Summary Background Proliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal ...laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept. Methods In this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as −5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582. Findings We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters 95% CI 2·3–5·6, p<0·0001) and the per-protocol population (4·0 letters 2·4–5·7, p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of −5 letters at both 12 weeks and 52 weeks. Interpretation Patients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care. Funding The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends ...on detecting a creatinine rise. A biomarker to diagnose transplant rejection at an earlier time point than current practice, or to inform earlier decision making to biopsy, could be transformative. It has previously been shown that urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice.
We conducted a prospective observational study, recruiting renal transplant participants over an 18-month period. We made no alterations to the patients' clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance. We assessed the urinary nitrate to creatinine ratio (uNCR) between patient groups: routine attendances, biopsy proven rejection, biopsy proven no rejection and other call backs. uNCR was examined over time for those with biopsy proven transplant rejection. These four groups were compared using an ANOVA test.
A total of 2656 samples were collected. uNCR during biopsy proven rejection, n = 15 (median 49 μmol/mmol, IQR 23-61) was not significantly different from that of routine samples, n = 164 (median 55 μmol/mmol, IQR 37-82) (p = 0.55), or biopsy proven no rejection, n = 12 (median 39 μmol/mmol, IQR 21-89) (P = 0.77). Overall uNCR was highly variable with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. The total taking Tacrolimus was 204 patients, with no statistical difference between the uNCR of all those on Tacrolimus, against those not, p = 0.18.
The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.
Transplant candidates should undergo an assessment of their mental health, social support, lifestyle, and behaviors. The primary aims of this "psychosocial evaluation" are to ensure that ...transplantation is of benefit to life expectancy and quality of life, and to allow optimization of the candidate and transplant outcomes. The content of psychosocial evaluations is informed by evidence regarding pretransplant psychosocial predictors of transplant outcomes. This review summarizes the current literature on pretransplant psychosocial predictors of transplant outcomes across differing solid organ transplants and discusses the limitations of existing research. Pretransplant depression, substance misuse, and nonadherence are associated with poorer posttransplant outcomes. Depression, smoking, and high levels of prescription opioid use are associated with reduced posttransplant survival. Pretransplant nonadherence is associated with posttransplant rejection, and nonadherence may mediate the effects of other psychosocial variables such as substance misuse. There is evidence to suggest that social support is associated with likelihood of substance misuse relapse after transplantation, but there is a lack of consistent evidence for an association between social support and posttransplant adherence, rejection, or survival across all organ transplant types. Psychosocial evaluations should be undertaken by a trained individual and should comprise multiple consultations with the transplant candidate, family members, and healthcare professionals. Tools exist that can be useful for guiding and standardizing assessment, but research is needed to determine how well scores predict posttransplant outcomes. Few studies have evaluated interventions designed to improve psychosocial functioning specifically pretransplant. We highlight the challenges of carrying out such research and make recommendations regarding future work.
Background
Panretinal photocoagulation (PRP) has been the standard of care for patients with proliferative diabetic retinopathy (PDR) for the last 40 years. It prevents severe visual loss in PDR but ...is also associated with adverse effects on visual functions.
Objectives
The clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (CLARITY) trial evaluated the clinical efficacy, mechanisms and cost-effectiveness of intravitreal aflibercept (Eylea
®
, Regeneron, Tarrytown, NY, USA/Bayer Pharma AG, Berlin, Germany therapy for PDR.
Design
A multicentre, prospective, individually randomised, single-masked, active-controlled trial with concurrent economic evaluation that tested the non-inferiority of intravitreal aflibercept versus standard care PRP at 52 weeks. A subset of the participants enrolled in a mechanistic evaluation substudy.
Setting
22 UK NHS clinical sites.
Participants
Patients aged at least 18 years having either treatment-naive PDR or active retinal neovascularisation (NV) despite prior PRP requiring treatment and best corrected visual acuity (BCVA) of 54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or better in the study eye were included. Eyes with evidence of macular oedema at baseline confirmed by central subfield thickness > 320 µm on spectral-domain optical coherence tomography were excluded.
Intervention
In the intervention arm, intravitreal aflibercept injections were given at baseline, 4 and 8 weeks and patients were subsequently reviewed every month and injected pro re nata based on the treatment response defined by degree of regression of retinal NV. In the comparator arm, PRP was completed in 2-weekly sessions and then supplemented if necessary at 8-weekly intervals.
Main outcome measures
The primary outcome was the mean change in BCVA at 52 weeks utilising a linear mixed-effects model incorporating data from both week 12 and week 52.
Results
A total of 232 participants (116 per arm) were recruited between August 2014 and November 2015. A total of 221 and 210 participants contributed to the intention-to-treat (ITT) model and per-protocol (PP) analysis, respectively. Economic evaluation was undertaken on 202 participants (101 per arm) with complete cost and outcome data. Aflibercept was non-inferior and superior to PRP in both the ITT population mean BCVA difference 3.9 letters, 95% confidence interval (CI) 2.3 to 5.6 letters;
p
< 0.0001 and the PP population (difference 4.0 letters, 95% CI 2.4 to 5.7 letters;
p
< 0.0001). From a public sector multiagency perspective that covers health and social care services, treatment with aflibercept costs more in terms of total resource use (mean adjusted total additional cost per patient = £5475, bootstrapped 95% CI £5211 to £5750) than PRP over a 12-month follow-up period. There were a small number of important safety events in each arm. Patients were more satisfied with aflibercept than PRP.
Limitations
This study is limited to 1 year of follow-up.
Conclusions
At an additional cost, the study shows that intravitreal aflibercept is an effective alternative treatment option for PDR in the first year.
Future work
Future research is needed to evaluate the long-term benefits of aflibercept in comparison with PRP and other anti-vascular endothelial growth factor agents for this condition.
Trial registration
Current Controlled Trials ISRCTN32207582.
Funding
This project was funded by the National Institute for Health Research (NIHR) Efficacy and Mechanistic Evaluation programme, a Medical Research Council and NIHR partnership. Aflibercept was supplied by Bayer Plc (Reading, UK). The study was sponsored by NIHR Moorfields Biomedical Research Centre and supported by the UK Clinical Research Network. The research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, the NIHR Moorfields Clinical Research Facility and the UK Clinical Reasearch Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is partly funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London.
Cystic fibrosis (CF) is a genetic condition primarily affecting the respiratory system, with the associated progressive lung damage and loss of function resulting in reduced lifespan. Bone health is ...also impaired in individuals with CF, leading to much higher fracture risk even in adolescence. However, the development of these deficits during growth and the relative contributions of puberty, body size and muscular loading remain somewhat unexplored.
We therefore recruited 25 children with CF (10 girls, mean age 11.3 ± 2.9y) and 147 children without CF (75 girls, mean age 12.4 ± 2.6y). Bone characteristics were assessed using peripheral quantitative computed tomography (pQCT) at 4 % and 66 % distal-proximal tibia. Muscle cross-sectional area (CSA) and density (an indicator of muscle quality) were also assessed at the latter site. Tibial bone microstructure was assessed using high-resolution pQCT (HR-pQCT) at 8 % distal-proximal tibial length. In addition, peak jump power and hop force were measured using jumping mechanography. Group-by-age interactions and group differences in bone and muscle characteristics were examined using multiple linear regression, adjusted for age, sex and pubertal status and in additional models, height and muscle force.
In initial models group-by-age interactions were evident for distal tibial total bone mineral content (BMC) and trabecular volumetric bone mineral density (vBMD), with a lower rate of age-related accrual evident in children with CF. In assessments of distal tibial microstructure, similar patterns were observed for trabecular number and thickness, and cortical CSA. In the tibial shaft, group-by-age interactions indicating slower growth in CF were evident for total BMC and cortical CSA, whilst age-independent deficits in CF were observed for several other variables. Peak jump power and hop force also exhibited similar interactions. Group-by-age interactions for bone were partially attenuated at the distal tibia and fully attenuated at the tibial shaft by adjustment for muscle force.
These results suggest that bone and muscle deficits in children with CF develop throughout later childhood, independent of differences in pubertal stage and body size. These diverging growth patterns appear to be mediated by differences in muscle function, particularly for bone characteristics in the tibial shaft. Given the high fracture risk in this population from childhood onwards, development of interventions to improve bone health would be of substantial clinical value.
•Cystic fibrosis (CF) is associated with impaired bone mass and higher fracture risk•Little is known about bone development across childhood in CF•We assessed tibia bone with pQCT in 25 children with CF and 147 controls aged 8-16y•We found progressive bone mass deficits in CF, developing from mid-childhood•These deficits were in part related to impaired development of muscle function in CF
Neurofibromatosis type 1 (NF1) is associated with lower bone mass and increased risk of fracture. Children with NF1 display faltering growth from mid-childhood. However, to date tibia bone ...development in children with NF1 across childhood and the role of body size have not been explored.
Therefore, we recruited 24 children with NF1 (12 girls, mean age 8.2 ± 1.1y) and 104 children without NF1 (52 girls, mean age 11 ± 1.7y). Tibia and fibula bone characteristics were assessed at 4% and 38% distal-proximal tibia length in all children at baseline using peripheral quantitative computed tomography (pQCT). Longitudinal scans were obtained in 21 children with NF1 (12 girls) over 3.4 ± 0.3y and 71 children without NF1 (34 girls) over 1.1 ± 0.1y, such that at follow-up mean age of both groups (NF1 10.9 ± 1.3y, controls 11.4 ± 1.4y) were similar. Effects of group (NF1/control) on bone outcomes as well as group-by-age interactions, indicating differences in rate of change in bone outcome bone outcomes were assessed via linear mixed effects models with adjustment for sex, age, pubertal status and in additional models with adjustment for height and weight Z-scores.
Group (NF1/control)-by-age interactions indicated a slower rate of tibia and fibula bone mass accrual in children with NF1 at all measured sites. These associations were attenuated by 25–50% by adjustment for height and weight Z-scores. At the 4% site, deficits in bone mass at older ages were related to slower trabecular BMD accrual. At the 38% site, group-by-age interactions suggested that bone mass deficits resulted from poorer accrual of cortical CSA and to a lesser extent cortical BMD.
Lower limb bone mass deficits evident in children with NF1 appear to be progressive and emerge in mid-childhood. In part, they are related to development of a similar pattern of deficits in longitudinal growth and body weight in NF1. Interventions promoting muscle development or physical activity may be partially effective in attenuating bone mass accrual deficits in this population.
•Neurofibromatosis type 1 (NF1) is associated with bone weakness, higher fracture risk.•Bone development across childhood in NF1 is unexplored including effects of body size.•We assessed tibia and fibula bone using pQCT in 24 children with NF1 and 104 controls.•We found progressive bone mass deficits in NF1, which emerge in mid-childhood.•These deficits appear to result in part from impaired growth in body size in NF1.
Abstract
Background and Aims
Transplanting renal centres have a duty to use the finite resource of the deceased-donor kidney pool to benefit potential recipients without exposing them to excessive ...risk. However, there is known variation in centre and clinician practice. This may relate to clinicians’ attitude to risk, knowledge of the recipient and unit culture. Centre differences in acceptability of donor organs is evidenced by variation in NHS blood and transplant registry data. Use of marginal donors has become more frequent, especially for older recipients with higher comorbidity. In the UK this year we will see whether switching to an ‘opt out’ donation law further increases this proportion of donors.
We developed a systematic method to retrospectively review donation after brain death (DBD) kidney offers declined by our centre, with the intention of reducing variation in practice between clinicians, and identifying cases where offer acceptance may have been appropriate
Method
All DBD kidney offers declined by the Richard Bright Renal Service between June 2018 and May 2019 were reviewed. Data were collected by casenotes review and by contact with other transplanting units to establish the outcome of donor kidneys and recipient progress. Reasons for offer decline were recorded. Donor and recipient risk indices (DRI and RRI) were calculated. For patients now transplanted, the DRI of the declined offer was compared to the DRI of the transplanted kidney.
Results
During the study period, 98 DBD kidneys were declined. A donor organ identifier was not available in 8 cases, so 90 are considered here. Average donor age was 57 years with 52% having a Donor Risk Index (DRI) score of 4, and 74.7% a DRI score ≥3. The most common reasons for organ decline were donor related (65%), of which 27% were due to poor kidney function and 22% age mismatch; or recipient related (35%), where 30% were deemed inadequate quality for the recipient and 30% were unavailable or unwell. Of those kidneys which were transplanted elsewhere, 88% were functioning at 6 months with a median creatinine of 119 (IQR 106-148).
There were 60 potential recipients, 61% of whom had a RRI score ≥3; 44% had a RRI equal to or less than the DRI of the declined organ. Those who have still not been transplanted have accrued a median of 352 extra days on dialysis. 31 recipients (52%) have been transplanted since their declined offer. The median change in DRI score from the declined offer to the accepted offer was -1 (IQR -2 to 1), and offers were accepted after a median of 45 (IQR 14-143) additional dialysis days. Of those who were transplanted after declining a donor offer, 11 (39%) received a kidney from a donor with equal or worse DRI than the original offer, after a median of 49 further days on dialysis.
Conclusion
This review process highlights the effect of kidney offer decline on future progress of the potential recipient, as well as differences in our centre practice compared to other centres. Key to this review is to highlight the risks involved with DBD organ decline- 18% of recipients ultimately received an equal or inferior kidney while accruing additional time on dialysis. Alongside this review we have implemented strategies including a policy on AKI in donors and monthly multidisciplinary meetings to discuss individual DBD decline cases. We aim to standardize decision making and increase our utilization of all as well as marginal DBD organs, and expect to show a reduction in variation in practice in future reviews. Use of this process in other units or at a national level could reduce unwarranted variation in the utilization of the donor organ pool.
Eculizumab, a terminal complement inhibitor, has recently been used successfully to both prevent and treat the recurrence of atypical hemolytic uremic syndrome (aHUS) post renal transplantation. We ...describe a case that highlights the need to monitor the effects of eculizumab on the complement system and in this case alter the dosage. Despite taking the standard recommended dose of eculizumab for an adult, this aHUS patient developed a low-grade thrombotic microangiopathy on biopsy within months of renal transplantation. Complement assays (trough CH50) showed small amounts of residual terminal pathway activity suggesting inadequate complement blockade on 1,200 mg eculizumab every 2 weeks. Following an increase in the dose of eculizumab to 1,500 mg every 2 weeks, lactate dehydrogenase (LDH), proteinuria, and creatinine decreased, and CH50 assay showed 0%. This case emphasizes the need to monitor clinical parameters and complement activity to ensure that adequate therapeutic blockade is achieved. .
The purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of ...neovascularization in proliferative diabetic retinopathy.
This is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA).
The AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, -0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45).
Intravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.
Abstract
Background and Aims
Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and ...recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection, either at an earlier time point, or to inform earlier decision making to biopsy, could be transformative. Urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. Historically, assays for measurement of inorganic nitrate in biological fluids have been too time consuming to be useful in a clinical setting. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice.
Method
We conducted a prospective observational study, recruiting renal transplant participants over an 18 month period. We made no alterations to the patients’ clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance including routine attendances, unscheduled attendances for acute clinical indications, and on the day of attendance for biopsy, for those who underwent biopsy. We measured the urinary nitrate to creatinine ratio (uNCR) between patient groups including routine attendances, biopsy proven rejection and biopsy proven “no rejection”. uNCR was examined over time for those with transplant rejection. Groups were compared using a 2 tail t-test of unequal variance, for statistical significance.
Results
A total of 2656 samples were collected. uNCR during biopsy proven rejection, median 49 µmol/mmol, IQR 23-61, was not significantly different from that of routine samples, median 55 µmol/mmol, IQR 37-82 (p=0.56), or biopsy proven “no rejection”, median 39 µmol/mmol, IQR 21-89, (P=0.77). Overall uNCR was highly variable; median 52 µmol/mmol, IQR 31-81, with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection.
Conclusion
The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.
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