This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2) = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2) = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2) = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

Background and objectives: The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurements: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.Results: Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467;P6 months post-transplant; 8 of 321 versus 27 of 467;P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467;P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (Pvalue for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).Conclusions: HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease but the relevance of reduced kidney function to cancer risk is uncertain. Individual patient data were collected from six studies (32,057 participants); including one population-based cohort and five randomized controlled trials. Participants were grouped into one of five CKD categories (estimated glomerular filtration rate [eGFR] ≥75 mL/min/1.73 m2; eGFR ≥60 to <75 mL/min/1.73 m2; eGFR ≥45 to <60 mL/min/1.73 m2; eGFR <45 mL/min/1.73 m2; on dialysis). Stratified Cox regression was used to assess the impact of CKD category on cancer incidence and cancer death. Over a follow-up period of 170,000 person-years (mean follow-up among survivors 5.6 years), 2626 participants developed cancer and 1095 participants died from cancer. Overall, there was no significant association between CKD category and cancer incidence or death. As compared with the reference group with eGFR ≥75 mL/min/1.73 m2, adjusted hazard ratio (HR) estimates for each category of renal function, in descending order, were: 0.98 (95 % CI 0.87–1.10), 0.99 (0.88–1.13), 1.01 (0.84–1.22) and 1.24 (0.97–1.58) for cancer incidence, and 1.03 (95 % CI 0.86–1.24), 0.95 (0.78–1.16), 1.00 (0.76–1.33), and 1.58 (1.09–2.30) for cancer mortality. Among dialysis patients, there was an excess risk of cancers of the urinary tract (adjusted HR: 2.34; 95 % CI 1.10–4.98) and endocrine cancers (11.65; 95 % CI: 1.30–104.12), and an excess risk of death from digestive tract cancers (2.11; 95 % CI: 1.13–3.99), but a reduced risk of prostate cancers (0.38; 95 % CI: 0.18–0.83). Whilst no association between reduced renal function and the overall risk of cancer was observed, there was evidence among dialysis patients that the risk of cancer was increased (urinary tract, endocrine and digestive tract) or decreased (prostate) at specific sites. Larger studies are needed to characterise these site-specific associations and to identify their pathogenesis.

Background: Prolonged duration of delayed graft function (DGF) may be associated with adverse allograft outcomes, but the association between threshold duration of DGF, acute rejection and long-term allograft loss remains undefined. We aimed to determine the impact of DGF duration on allograft outcomes and to assess whether this association was mediated by acute rejection. Methods: Using data from the Australian and New Zealand Dialysis and Transplant Registry, Cox proportional modeling was used to determine the association between quartiles of DGF duration, acute rejection at 6 months and death-censored graft loss (DCGL). Mediation analysis was conducted to determine whether acute rejection was a causal intermediate between DGF and DCGL. Results: Of 7668 deceased donor kidney transplants between 1997 and 2014, 1497 (19.5%) recipients experienced DGF requiring dialysis. The median (interquartile range) duration of DGF was 7 (9) days, with 25% requiring dialysis for 14 days or longer. Among recipients who had experienced a DGF duration of 1 to 4 days, the adjusted hazard ratio for duration of 5 to 7, 8 to 13, and 14 days or longer were 1.13 (95% confidence interval [CI], 0.83-1.55; P = 0.43), 1.44 (95% CI, 1.08-1.91; P = 0.013), and 1.99 (95% CI, 1.50-2.65; P < 0.001), respectively, for acute rejection; and were 1.10 (95% CI< 0.73-1.67; P = 0.64), 1.45 (95% CI, 1.00-2.11; P = 0.05) and 1.60 (95% CI, 1.10-2.31; P = 0.01), respectively, for DCGL. On average, 8% of the effects between DGF duration and DCGL were explained by acute rejection. Conclusions: There was a direct dose-dependent effect between DGF duration and DCGL, with acute rejection explaining less than 10% of the effects between DGF duration and DCGL. Future research identifying other potential modifiable mediators that lies in the causal pathway between DGF duration and allograft loss is essential.

Background High levels of pretransplant panel reactive antibodies (PRA) are known to be associated with detrimental effects on graft outcomes, but the association between pretransplant PRA levels and long-term patient outcomes is unclear. Methods Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the risk of rejection, graft failure, mortality and cancer in kidney transplant recipients with varying peak PRA levels. Results In 7,118 kidney transplant recipients between 1997 and 2009, there were a total of 3,171 (44.6%), 3,306 (46.4%), 323 (4.5%), and 318 (4.5%) recipients with peak PRA levels of 0%, 1% to 50%, 51% to 80%, and greater than 80%, respectively. Compared to recipients with 0% peak PRA level, recipients with peak PRA levels greater than 80% were at increased risk of acute rejection (odds ratio, 1.81, 95% confidence interval [95% CI], 1.30–2.35; P < 0.001), death censored graft failure (hazard ratio [HR], 2.06; 95% CI, 1.46–2.91; P < 0.001), all-cause mortality (HR, 1.56; 95% CI, 1.15–2.11; P < 0.001) and cancer (HR, 1.94; 95% CI, 1.26–2.97; P = 0.002) in the adjusted models independent of human leukocyte antigen mismatches and initial immunosuppression. Conclusion Highly sensitized kidney transplant recipients with peak PRA greater than 80% had a greater risk of rejection, graft failure, cancer and death independent of age and time on dialysis. Strategies to reduce transplant waiting time and avoidance of sensitization in all potential transplant candidates are imperative to improve the overall graft and patient survival.