Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients

Background Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non‐depleting interleukin‐2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte‐depleting antibodies but the relative benefits and harms of the available agents are uncertain. Objectives We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). Search methods We searched the Cochrane Kidney and Transplant's Specialised Register to 29 August 2016 through contact with the Information Specialist using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). Main results We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates. Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death‐censored graft loss was uncertain at 1 to 2 years and 5 years. In non‐CNI studies, ATG had uncertain effects on death but reduced death‐censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non‐CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all‐cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death‐censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post‐transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT). Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death‐censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD ‐13.35 mL/min, ‐23.91 to ‐2.80) and 2 years (2 studies: MD ‐12.86 mL/min, ‐23.73 to ‐2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all‐cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance. Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all‐cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD. Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. Authors' conclusions ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non‐CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection. In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG. Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient‐centred outcomes (reduced death or lower toxicity) do not appear to be improved

Student Pharmacists’ Personal Finance Perceptions, Projected Indebtedness upon Graduation, and Career Decision-Making

Objectives: To evaluate the extent to which students’ personal finance perceptions, projected student loan indebtedness, and demographic characteristics predict post-PharmD career intentions. Methods: Students at three pharmacy colleges completed a 31-item survey instrument that assessed personal finance perceptions, self-efficacy beliefs, anticipated student loan debt upon graduation, postgraduate intentions, anticipated practice setting upon graduation, and demographic characteristics. Logistic regression models were used to examine the extent to which personal finance perceptions, student loan indebtedness, and demographic characteristics predicted postgraduate intentions and anticipated practice setting. Results: A total of 763 usable responses were obtained (response rate=90.3%). Students reported an anticipated personal student loan debt mean at graduation of $162,747±87,093 and an estimated 7.4±5.8 years to pay off non-mortgage debt post-graduation. Fifty-three percent of students reported planning to practice in a community pharmacy setting post-graduation, and 54% indicated intentions to enter practice directly. Student loan indebtedness was not a significant predictor of planning to pursue postgraduate training. There was a significant association between debt influence and pressure perceptions and pursuance of postgraduate training (aOR=0.78;p=0.009). The odds of indicating hospital (vs. chain community) pharmacy as the anticipated setting decreased 36% with every 1-point increase in debt influence and pressure perceptions (aOR=0.64;p\u3c0.001 Conclusions: Perceived debt pressure and influence predicted intention to enter practice directly (vs. pursuing postgraduate training) and selection of chain community pharmacy (vs. hospital pharmacy). Student loan indebtedness was not a significant predictor of postgraduate training intentions. Interventions that equip students to manage pressure associated with student loan debt should be explored

Antihypertensive Treatment for Kidney Transplant Recipients

Background: In some nontransplant populations, effects of different antihypertensive drug classes vary. Relative effects in kidney transplant recipients are uncertain. Objectives: To assess comparative effects of different classes of antihypertensive agents in kidney transplant recipients. Search strategy: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings and reference lists of identified studies were searched. Selection criteria: Randomised controlled trials of any antihypertensive agent applied to kidney transplant recipients for at least two weeks were included. Data collection and analysis: Data was extracted by two investigators independently. Study quality, transplant outcomes and other patient centred outcomes were assessed using random effects meta-analysis. Risk ratios (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, both with 95% confidence intervals (CI) were calculated. Stratified analyses and meta-regression were used to investigate heterogeneity. Main results: We identified 60 studies, enrolling 3802 recipients. Twenty-nine studies (2262 participants) compared calcium channel blockers (CCB) to placebo/no treatment, 10 studies (445 participants) compared angiotensin converting enzyme inhibitors (ACEi) to placebo/no treatment and seven studies (405 participants) compared CCB to ACEi. CCB compared to placebo/no treatment (plus additional agents in either arm as required) reduced graft loss (RR 0.75, 95% CI 0.57 to 0.99) and improved glomerular filtration rate (GFR), (MD, 4.45 mL/min, 95% CI 2.22 to 6.68). Data on ACEi versus placebo/no treatment were inconclusive for GFR (MD -8.07 mL/min, 95% CI -18.57 to 2.43), and variable for graft loss, precluding meta-analysis. In direct comparison with CCB, ACEi decreased GFR (MD -11.48 mL/min, 95% CI -5.75 to -7.21), proteinuria (MD -0.28 g/24 h, 95% CI -0.47 to -0.10), haemoglobin (MD -12.96 g/L, 95% CI -5.72 to -10.21) and increased hyperkalaemia (RR 3.74, 95% CI 1.89 to 7.43). Graft loss data were inconclusive (RR 7.37, 95% CI 0.39 to 140.35). Other drug comparisons were compared in small numbers of participants and studies. Authors' conclusions: These data suggest that CCB may be preferred as first line agents for hypertensive kidney transplant recipients. ACEi have some detrimental effects in kidney transplant recipients. More high quality studies reporting patient centred outcomes are required

Sex differences in colon cancer metabolism reveal a novel subphenotype

Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients