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  • Astaxanthin has no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients: a randomized controlled trial (the XANTHIN trial)
    The American journal of clinical nutrition. 2016;103(1):283-9

    Study Details

    Aims: To investigate the effects of oral astaxanthin on arterial stiffness, oxidative stress, and inflammation in renal transplant recipients.
    Interventions: Participants were randomized to receive either 12mg astaxanthin orally, or placebo every day for a year.
    Participants: 61 renal transplant recipients aged 18-85 years
    Outcomes: Primary outcomes measured were arterial stiffness, oxidative stress and inflammation. Secondary outcomes were vascular function, carotid artery intima-media thickness, augmentation index, central blood pressure, subendocardial viability ratio, and additional measures of oxidative stress and inflammation.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This well designed, double-blind placebo controlled trial investigated the role of the antioxidant Astaxanthin on arterial stiffness and biomarkers of inflammation and oxidative stress in renal transplant recipients. Animal studies and small human series had suggested a potential benefit, which could be of clinical importance given the high rates of cardiovascular disease in transplant recipients. In fact, no difference in any of the measured parameters was found in this study.

    Expert Review

    Reviewer: Professor J Andrew Bradley, University of Cambridge, United Kingdom
    Conflicts of interest: No
    Clinical Impact Rating : ★★☆☆☆ (2 of 5)
    Cardiovascular disease is the major cause of mortality and morbidity in renal transplant recipients, and effective interventions are needed to reduce the impact of cardiovascular disease. Anti-oxidants may represent one such intervention, but evidence for efficacy is lacking. The authors report a multicentre placebo controlled double blind trial to assess the beneficial properties of the oral anti-oxidant astaxanthin (a xanthophyll carotenoid) in renal transplant recipients. The active agent was given for 12 months and found to be safe, but showed no effect on the primary end-points of arterial stiffness (pulse wave velocity), and biomarkers of oxidative stress and inflammation (plasma F2-isoprostanes and pentraxin-3, respectively) at 6 and 12 months. A total of 58 patients completed the study (32 patients receiving astaxanthin and 26 receiving placebo). The trial was powered to detect a change in pulse wave velocity of 1m/s over 12 months (power 90%, alpha 0.05) and aimed to analyse a sample size of 66 patients. However, there was more variability within the overall sample in pulse wave velocity than anticipated, which weakened the power of the trial and meant that the authors could not exclude with confidence the possibility of a type two statistical error. There is not sufficient evidence to recommend the use of anti-oxidants to offset the risk of cardiovascular disease in the renal transplant population and further appropriately powered studies are required.

    Abstract

    BACKGROUND There is evidence that renal transplant recipients have accelerated atherosclerosis that is manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress, and inflammation associated with immunosuppressive therapy. The carotenoid astaxanthin has shown potent antioxidant and anti-inflammatory properties. OBJECTIVE The aim was to investigate the effects of oral astaxanthin on arterial stiffness, oxidative stress, and inflammation in renal transplant recipients. DESIGN This trial used a randomized, placebo-controlled, double-blind design in which 61 patients received either 12 mg astaxanthin/d or an identical placebo orally for 1 y. Primary outcomes were 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by total plasma F2-isoprostanes, and 3) inflammation assessed by plasma pentraxin-3. Secondary outcomes included vascular function, carotid artery intima-media thickness, augmentation index, central blood pressure, subendocardial viability ratio, and additional measures of oxidative stress and inflammation. Patients underwent assessments at baseline and at 6 and 12 mo. RESULTS Fifty-eight participants completed the study. There were no significant between-group differences in the changes in any of the primary outcome measures (PWV changed by +9.5% and +6.0%, F2-isoprostanes changed by -3.0% and -9.7%, and pentraxin-3 changed by +50.6% and -11.0% in the placebo and astaxanthin groups, respectively). There were no significant between-group differences in secondary outcome measures. Larger-than-expected variability decreased the power of the study and increased the possibility of a type 2 statistical error. CONCLUSION Astaxanthin (12 mg/d for 12 mo) had no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients. This trial was registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12608000159358.
  • Effect of twice-yearly denosumab on prevention of bone mineral density loss in de novo kidney transplant recipients: a randomized controlled trial
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016;16(6):1882-91

    Study Details

    Aims: To study the efficacy and safety of Receptor Activator of Nuclear Factor κB Ligand (RANKL) inhibition with denosumab in preventing the loss of bone mineral density in de novo kidney transplant recipients.
    Interventions: Participants were randomized to receive subcutaneous injections of 60 mg denosumab at baseline and after 6 months, or no treatment.
    Participants: 90 kidney transplant recipients transplated <28 days prior to the study, receiving standard triple immunosuppression including a calcineurin antagonist, mycophenolate and corticosteroids.
    Outcomes: The primary outcome measured was the percentage change in baseline areal bone mineral density (aBMD) at the total lumbar spine. Secondary outcomes included changes in aBMD at total hip and femoral neck, and changes in biomarkers of bone turnover.

    CET Conclusion

    Reviewer: Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This is a carefully done study of a new monoclonal antibody, Denosumab, which interacts with the receptor activator of nuclear factor kB ligand (RANKL). This humanised monoclonal antibody was developed for treatment of osteoporosis and prevention of fractures by inhibiting the development and activity of osteoclasts, thus leading to a decrease in bone absorption and an increase in bone density. It has been shown to be superior to bisphosphonates in improving bone mineral density and preventing fractures in post-menopausal women with osteoporosis. In this study 90 patients were randomised to receive Denosumab or no treatment. All patients received calcium and vitamin D supplements. The Denosumab was given by injections at base line and again at six months and the follow-up was over 12 months. At 12 months total lumbar spine bone mineral density (BMD) was increased by 4.6% and this was a highly significant improvement. Denosumab also increased BMD in the total hip and in a subgroup there was an improvement of volumetric BMD in the distal tibia and radius. Biomarkers of bone turnover were markedly decreased in the Denosumab group. The major adverse events were episodes of cystitis and asymptomatic hypocalcaemia, seen more often in the treatment group but there were no differences in graft function or the rate of rejection episodes. The authors conclude that Denosumab increases BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection. This, as I already mentioned, is a very carefully planned study which has produced very interesting results and these findings should be followed up for confirmation.

    Expert Review

    Reviewer: Professor Maurizio Salvadori, Careggi University Hospital, University of Florence, Italy.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★☆ (4 of 5)
    The Bonani and others study discusses the relevant issue of bone loss after kidney transplantation. Bone loss mainly related either to the previous condition of chronic kidney disease and the immunosuppressive treatment after transplantation might lead to bone fractures that represent a serious disabling problem with reduction of the QoL. In addition to Ca and vitamin D supplementations other drugs such as bisphosphonate failed to be effective and might involve nephrotoxicity. The Denosumab, an anti RANKL fully human monoclonal antibody was examined in this RCT with good results either on bone loss and mineral metabolism in the first year of transplantation. As the authors recognize, several questions remain open and might be the object of future studies. Indeed, the effects on bone fractures could not be documented for the short time of the study and the limited number of patients enrolled. In a study enrolling a larger number of patients, questions might be answered as: How long should be the duration of the treatment? The risk of adynamic bone disease does not concern this drug? Which is the influence of pre-transplant steroid administration on bone loss after transplantation? Finally the cause of this so high rate of urinary infections might have its explanation.

    Abstract

    We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of BMD in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 two weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine aBMD increased by 4.6% (95% CI 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8-0.9%) in 44 patients in the control group (between-group difference 5.1% (95% CI 3.1-7.0%), P<0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1 to 3.7%; P=0.035) over that in the control group at 12 months. HR-pQCT in a subgroup of 24 patients showed that denosumab increased vBMD at the distal tibia and radius (all P<0.05). Biomarkers of bone turnover (beta-CTX, P1NP) markedly decreased with denosumab (all P<0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection. This article is protected by copyright. All rights reserved.
  • A Randomized Controlled Trial of a Mobile Health Intervention to Promote Self-Management after Lung Transplantation
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016;16(7):2172-80

    Study Details

    Aims: To compare the mobile health intervention pocket PATH in promoting self-management behaviours versus usual care in lung transplant recipients.
    Interventions: Participants were randomized to receive either Pocket PATH or usual care.
    Participants: 201 lung transplant recipients aged > 18 years.
    Outcomes: Primary outcomes measured were self-monitoring, adhering to the regime, and reporting critical health changes. Secondary measured outcomes were perceived capability to engage in self care, rehospitalisation and mortality.

    CET Conclusion

    Reviewer: Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This is a very nice study from Pittsburgh evaluating the use of a mobile health intervention (Pocket PATH) to allow patients after lung transplantation to monitor their own course. The outcomes were compared with a similar group of recipients who just had usual care. Two hundred and one patients were randomised in this study (so it is a sizeable group) and the self-management behaviours, such as self-care, rehospitalisation and mortality, were evaluated during the first year after transplantation. The mobile mHealth intervention group performed better with self-monitoring, adherence to the medical regimen and the reporting of abnormal health indicators than the usual care group, but there was no difference in rehospitalisation or mortality between the two groups. Thus, as the authors suggest, this mHealth intervention on self-management behaviours does hold promise and warrants further testing. I could not agree more and this approach might well be applicable to transplantation of other organs.

    Expert Review

    Reviewer: Associate Professor Lianne G. Singer and Ms Paulette Dalton, University of Toronto and Toronto Lung Transplant Program, Canada
    Conflicts of interest: No
    Clinical Impact Rating : ★★★☆☆ (3 of 5)
    This is a good quality RCT conducted in Pittsburgh to evaluate the effectiveness of a mobile health intervention (Pocket PATH) in 201 lung transplant recipients recruited prior to discharge and followed for one year. The study reports improved self-management behaviours in the Pocket PATH group over usual care, specifically self-monitoring, adherence and reporting critical abnormal health indicators. Of note though, both groups showed a decline in self-management behaviours over time, which perhaps contributed to the lack of difference noted in health outcomes (survival and readmission) between the two groups. Limitations to generalizability include the relatively old patient cohort (either mainly or exclusively in their 50s and 60s), whereas nonadherence may be more prevalent among younger patients. Furthermore about half the patients had obstructive disease as the indication for transplantation which may not be representative of many contemporary transplant programs. The exact study intervention may not be easy to replicate in other programs since it required provision of smartphones to patients and may not use contemporary technology. However the study serves as a good model for other programs, highlighting the promise and pitfalls of mobile health interventions.

    Abstract

    Lung transplant recipients are encouraged to perform self-management behaviors including: 1) monitoring health indicators, 2) adhering to their regimen, and 3) reporting abnormal health indicators to the transplant coordinator, yet performance is suboptimal. When hospital discharge was imminent, this two-group trial randomized 201 recipients to use either the mHealth intervention (n=99), or usual care (n=102), to compare efficacy for promoting self-management behaviors (primary outcomes) and self-care agency, re-hospitalization and mortality (secondary outcomes) at home during the first year after transplant. The mHealth intervention group performed self-monitoring (OR=5.11, 95% CI 2.95-8.87, p<.001), adhered to medical regimen (OR=1.64, 95% CI 1.01-2.66, p=0.046) and reported abnormal health indicators (OR= 8.9, 95% CI 3.60-21.99, p<.001) more frequently than the usual care group. However, the two groups did not differ in re-hospitalization (OR= 0.78, 95% CI 0.36-1.66, p=.51) or mortality (HR= 1.71, 0.68-4.28, p=.25). The positive impact of the mHealth intervention on self-management behaviors suggests that the intervention holds promise and warrants further testing. This article is protected by copyright. All rights reserved.
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