Successful ABO and HLA incompatible kidney transplantation in children in the UK.

BACKGROUND: There is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK. METHODS: Questionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups. RESULTS: Among 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6-14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder. CONCLUSION: Longer term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible. A higher resolution version of the Graphical abstract is available as Supplementary information.

The role of circadian phase in sleep and performance during Antarctic winter expeditions.

The Antarctic environment presents an extreme variation in the natural light-dark cycle which can cause variability in the alignment of the circadian pacemaker with the timing of sleep, causing sleep disruption, and impaired mood and performance. This study assessed the incidence of circadian misalignment and the consequences for sleep, cognition, and psychological health in 51 over-wintering Antarctic expeditioners (45.6 ± 11.9 years) who completed daily sleep diaries, and monthly performance tests and psychological health questionnaires for 6 months. Circadian phase was assessed via monthly 48-h urine collections to assess the 6-sulphatoxymelatonin (aMT6s) rhythm. Although the average individual sleep duration was 7.2 ± 0.8 h, there was substantial sleep deficiency with 41.4% of sleep episodes <7 h and 19.1% <6 h. Circadian phase was highly variable and 34/50 expeditioners had sleep episodes that occurred at an abnormal circadian phase (acrophase outside of the sleep episode), accounting for 18.8% (295/1565) of sleep episodes. Expeditioners slept significantly less when misaligned (6.1 ± 1.3 h), compared with when aligned (7.3 ± 1.0 h; p < .0001). Performance and mood were worse when awake closer to the aMT6s peak and with increased time awake (all p < .0005). This research highlights the high incidence of circadian misalignment in Antarctic over-wintering expeditioners. Similar incidence has been observed in long-duration space flight, reinforcing the fidelity of Antarctica as a space analog. Circadian misalignment has considerable safety implications, and potentially longer term health risks for other circadian-controlled physiological systems. This increased risk highlights the need for preventative interventions, such as proactively planned lighting solutions, to ensure circadian alignment during long-duration Antarctic and space missions.

Transitional B cell cytokines predict renal allograft outcomes.

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade.

Utilization and Outcomes of Single and Dual Kidney Transplants from Older Deceased Donors in the United Kingdom.

BACKGROUND AND OBJECTIVES: Kidneys from elderly deceased donors are often discarded after procurement if the expected outcomes from single kidney transplantation are considered unacceptable. An alternative is to consider them for dual kidney transplantation. We aimed to examine the utilization of kidneys from donors aged ≥60 years in the United Kingdom and compare clinical outcomes of dual versus single kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the United Kingdom Transplant Registry from 2005 to 2017 were analyzed. We examined utilization rates of kidneys retrieved from deceased donors aged ≥60 years, and 5-year patient and death-censored graft survival of recipients of dual and single kidney transplants. Secondary outcomes included eGFR. Multivariable analyses and propensity score analysis were used to correct for differences between the groups. RESULTS: During the study period, 7841 kidneys were procured from deceased donors aged ≥60 years, of which 1338 (17%) were discarded; 356 dual and 5032 single kidneys were transplanted. Donors of dual transplants were older (median, 73 versus 66 years; P<0.001) and had higher United States Kidney Donor Risk Indices (2.48 versus 1.98; P<0.001). Recipients of dual transplants were also older (64 versus 61 years; P<0.001) and had less favorable human leukocyte antigen matching (P<0.001). After adjusting for confounders, dual and single transplants had similar 5-year graft survival (hazard ratio, 0.81; 95% CI, 0.59 to 1.12). No difference in patient survival was demonstrated. Similar findings were observed in a matched cohort with a propensity score analysis method. Median 12-month eGFR was significantly higher in the dual kidney transplant group (40 versus 36 ml/min per 1.73 m2; P<0.001). CONCLUSIONS: Recipients of kidneys from donors aged ≥60 years have similar 5-year graft survival and better graft function at 12 months with dual compared with single deceased donor kidney transplants.

Management of chronic renal allograft dysfunction and when to re-transplant.

Despite the advances in renal transplantation over the last decades, chronic allograft dysfunction remains the largest concern for patients, their families, clinicians and other members of the multi-disciplinary team. Although we have made progress in improving patient and renal allograft survival within the first year after transplantation, the rate of transplant failure with requirement for commencement of dialysis or re-transplantation has essentially remained unchanged. It is important that paediatric and adult nephrologists and transplant surgeons, not only manage their patients and their renal transplants but provide the best chronic kidney disease management during the time of decline of renal allograft function. The gold standard for patients with Stage V chronic kidney disease is to have pre-emptive living donor transplants, where possible and the same is true for healthy renal transplant recipients with declining renal allograft function. The consideration for children and young people as they embark on their end-stage kidney disease journey is the risk-benefit profile of giving the best immunologically matched and good quality renal allografts as they may require multiple renal transplantation operations during their lifetime.

Validation of gait event detection by centre of pressure during target stepping in healthy and paretic gait.

BACKGROUND: Target-stepping paradigms are increasingly used to assess and train gait adaptability. Accurate gait-event detection (GED) is key to locating targets relative to the ongoing step cycle as well as measuring foot-placement error. In the current literature GED is either based on kinematics or centre of pressure (CoP), and both have been previously validated with young healthy individuals. However, CoP based GED has not been validated for stroke survivors who demonstrate altered CoP pattern. METHODS: Young healthy adults and individuals affected by stroke stepped to targets on a treadmill, while gait events were measured using three detection methods; verticies of CoP cyclograms, and two kinematic criteria, (1) vertical velocity and position and of the heel marker, (2) anterior velocity and position of the heel and toe marker, were used. The percentage of unmatched gait events was used to determine the success of the GED method. The difference between CoP and kinematic GED methods were tested with two one sample (two-tailed) t-tests against a reference value of zero. Differences between group and paretic and non-paretic leg were tested with a repeated measures ANOVA. RESULTS: The kinematic method based on vertical velocity only detected about 80% of foot contact events on the paretic side in stroke survivors while the method on anterior velocity was more successful in both young healthy adults as stroke survivors (3% young healthy and 7% stroke survivors unmatched). Both kinematic methods detected gait events significantly earlier than CoP GED (p < 0.001) except for foot contact in stroke survivors based on the vertical velocity. CONCLUSIONS: CoP GED may be more appropriate for gait analyses of SS than kinematic methods; even when walking and varying steps.

Renal transplant from infant and neonatal donors is a feasible option for the treatment of end-stage renal disease but is associated with increased early graft loss.

Kidney transplants from young pediatric donors are uncommonly performed in the UK. Published literature of kidney transplant from donors weighing less than 5 kg is sparse. We present our initial experience of en bloc kidney transplantation (EKT) from donors weighing less than 20 kg, including neonatal donors. All recipients undergoing EKT from donors under 20 kg at our center from January 2005 to October 2016 were included. Donor and recipient details were recorded from a prospective database. Electronic patient records were examined for follow-up data. Of 30 EKTs included, 15 were from ≤5 kg donors and 15 from >5 kg donors (median weight 3.4 and 12.7 kg, respectively). One-year graft survival for ≤5 kg and >5 kg donors for EKT was 86.7% and 93.3% (P = 0.85), respectively. Progressive improvement in estimated GFR (eGFR) was noted in both donor categories through first-year posttransplant but in the ≤5 kg donor category significant improvement was seen at 12 months compared to 3 months after transplantation (median eGFR 37.3 vs 70.0 mL/min/1.73 m2 , P = 0.03). Two early graft losses were attributable to early vascular complications and one graft loss due to primary nonfunction. Our data show that kidney transplantation from such donors is a feasible option at centers with experience of EKT, albeit with increased risk of early graft loss.

No evidence for enhanced processing of speech that is low-pass filtered near the edge frequency of cochlear dead regions in children.

OBJECTIVES: Cochlear dead regions (DRs) are regions in the cochlea where the inner hair cells and/or neurons are not functioning. Adults with extensive high-frequency DRs have enhanced abilities in processing sounds with frequencies just below the edge frequency, fedge, of the DR. It was assessed whether the same is true for children. DESIGN: Performance was compared for children aged 8 to 13 years with: DRs (group DR), hearing impairment but without DRs (group NODR), and normal hearing (group NH). Seven ears in each group were tested. Each ear in the DR group was matched in age and low-frequency hearing with an ear in the NODR group, and in age with an ear in the NH group, giving seven "triplets". Within each triplet, the percent correct identification of vowel-consonant-vowel stimuli was measured using stimuli that were low-pass filtered at fedge and 0.67fedge, based on the ear with a DR. For the hearing-impaired ears, stimuli were given frequency-selective amplification as prescribed by DSL 4.1. RESULTS: No significant differences in performance were found between groups for either low-pass cut-off frequency. CONCLUSION: Unlike adults, the children with DRs did not show enhanced discrimination of speech stimuli with frequencies below fedge.

Early Outcomes of the New UK Deceased Donor Kidney Fast-Track Offering Scheme.

BACKGROUND: The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012 to identify kidneys at high risk of discard and to rapidly facilitate transplantation. A retrospective analysis of kidneys transplanted through the KFTS was undertaken. METHODS: UK Transplant Registry data were collected on deceased donor kidneys implanted between November 1, 2012, and April 30, 2015, (donation after brain death [DBD] donors) and March 1, 2013, and April 30, 2015 (donation after circulatory death [DCD] donors). Posttransplant outcomes included 1-year estimated glomerular filtration rate and death-censored graft survival (DCGS). RESULTS: Over the study period, 523 deceased donor kidneys were transplanted through the KFTS and 4174 via the standard National Kidney Allocation Scheme (NKAS). Kidneys in the KFTS were more likely to be from older diabetic donors, had a higher frequency of poor ex vivo perfusion, had longer cold ischemic times, and were transplanted into older recipients. One-year DCGS of KFTS and NKAS DBD donor kidneys was similar (94% vs 95%; P = 0.70), but for DCD donor kidneys, DCGS was lower in those allocated via the KFTS (91% versus 95%; P = 0.04). Median 1-year estimated glomerular filtration rate for DBD donor kidneys was lower in those allocated via the KFTS (49 vs 52 mL/min per 1.73 m; P = 0.01), but for DCD kidneys, there was no difference (45 vs 48 mL/min per 1.73 m; P = 0.10). CONCLUSIONS: Although KFTS kidneys have less favorable donor, graft, and recipient risk factors than NKAS kidneys, short-term graft and patient outcomes are acceptable. National schemes that identify and rapidly offer kidneys at high risk of discard may contribute to minimizing the unnecessary discard of organs.

Renal association clinical practice guideline in post-operative care in the kidney transplant recipient.

These guidelines cover the care of patients from the period following kidney transplantation until the transplant is no longer working or the patient dies. During the early phase prevention of acute rejection and infection are the priority. After around 3-6 months, the priorities change to preservation of transplant function and avoiding the long-term complications of immunosuppressive medication (the medication used to suppress the immune system to prevent rejection). The topics discussed include organization of outpatient follow up, immunosuppressive medication, treatment of acute and chronic rejection, and prevention of complications. The potential complications discussed include heart disease, infection, cancer, bone disease and blood disorders. There is also a section on contraception and reproductive issues.Immediately after the introduction there is a statement of all the recommendations. These recommendations are written in a language that we think should be understandable by many patients, relatives, carers and other interested people. Consequently we have not reworded or restated them in this lay summary. They are graded 1 or 2 depending on the strength of the recommendation by the authors, and AD depending on the quality of the evidence that the recommendation is based on.

Reduced human transitional B cell T1/T2 ratio is associated with subsequent deterioration in renal allograft function.

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for-cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression.

The effects of progressive resistance training on daily physical activity in young people with cerebral palsy: a randomised controlled trial.

PURPOSE: To examine if individualised resistance training increases the daily physical activity of adolescents and young adults with bilateral spastic cerebral palsy (CP). METHOD: Young people with bilateral spastic CP were randomly assigned to intervention or to usual care. The intervention group completed an individualised lower limb progressive resistance training programme twice a week for 12 weeks in community gymnasiums. The primary outcome was daily physical activity (number of steps, and time sitting and lying). Secondary outcomes included muscle strength measured with a one-repetition maximum (1RM) leg press and reverse leg press. Outcomes were measured at baseline, 12 weeks and 24 weeks. RESULTS: From the 36 participants with complete data at 12 weeks, there were no between-group differences for any measure of daily physical activity. There was a likely increase in leg press strength in favour of the intervention group (mean difference 11.8 kg; 95% CI -1.4 to 25.0). No significant adverse events occurred during training. CONCLUSIONS: A short-term resistance training programme that may increase leg muscle strength was not effective in increasing daily physical activity. Other strategies are needed to address the low-daily physical activity levels of young people with bilateral spastic CP. IMPLICATIONS FOR REHABILITATION: Progressive resistance training may increase muscle strength but does not lead to increases in daily physical activity of young people with bilateral spastic cerebral palsy (CP) and mild to moderate walking disabilities. Other strategies apart from or in addition to resistance training are needed to address the low daily physical activity levels of young people with bilateral spastic CP and mild to moderate walking disabilities.

Gross motor function is an important predictor of daily physical activity in young people with bilateral spastic cerebral palsy.

AIM: The aim of the study was to describe daily physical activity levels of adolescents and young adults with bilateral spastic cerebral palsy (CP) and to identify factors that help predict these levels. METHOD: Daily physical activity was measured using an accelerometer-based activity monitor in 45 young people with bilateral spastic CP (23 males, 22 females; mean age 18y 6mo [SD 2y 5mo] range 16y 1mo-20y 11mo); classified as Gross Motor Function Classification System (GMFCS) level II or III and with contractures of <20° at hip and knee. Predictor variables included demographic characteristics (age, sex, weight) and physical characteristics (gross motor function, lower limb muscle strength, 6min walk distance). Data were analyzed using the information-theoretic approach, using the Akaike information criterion (AIC) and linear regression. RESULTS: Daily activity levels were low compared with published norms. Gross Motor Function Measure Dimension-E (GMFM-E; walking, running, and jumping) was the only common predictor variable in models that best predicted energy expenditure, number of steps, and time spent sitting/lying. GMFM Dimension-D (standing) and bilateral reverse leg press strength contributed to the models that predicted daily physical activity. INTERPRETATION: Adolescents and young adults with bilateral spastic CP and mild to moderate walking disabilities have low levels of daily activity. The GMFM-E was an important predictor of daily physical activity.

Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells.

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.

En bloc kidney transplant from young pediatric donors: a scope to increase the donor pool.

We report 2 cases of en bloc kidney transplants from young pediatric donors with successful outcomes. We underscore the underuse of this significant donor source, and discuss the factors that may be related to the reasons for reluctance in accepting these kidneys for transplant.

Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial.

BACKGROUND: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). METHODS: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. RESULTS: The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. CONCLUSIONS: Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.