysis software. Confidence intervals were set at 95%. Results. Nineteen relevant studies were identified, including a total of 3143 patients. MMF significantly reduces the risk of acute rejection when used in combination with any calcineurin inhibitor (relative risk 0.62, 0.55–0.87, P<0.00001). The hazard for graft loss, including death with a functioning graft, is also significantly reduced in patients treated with MMF (hazard ratio 0.76, 0.59–0.98, P=0.037). There is no significant difference in patient survival or renal transplant function between groups. Risk of adverse events, including cytomegalovirus infection, anemia, leukopenia or rates of malignancy, does not differ significantly. A greater risk of diarrhea is seen in MMF-treated patients. Conclusions. We have shown that MMF used with a calcineurin inhibitor does indeed confer a clinical benefit over AZA by reducing the risk of acute rejection and also possibly reducing graft loss. This effect is independent of whether MMF is used in combination with sandimmune, neoral or tacrolimus.

Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review.

Background. The use of mycophenolate mofetil (MMF) as a primary immunosuppressant after transplantation is increasing. A number of factors interact to result in variability in blood levels of mycophenolic acid (MPA) increasing the risk of toxicity. This has led to interest in the application of therapeutic drug monitoring to optimize its use. Methods. A systematic literature search was performed using Medline, Embase, the Cochrane Central Registry of Clinical Trials, the Transplant Library, and clinical trial registries for studies investigating the clinical role of MMF pharmacokinetic drug monitoring. Studies relating monitoring regimens to clinical outcomes were included. Results. The majority of studies are retrospective in nature, demonstrating good correlation between the full total MPA area-under-the-curve and the risk of acute rejection, but not toxicity. Free MPA levels may better predict toxicity. Single-point parameters, in particular trough levels, show poor correlation with the risk of acute rejection and toxicity, and in prospective studies do not improve clinical outcomes. Limited sampling strategies using samples from the first few hours postdose allow good prediction of the full area-under-the-curve, and monitoring using these strategies may improve clinical outcomes. Conclusions. The current data regarding therapeutic monitoring of MMF is of limited quality. The most promising results to date come from limited sampling strategies, with benefit seen in one prospective randomized trial. Further prospective trials and longer follow-up are required to investigate the optimum sampling strategy and subsets of patients who may benefit from monitoring, but the current evidence in favor of monitoring is weak.

The clinical benefits of cyclosporine C2-level monitoring: a systematic review.

Background. Monitoring of cyclosporine microemulsion (Neoral) using 2-hour postdose (C2) levels is alleged to improve clinical outcomes, but the efficacy of this strategy is uncertain. Methods. A systematic literature search was performed for trials directly comparing patients monitored with C2 levels with those monitored by trough (C0) levels. Primary outcomes assessed were renal function and acute rejection. Results. A total of 29 studies met the inclusion criteria. Only 10 of these were randomized controlled trials. Overall quality was poor and this precluded meta-analysis. The most consistent finding in de novo renal, hepatic, and cardiac transplant recipients is a higher mean cyclosporine dose in the early postoperative period in C2 monitored patients. There is no clear evidence that this leads to impaired renal function. In the majority of studies, the monitoring strategy had no significant effect on the rate of acute rejection. In stable transplant recipients, the majority of studies show a reduction in mean cyclosporine dose with adoption of C2 monitoring. No obvious clinical benefit was derived from this reduction in dose. Conclusion. In de novo transplant patients, there is little evidence from prospective studies to support the theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no short-term clinical benefit is seen. Quality of studies in this area is poor, and the practical limitations of C2 monitoring mean that further evidence is required before a strategy for the administration of cyclosporine based on C2 levels can be recommended.

Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes.

Adequate preservation of renal allografts for transplantation is important for maintaining and improving transplant outcomes. There are two prevalent methods: hypothermic machine perfusion and static cold storage. The preferred method of storage, however, remains controversial. The objective was to review systematically the evidence comparing outcomes from these two modalities.

Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis.

Background Alemtuzumab (MabCampath or Campath; Genzyme, Cambridge, MA) is a CD52-specific monoclonal antibody that causes profound and sustained lymphocyte depletion. Its use as an induction therapy in organ transplantation is increasing. Since our last systematic review in 2006, where we identified the need for good-quality randomized controlled trials (RCTs), several RCTs have been published that examine its efficacy and safety in kidney transplantation. The aim of this study was to evaluate the current evidence for alemtuzumab induction therapy in kidney transplantation. Methods We performed a systematic literature search using Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Transplant Library from the Centre for Evidence in Transplantation, and International Clinical Trials Registry Platform. Inclusion criteria specified all RCTs in which kidney transplant recipients receiving induction with alemtuzumab were compared with those receiving another induction agent or no induction. Studies were assessed for methodological quality. The primary outcome was the incidence of biopsy-proven acute rejection (BPAR) (Banff grade ≥1), and secondary outcomes included graft loss, renal function, delayed graft function (DGF), patient death, and the incidence of infection, autoimmunity, malignancy, and new-onset diabetes mellitus after transplantation. Results Ten RCTs, with a total of 1223 patients, were included. Studies were grouped according to induction regimens. Alemtuzumab induction has a lower risk of BPAR compared with induction with the interleukin-2 receptor antibodies (IL-2RAs): basiliximab (Simulect; Novartis, Basel, Switzerland) and daclizumab (Zenapax; Roche, Basel, Switzerland) combined (relative risk, 0.54; 95% confidence interval, 0.37–0.79; P<0.01). No significant difference was observed in the risk of BPAR when alemtuzumab induction was compared with rabbit antithymocyte globulin (rATG) (Thymoglobulin [Genzyme] or ATG-Fresenius S [Fresenius, Munich, Germany]) (relative risk, 0.79; 95% confidence interval, 0.52–1.21; P=0.28). There was no difference in graft loss, DGF, patient death, and new-onset diabetes mellitus after transplantation when alemtuzumab was compared with IL-2RAs or rATG induction. The effect of alemtuzumab induction on renal function and the incidence of infection, malignancy, and autoimmunity were limited by the data available. There were two trials comparing alemtuzumab with no induction, but neither trial reported a significant reduction in BPAR at 12 months. Conclusions Alemtuzumab induction reduces the risk of BPAR compared with IL-2RAs but not rATG. Because the incidence of other efficacy outcomes (graft loss, DGF, and patient death) was similar, if it is felt that an induction agent is necessary, then our analysis suggests that it is more acceptable to base the choice of induction agent on safety outcomes and/or costs.

Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis

Static cold storage is the most prevalent method for renal allograft preservation. Several solutions have been designed to counteract the detrimental effects of cold ischemia and reperfusion. The aim of this study was to appraise the evidence for the currently available preservation solutions. We performed a systematic literature search using MEDLINE, EMBASE, the Cochrane Library, the Transplant Library and trial registries. Inclusion criteria specified any comparative, prospective study for deceased donor renal allografts. Studies were assessed for methodological quality. The primary outcome was delayed graft function (DGF). Fifteen trials with a total of 3584 kidneys were included. Eurocollins was associated with a higher risk of DGF than University of Wisconsin solution (UW) in two randomized controlled trials (RCTs) and histidine–tryptophan–ketoglutarate (HTK) in two RCTs. UW was associated with an equal risk of DGF compared with Celsior in three RCTs and HTK in two RCTs. There was limited data regarding other comparisons and outcomes. The choice of preservation solution has an effect on the incidence of DGF, which might, in turn, affect long‐term outcomes. Both UW and HTK have lower rates of DGF than Eurocollins. There is no difference in the incidence of DGF with the use of Celsior, HTK and UW. These findings are supported by registry data.

Tuberculosis in Renal Transplant Recipients: The Evidence for Prophylaxis

Background. Tuberculosis (TB) remains a leading cause of death in endemic countries and is 20 to 70 times more common in renal transplant recipients, where it contributes to both increased morbidity and mortality. This review will focus on the epidemiology of TB in renal transplant recipients and critically appraise the published literature on isoniazid prophylaxis in renal transplantation. Methods. A literature search for randomized and nonrandomized studies investigating the use of isoniazid prophylaxis in renal transplant recipients was conducted using Ovid MEDLINE, the Cochrane Library, the Transplant Library, and EMBASE. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis of the randomized controlled trials (RCTs) was performed with a fixed-effects model. Results. Eleven relevant studies were identified; six nonrandomized and five RCTs. The nonrandomized studies indicate a reduced risk of TB with isoniazid prophylaxis. The RCTs demonstrated conflicting results, with two studies finding a reduction in TB with prophylaxis and two studies finding no difference. Meta-analysis of the 709 patients from the four RCTs demonstrated a reduced risk of TB with isoniazid prophylaxis (RR, 0.31; 95% CI, 0.19–0.51). No significant difference was found in the incidence of hepatitis (RR, 1.22; 95% CI, 0.91–1.65). Conclusion. Both randomized and nonrandomized studies support the value of isoniazid as TB prophylaxis in renal transplant recipients at risk of active infection. Clinicians should consider prophylaxis in renal transplant recipients in endemic areas or in recipients in nonendemic countries who are at risk. However, the evidence for the benefit of isoniazid prophylaxis in renal transplantation is not robust and there is still a need for a large multicenter trial of isoniazid prophylaxis in kidney transplantation in an endemic area.

A systematic review of the use of rituximab for desensitization in renal transplantation.

Background Rituximab is a B lymphocyte–depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible and highly sensitized recipients undergoing renal transplantation. Methods A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four databases and three trial registries were searched for studies comparing rituximab with non-rituximab desensitization protocols. A lack of randomized evidence precluded meta-analysis, and thus a narrative review was conducted. Results Forty-five records met the inclusion criteria, relating to 21 individual studies (two randomized controlled trials and 19 retrospective cohort studies). Ten studies investigated the use of rituximab in ABO-incompatible patients; most found no significant differences in patient and graft outcomes when compared most frequently to splenectomy-based protocols. Nine studies of limited quality focused on highly sensitized recipients (positive cross-match, donor-specific antibody, and elevated panel reactive antibody) and demonstrated some benefits in graft survival, acute and chronic rejection, and sensitization levels with rituximab. The remaining two studies combined ABO-incompatible and highly sensitized recipients and found no statistically significant increase in infectious complications with rituximab. Conclusion Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting.

The Role of Cancer-Testis Antigens as Predictive and Prognostic Markers in Non-Small Cell Lung Cancer

Background Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. Methods We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. Results NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28–5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07–0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. Conclusions NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.