Winnie Chan

Assessing and comparing rival definitions of delayed renal allograft function for predicting subsequent graft failure.

Background. The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and “functional” definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF. Methods. We studied 750 adult deceased donor kidney transplant recipients (1996–2006) and analyzed the association between these two DGF definitions and long-term graft outcome. Results. Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16–2.18; P=0.004 and HR 1.72; 95% CI 1.26–2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03–2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06–2.03; P=0.02). Results were similar for overall graft failure. Conclusions. This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint.

Predictors and consequences of fatigue in prevalent kidney transplant recipients.

Background Fatigue has been underinvestigated in stable kidney transplant recipients (KTRs). The objectives of this study were to investigate the nature, severity, prevalence, and clinical awareness of fatigue in medically stable KTRs, examine the impact of fatigue on quality of life (QoL), and explore the underlying causes of posttransplantation fatigue. Methods This single-center cross-sectional study enrolled 106 stable KTRs. Multi-dimensional Fatigue Inventory-20 was used to measure five fatigue dimensions: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue. Clinical awareness of fatigue was determined by reviewing medical records. QoL was assessed by Medical Outcomes Study Short Form-36 Questionnaire. Demographic, clinical, psychosocial, and behavioral parameters were evaluated as fatigue predictors. Results Fatigue was found in 59% of KTRs. Only 13% had this symptom documented in medical records. Fatigue in KTRs was in the same range as chronically unwell patients, with Physical Fatigue, Reduced Activity, and Reduced Motivation approached levels observed in chronic fatigue syndrome. All fatigue dimensions significantly and inversely correlated with QoL (P<0.001 for all associations). Demographic predictors were male, older age, and non-Caucasian ethnicity (P⩽0.05 for all associations). Clinical predictors included elevated highly sensitive C-reactive protein (inflammation), decreased estimated glomerular filtration rate (graft dysfunction), and reduced lean tissue index (P⩽0.05 for all associations). Psychosocial and behavioral predictors were inferior sleep quality, anxiety, and depression (P<0.01 for all associations). Conclusions Fatigue is common and pervasive in clinically stable KTRs. It is strongly associated with reduced QoL. This study identified modifiable fatigue predictors and sets the scene for future interventional studies.

Hyperglycaemia and vitamin D: a systematic overview.

Vitamin D plays a role in a range of functions that may impact on glycaemic control. In this study we systematically report on clinical studies evaluating the impact of vitamin D on aspects of hyperglycaemia in non-pregnant adults. A total of 1,294 articles, of which 417 were reviews, were identified. No well-designed randomised, controlled trials were identified that specifically investigated the effects of vitamin D supplementation on glucose and insulin concentrations. The majority of the studies that are available were poorly designed, having limited numbers, short study duration, or were conducted in volunteers with normal baseline, as measured by 25-hydroxyvitamin D (25(OH)D), concentrations or used inadequate doses of the supplements to normalise vitamin D concentrations, or used inappropriate analyses. Most studies did not observe improvements in glycaemia, with few exceptions. The results were more equivocal for aspects of insulin resistance. Most found no benefit on measures of insulin resistance, although some did. However, more studies described improved insulin release, although data from the studies to date are really inadequate to provide any reliable conclusions. Well-conducted randomised, controlled trials with adequate vitamin D doses are required to effectively assess whether this vitamin can reduce the incidence of diabetes.

Cardiovascular, Muscular and Perceptual Contributions to Physical Fatigue in Prevalent Kidney Transplant Recipients

Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single‐centre observational cross‐sectional study enrolled 55 KTRs. Muscle mass was quantified using dual‐energy x‐ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age‐adjusted Borg scale‐ratings. Physical fatigue was measured using Multi‐Dimensional Fatigue Inventory‐20. QoL was assessed using Medical Outcomes Study Short Form‐36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions.

β Cell Glucotoxic-Associated Single Nucleotide Polymorphisms in Impaired Glucose Tolerance and New-Onset Diabetes After Transplantation

Emerging paradigms of new-onset diabetes after transplantation (NODAT) have focused on pathways and risk factors (e.g., posttransplant hyperglycemia and immunosuppressive agents) to its pathogenesis with the aim of identifying those at risk and developing preventative strategies (1). Identification of potential NODATassociated single nucleotide polymorphisms (SNPs) has increased our knowledge base of these pathways (2, 3). In particular, a recent genome-wide association study of 26 NODAT patients (and 230 controls), with subsequent de novo SNP genotyping in 57 NODAT patients (and 383 controls), discovered eight SNPs associated with pancreatic A-cell apoptosis (4). This Belfast cohort was limited to white, nondiabetic adult recipients who had received a cadaveric renal transplant between 1986 and 2005. New-onset diabetes after transplantation was defined as a new requirement for oral hypoglycemics or insulin after transplantation until August 2012. However, evidence is now emerging to identify abnormal glucose metabolism post transplantation by means of biochemical analyses including the oral glucose tolerance test (OGTT) (5, 6). We sought to examine the association of the identified eight SNPs in an independent cohort using biochemical diagnoses of impairedglucosetolerance(IGT)andNODAT. From 2009 to 2012, 112 patients were prospectively followed up over a 12-month period in a single-center adult tertiary center. To exclude preexisting diabetes, patients underwent glucose testing (minimum 8 hr fasting) immediately before transplantation and excluded if 6.1 mmol/L or higher or HbA1c of 6.5% or higher. In addition, live donor recipients underwent OGTTs within a week of transplantation. Oral glucose tolerance tests were then performed at 7 days, and then 3 months and 12 months for all renal transplants if fasting glucose was less than 7.0 mmol/L, to confirm the presence or persistence of posttransplant hyperglycemia. Impaired glucose tolerance was diagnosed if 2-hr OGTT glucose was 7.8 to 11 mmol/L. New-onset diabetes after transplantation was diagnosed if fasting glucose was 7 mmol/L or higher or 2-hr OGTT was 11.1 mmol/L or higher from day 7 onward, or HbA1c was 6.5% or higher from 3 months onward. Exclusion criteria of pretransplant diabetes and non-white ethnicity resulted in 68 patients being tested for the eight candidate SNPs (rs10484821, rs11580170, rs1836882, rs198372, rs2020902, rs2861484, rs4394754, rs7533125); genotyping was performed using Sequenom iPLEX and Taqman technologies. Event analyses using binary logistic regression was used adjusting for age, sex, baseline body mass index (BMI), and change in BMI over 12 months from transplantation. All patients had a homogenous immunosuppression regimen over the 12 months consisting of CD25 monoclonal antibody induction and maintenance tacrolimus, mycophenolic acid, and prednisolone. The cohort was aged 45 years (T15), 2.81 (T1.41) human leukocyte antigen mismatch, were 59% men, and 73% live donor recipients. Either IGT or NODAT occurred in over half the study population, with median time of onset 7 days and 18 days, respectively, after transplantation (IGT, 18/68 patients; NODAT, 18/68 patients). Significant differences were seen in the BMI change over 12 months for those who developed IGT (P=0.007) and NODAT (P=0.002) compared to those who did not. The NODAT group were also significantly older compared to those without NODAT (54 vs. 41 years; P=0.002). One candidate SNP that was found to be associated with posttransplant hyperglycemia in both cohorts was rs198372 for gene NPPA. Rs198372 genotype GG (vs. non-GG) was protective for IGT-onset on univariate (P=0.015) and multivariate analysis (OR, 0.21 [0.05Y 0.88]; P=0.033) in the adjusted model. No other SNPs demonstrated statistical significance for association with NODAT or IGT, although the power to detect an effect size of 1.5 was on average 10.2% across the tested SNPs and therefore (as expected) the possibility of a type II error certainly exists. NPPA encodes natriuretic peptides that inhibit cytokine and leptin production that are associated with inflammation and insulin resistance in human adipose tissue. Indeed, the Birmingham cohort who developed IGT exhibited an average increase in BMI of 2.3 kg/m at 1 year after transplantation, consistent with leptin level or weight gain known association (7). Elevated leptin levels increase interleukin-1A promoting Acell apoptosis in pancreatic islets and free fatty acids inducing apoptosis by caspase activation (4). McCaughan et al. (4) reported a 9.6% NODAT incidence over 12 years follow-up (57 patients with a median onset of 100 months), whereas in Birmingham at only 12 months, over 25% (18 patients) developed IGT and the same number had NODAT. This may reflect differences between the cohorts (for instance, all patients in Birmingham received maintenance CNI therapy compared with 75% in Belfast). However, it also highlights the importance of the use of detailed OGTT data in unmasking posttransplant glucose abnormalities. Also, this in turn may influence the genotype-phenotype relationship. This study supports further replication of the initial Belfast findings in regard to rs198372 as a candidate SNP for identifying patients at risk for developing posttransplant hyperglycemia and a potential biochemical pathway for manipulation.

The role of hepcidin-25 in kidney transplantation

Background Hepcidin-25 is a peptide hormone involved in iron absorption and homeostasis and found at increased serum levels in conditions involving systemic inflammation, renal dysfunction, and increased adiposity. Hepcidin may play a role in the pathogenesis of anemia, but its role in kidney transplantation is undefined. Methods This study enrolled 100 stable patients beyond 12 months after transplantation, from a large single United Kingdom center. Serum hepcidin-25 level, and relevant demographic and laboratory data pertinent to posttransplantation anemia, were measured and collected. Independent predictors of serum hepcidin were evaluated, and the relationship between hepcidin and hemoglobin, assessed. Results Independent associations were seen between higher hepcidin levels and allograft dysfunction (estimated glomerular filtration rate), increased inflammation (high-sensitivity C-reactive peptide), higher transferrin saturation (a marker of iron stores), and the use of marrow-suppressive medication (P<0.05 for all). Higher fat tissue index (whole-body multifrequency bioimpedance measurement) was also associated with higher hepcidin levels, but this relationship did not persist after adjustment for inflammation (high-sensitivity C-reactive peptide). In turn, inflammation was associated with increased fat tissue index (P=0.01) and male gender (P=0.04). A nonlinear association between serum hepcidin level and hemoglobin was seen, with a progressive fall in hemoglobin as hepcidin levels rose to 100 ng/mL, but little effect thereafter (P=0.009). This association was independent of renal dysfunction and female gender, both of which were also independently associated with a lower hemoglobin level. Conclusions These results highlight possible mechanisms of hemoglobin reduction in kidney transplantation patients, and the therapeutic opportunities from understanding the role of hepcidin in this context.

The Mechanisms of Physical Fatigue in Kidney Transplant Recipients.: Abstract# D2721

D2721 The Mechanisms of Physical Fatigue in Kidney Transplant Recipients. W. Chan,1,2 D. Jones,2 J. Bosch,2 N. Crabtree,1 O. Kaur,1 A. McClean,1,2 L. Harper,1,2 A. Phillips,2 R. Borrows.1,2 1Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 2University of Birmingham, Birmingham, United Kingdom. PURPOSE The mechanisms of physical fatigue in kidney transplant recipients (KTRs) remained unexplored. The primary objectives were to determine the prevalence of physical fatigue in KTRs; assess its impact on quality of life (QoL); and identify the mechanisms of physical fatigue through examinations of cardiorespiratory function (VO2max), perceived exertion, as well as muscle mass, function and conditioning. The secondary objective was to investigate the predictors of raised perceived exertion, a determinant of physical fatigue in KTRs. METHODS This single-centre cross-sectional study enrolled 55 KTRs ≥1 year posttransplantation. Mean age=46±14 years; 58% male. Physical fatigue was measured by multi-dimensional fatigue inventory-20. QoL was assessed with SF-36. VO2max was estimated by sub-maximal exercise test. Rating of perceived exertion (RPE) was determined by age-adjusted Borg-ratings during exercise, with RPE index calculated. Lean body mass (LBM) was quantifi ed with dual energy x-ray absorptiometry. Muscle function was assessed by jumping mechanography (single 2-legged jump [S2LJ] and chair rise test [CRT]). Muscle conditioning was determined by changes in myokine (serum IL-6) levels, taken at rest (Trest), immediately (Timmediate) and 1-hour (T1-hour) after exercise. Demographic, clinical, psychosocial and behavioural predictors of perceived exertion were assessed. RESULTS Physical fatigue was found in 22% of KTRs, and exerted a negative impact on QoL (p<0.001). Median RPE index=1.2 (0.8-2.0). Mean values of VO2max=26.7±9.0 ml/ kg/min; LBM=50.7±11.5 kg; muscle function measured by S2LJ=4045±1136 W, and CRT=1118±268 W. No signifi cant changes of serum IL-6 levels were detected between Trest, Timmediate, and T1-hour. Independent predictors of physical fatigue were reduced VO2max in male (p=0.04) and increased perceived exertion in female (p=0.003). Independent predictors of raised perception were mental fatigue (p=0.03), anxiety (p=0.01), new-onset diabetes after transplantation (p=0.04), absence of cyclosporine (p=0.03), and low alcohol intake (p=0.03). CONCLUSION Physical fatigue in KTRs is driven by reduced VO2max in male, and increased perception in female. Predictors of raised perception were identifi ed, paving the way for future interventional studies. Further research is needed to identify causes of reduced VO2max in KTRs. Abstract# D2722 Cardiorespiratory Fitness in Kidney Transplant Recipients. W. Chan,1,2 D. Jones,2 A. Phillips,2 J. Bosch,2 O. Kaur,1 A. McClean,1,2 L. Harper,1,2 R. Borrows.1,2 1Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 2University of Birmingham, Birmingham, United Kingdom. PURPOSE Cardiorespiratory fi tness (VO2max) garners little attention in kidney transplant recipients (KTRs). The primary objectives were to establish the prevalence, impact and predictors of reduced VO2max. The role of VO2max assessment in potential KTRs remains controversial. The secondary objective was to evaluate the prognostic value of pre-transplant cardiorespiratory exercise test. METHODS Primary objectives were tested by a cross-sectional cohort of KTRs ≥1 year posttransplantation (n=55; mean age=46±14 years; 58% male). Secondary objectives were tested by a longitudinal cohort of living-donor KTRs within 1 month pretransplantation (n=26; mean age=41±16 years; 58% male). VO2max was estimated by submaximal exercise test. “Reduced” (≤0.81 predicted) and “severely reduced” (<0.62 predicted) VO2max were delineated. QoL was assessed with SF-36. Clinical outcome data were retrieved from medical records. Demographic, nutritional and clinical predictors of VO2max were assessed. RESULTS Mean KTRs’ VO2max=26.7±9.0 ml/kg/min. “Reduced VO2max” was found in 58% of KTRs, with 22% being “severely reduced”. Post-transplant VO2max positively correlated with QoL (p<0.001), but did not predict 2-year hospitalisation rates and days to fi rst hospitalisation. Predictors of reduced VO2max were female (p=0.004), increased fat mass (p=0.002), hypovolemia (p<0.001), and hypervolemia (p<0.001). In patients awaiting kidney transplantation, pre-transplant VO2max did not correlate with QoL up to 1 year post-transplantation, and did not predict 2-year hospitalisation rates and days to fi rst hospitalisation post-transplantation. Similarly, pre-transplant VO2max did not predict early clinical outcomes within the 1st week post-transplantation including systolic and diastolic blood pressure, lowest standardised early warning score, creatinine reduction ratio, and length of hospital stay. No patient required dialysis, inotropes, and ICU admission within the 1st week post-transplantation. There was no incidence of delayed graft function. CONCLUSION Reduced cardiorespiratory fi tness is common in KTRs, and is associated with reduced QoL. This study identifi ed potential modifi able predictors, setting the scene for interventional studies. The limited predictive value of pre-transplant cardiorespiratory exercise testing on post-transplant QoL and early clinical outcomes needs further validation. D2722 Cardiorespiratory Fitness in Kidney Transplant Recipients. W. Chan,1,2 D. Jones,2 A. Phillips,2 J. Bosch,2 O. Kaur,1 A. McClean,1,2 L. Harper,1,2 R. Borrows.1,2 1Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 2University of Birmingham, Birmingham, United Kingdom. PURPOSE Cardiorespiratory fi tness (VO2max) garners little attention in kidney transplant recipients (KTRs). The primary objectives were to establish the prevalence, impact and predictors of reduced VO2max. The role of VO2max assessment in potential KTRs remains controversial. The secondary objective was to evaluate the prognostic value of pre-transplant cardiorespiratory exercise test. METHODS Primary objectives were tested by a cross-sectional cohort of KTRs ≥1 year posttransplantation (n=55; mean age=46±14 years; 58% male). Secondary objectives were tested by a longitudinal cohort of living-donor KTRs within 1 month pretransplantation (n=26; mean age=41±16 years; 58% male). VO2max was estimated by submaximal exercise test. “Reduced” (≤0.81 predicted) and “severely reduced” (<0.62 predicted) VO2max were delineated. QoL was assessed with SF-36. Clinical outcome data were retrieved from medical records. Demographic, nutritional and clinical predictors of VO2max were assessed. RESULTS Mean KTRs’ VO2max=26.7±9.0 ml/kg/min. “Reduced VO2max” was found in 58% of KTRs, with 22% being “severely reduced”. Post-transplant VO2max positively correlated with QoL (p<0.001), but did not predict 2-year hospitalisation rates and days to fi rst hospitalisation. Predictors of reduced VO2max were female (p=0.004), increased fat mass (p=0.002), hypovolemia (p<0.001), and hypervolemia (p<0.001). In patients awaiting kidney transplantation, pre-transplant VO2max did not correlate with QoL up to 1 year post-transplantation, and did not predict 2-year hospitalisation rates and days to fi rst hospitalisation post-transplantation. Similarly, pre-transplant VO2max did not predict early clinical outcomes within the 1st week post-transplantation including systolic and diastolic blood pressure, lowest standardised early warning score, creatinine reduction ratio, and length of hospital stay. No patient required dialysis, inotropes, and ICU admission within the 1st week post-transplantation. There was no incidence of delayed graft function. CONCLUSION Reduced cardiorespiratory fi tness is common in KTRs, and is associated with reduced QoL. This study identifi ed potential modifi able predictors, setting the scene for interventional studies. The limited predictive value of pre-transplant cardiorespiratory exercise testing on post-transplant QoL and early clinical outcomes needs further validation. Abstract# D2723 Changes in Functional Outcomes After an Inpatient Rehabilitation Program for Solid Organ Transplant Recipients. T. Janaudis-Ferreira,1,2 B. Cheung,1 K. Uy,1 J. Chawla,1 S. Mathur,2 J. Patcai.1 1St John’s Rehab Program, Sunnybrook Research Institute, Toronto, ON, Canada; 2Department of Physical Therapy, University of Toronto, Toronto, ON, Canada. Purpose: To describe the changes in functional outcomes after an inpatient rehabilitation program for solid organ transplant (SOT) recipients and determine whether any changes in functional mobility, lower body strength and lower limb muscle strength were associated with changes in functional exercise capacity. Methods: Twenty-one SOT recipients (7 liver; 2 liver + kidney; 1 kidney + pancreas; 2 heart; 2 single lung; 7 double lung; 58±8 yrs; 62% men (n = 13)) were enrolled in the study and participated in a multidisciplinary program (total duration: 23 ± 9 days) that was comprised of occupational therapy, physical therapy, psychological and nutritional support and nursing. Functional exercise capacity (2 Minute Walk test (2MWT)), balance (Berg Balance Scale (BBS)), functional mobility (Time Up and Go (TUG)), lower body strength (30 Second Sit-To-Stand Test), functional independence (Functional Independence Measure (FIM®)), self-reported performance during activities of daily living (ADL) (Canadian Occupational Performance Measure (COPM)) and health related quality of life (Rand-36) were measured before and after the rehabilitation program. Elbow fl exion and knee extension force were measured using a hand-held dynamometer. Results: Sixteen subjects completed the study and showed signifi cant improvements D2723 Changes in Functional Outcomes After an Inpatient Rehabilitation Program for Solid Organ Transplant Recipients. T. Janaudis-Ferreira,1,2 B. Cheung,1 K. Uy,1 J. Chawla,1 S. Mathur,2 J. Patcai.1 1St John’s Rehab Pr