Angela C Webster

Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.

Background The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. Methods With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a “Consensus Conference on Antibodies in Transplantation” in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. Results A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. Conclusions A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.

Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Abstract Objective To compare the positive and negative effects of tacrolimus and ciclosporin as initial treatment for renal transplant recipients. Design Systematic review. Data sources and study selection Reports of comparative randomised trials of tacrolimus and ciclosporin identified by searches of Medline, Embase, the Cochrane Register of Controlled Trials, the Cochrane Renal Group Specialist Register, and conference proceedings. Data extraction and synthesis Two reviewers assessed trials for eligibility and quality and extracted data independently. Data were synthesised (random effects model) and results expressed as relative risk (RR), with values < 1 favouring tacrolimus. Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions. Results 123 reports from 30 trials (4102 patients) were included. At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years. The relative reduction in graft loss with tacrolimus diminished with higher concentrations of tacrolimus (P = 0.04) but did not vary with ciclosporin formulation (P = 0.97) or ciclosporin concentration (P = 0.38). At one year, tacrolimus treated patients had less acute rejection (RR = 0.69, 0.60 to 0.79) and less steroid resistant rejection (RR = 0.49, 0.37 to 0.64) but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting. The relative excess of diabetes increased with higher concentrations of tacrolimus (P = 0.003). Ciclosporin treated recipients had significantly more constipation and cosmetic side effects. No differences were seen in infection or malignancy. Conclusions Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Optimal drug choice may vary between patients.

Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials.

Background. Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients. Methods. Databases (inception, June 2005) and conference proceedings (1996–2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values <1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). Results. Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74–1.44), but serum creatinine was lower (WMD, −18.31 &mgr;mol/L; 95% CI, −30.96 to −5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12–3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97–16.36; and anaemia: RR, 1.67; 95% CI, 1.27–2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71–0.99; RR, 0.49; 95% CI, 0.37–0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32–2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06–1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12–7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52–0.88), but calculated GFR was also reduced (WMD, −9.46 mL/min; 95% CI, −12.16 to −6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison. Conclusions. TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.

Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials

BACKGROUND Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. METHODS Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. FINDINGS Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34-0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48-0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43-0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08-0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. INTERPRETATION Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus-positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.

Sirolimus Is Associated with New-Onset Diabetes in Kidney Transplant Recipients

New-onset diabetes (NOD) is associated with transplant failure. A few single-center studies have suggested that sirolimus is associated with NOD, but this is not well established. With the use of data from the United States Renal Data System, this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes. Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine, sirolimus-treated patients were at increased risk for NOD, whether it was used in combination with cyclosporine (adjusted hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.36 to 1.90),tacrolimus (adjusted HR 1.66; 95% CI 1.42 to 1.93), or an antimetabolite (mycophenolate mofetil orazathioprine; adjusted HR 1.36; 95% CI 1.09 to 1.69). Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year. In conclusion, sirolimus is independently associated with NOD. Given the negative impact of NOD on posttransplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.

The views of patients and carers in treatment decision making for chronic kidney disease: systematic review and thematic synthesis of qualitative studies.

Objective To synthesise the views of patients and carers in decision making regarding treatment for chronic kidney disease, and to determine which factors influence those decisions. Design Systematic review of qualitative studies of decision making and choice for dialysis, transplantation, or palliative care, and thematic synthesis of qualitative studies. Data sources Medline, PsycINFO, CINAHL, Embase, social work abstracts, and digital theses (database inception to week 3 October 2008) to identify literature using qualitative methods (focus groups, interviews, or case studies). Review methods Thematic synthesis involved line by line coding of the findings of the primary studies and development of descriptive and analytical themes. Results 18 studies that reported the experiences of 375 patients and 87 carers were included. 14 studies focused on preferences for dialysis modality, three on transplantation, and one on palliative management. Four major themes were identified as being central to treatment choices: confronting mortality (choosing life or death, being a burden, living in limbo), lack of choice (medical decision, lack of information, constraints on resources), gaining knowledge of options (peer influence, timing of information), and weighing alternatives (maintaining lifestyle, family influences, maintaining the status quo). Conclusions The experiences of other patients greatly influenced the decision making of patients and carers. The problematic timing of information about treatment options and synchronous creation of vascular access seemed to predetermine haemodialysis and inhibit choice of other treatments, including palliative care. A preference to maintain the status quo may explain why patients often remain on their initial therapy.

Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients

Transplant recipients have increased cancer risk, but data on risk variation across different patient groups are sparse. Rates and standardized rate ratios (SRR) of cancer (all sites, excluding nonmelanocytic skin and lip cancer) compared to the general population were calculated, using Australia and New Zealand Dialysis and Transplant Registry data. Within the transplant population, risk factors were identified (hazard ratios: HR; 95% CI) and absolute risk estimated for recipient groups. A total of 1642 (10.8%) of 15 183 recipients developed cancer. Risk was inversely related to age (SRR 15–30 children, 2 if >65 years). Females aged 25–29 had rates equivalent to women aged 55–59 from the general population. Age trend for lymphoma, colorectal and breast risk was similar; melanoma showed less variability across ages, prostate showed no risk increase. Within the transplanted population, risk was affected by age differently for each sex (p = 0.007), elevated by prior malignancy (HR 1.40; 1.03–1.89), white race (HR 1.36; 1.12–1.89), but reduced by diabetic end‐stage kidney disease (ESKD) (HR 0.67; 0.50–0.89). Cancer rates in kidney recipients are similar to nontransplanted people 20–30 years older, but absolute risk differs across patient groups. Men aged 45–54 surviving 10 years have cancer risks varying from 1 in 13 (non‐white, no prior cancer, diabetic ESKD) to 1 in 5 (white, prior cancer, other ESKD).

Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials1

Background. Interleukin 2 receptor antagonists (IL-2Ra) are increasingly used to treat renal transplant recipients. This study aims to systematically identify and summarize the effects of using IL-2Ra as induction immunosuppression, as an addition to standard therapy, or as an alternative to other antibody therapy. Methods. Databases, reference lists, and abstracts of conference proceedings were searched extensively to identify relevant randomized controlled trials in all languages. Data were synthesized using the random effects model. Results are expressed as relative risk (RR), with 95% confidence intervals (CI). Results. A total of 117 reports from 38 trials involving 4,893 participants were included. When IL-2Ra were compared with placebo (17 trials; 2,786 patients), graft loss was not significantly different at 1 year (14 trials: RR 0.84; CI 0.64–1.10) or 3 years (4 trials: RR 1.08; CI 0.71–1.64). Acute rejection was significantly reduced at 6 months (12 trials: RR 0.66; CI 0.59–0.74) and at 1 year (10 trials: RR 0.67; CI 0.60–0.75). At 1 year, cytomegalovirus infection (7 trials: RR 0.82; CI 0.65–1.03) and malignancy (9 trials: RR 0.67; CI 0.33–1.36) were not significantly different. When IL-2Ra were compared with other antibody therapy, no significant differences in treatment effects were demonstrated, but IL-2Ra had significantly fewer side effects. Conclusions. Given a 40% risk of rejection, seven patients would need treatment with IL-2Ra in addition to standard therapy, to prevent one patient from undergoing rejection, with no definite improvement in graft or patient survival. There is no apparent difference between basiliximab and daclizumab.

A systematic review and meta-analysis of utility-based quality of life in chronic kidney disease treatments.

Melanie Wyld and colleagues examined previously published studies to assess pooled utility-based quality of life of the various treatments for chronic kidney disease. They conclude that the highest utility was for kidney transplants, with home-based automated peritoneal dialysis being second.

Association of CKD and Cancer Risk in Older People

People with ESRD are at increased risk for cancer, but it is uncertain when this increased risk begins in the spectrum of chronic kidney disease (CKD). The aim of our study was to determine whether moderate CKD increases the risk for cancer among older people. We linked the Blue Mountains Eye Study, a prospective population-based cohort study of 3654 residents aged 49 to 97 yr, and the New South Wales Cancer Registry. During a mean follow-up of 10.1 yr, 711 (19.5%) cancers occurred in 3654 participants. Men but not women with at least stage 3 CKD had a significantly increased risk for cancer (test of interaction for gender P = 0.004). For men, the excess risk began at an estimated GFR (eGFR) of 55 ml/min per 1.73 m2 (adjusted hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.00 to 1.92) and increased linearly as GFR declined. For every 10-ml/min decrement in eGFR, the risk for cancer increased by 29% (adjusted HR 1.29; 95% CI 1.10 to 1.53), with the greatest risk at an eGFR <40 ml/min per 1.73 m2 (adjusted HR 3.01; 95% CI 1.72 to 5.27). The risk for lung and urinary tract cancers but not prostate was higher among men with CKD. In conclusion, moderate CKD (stage 3) may be an independent risk factor for the development of cancer among older men but not women, and the effect of CKD on risk may vary for different types of cancer.