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Background Non-adherence to immunosuppressive medications following renal transplantation is a risk factor for rejection and graft loss. Despite the dire consequences, adherence lapses, both unintentional and intentional, are common and poorly understood. Objective The present study sets to compare the rates and determinants of unintentional, intentional and overall self-reported non-adherence. Setting Outpatient clinic at the National University Centre for Organ Transplantation, Singapore. Method This was a cross-sectional survey administered to N = 152 renal transplant recipients. Main outcome measure They completed the Transplant Effects Questionnaire, Beliefs about Medications Questionnaire, Multidimensional Scale of Perceived Social Support, the Depression, Anxiety and Stress Scale, and the Medication Adherence Report Scale. Clinical and laboratory information were also assessed. Results The prevalence rates for overall, unintentional, and intentional self-reported non-adherence were 19.7, 47.4, and 15.1% respectively. Unintentional non-adherence was predicted by engagement in formal work, a primary diagnosis of autoimmune nephritis, and being a recipient of a living-donor renal transplant (i.e. stable characteristics). In contrast, intentional non-adherence was predicted by co-morbid burden and patients’ evaluation of the side effects of their medications. Overall non-adherence was predicted by a deliberate decision-making process involving the weighing of the costs of using immunosuppressive drugs against their perceived benefits. Conclusion The survey highlighted the importance of making a distinction between unintentional and intentional non-adherence in renal transplant recipients, and suggested that modifiable factors may be targeted in different ways in interventions to increase adherence.

Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling. Here we provide a biochemical/biophysical and functional characterization of a human monoclonal alloantibody specific for a common HLA type, HLA-A*11:01. We present a 2.4 Å resolution map of the binding interface of this antibody on HLA-A*11:01 and compare the structural determinants with those utilized by T-cell receptor (TCR), killer-cell immunoglobulin-like receptor (KIR) and CD8 on the same molecule. These data provide a mechanistic insight into the paratope−epitope relationship between an alloantibody and its target HLA molecule in a biological context where other immune receptors are concomitantly engaged. This has important implications for our interpretation of serologic binding patterns of anti-HLA antibodies in sensitized individuals and thus, for the biology of human alloresponses. Anti-human leukocyte antigen (HLA) antibodies are important mediators of alloresponses, but structural insights on antibody:HLA interaction are still lacking. Here the authors provide a 2.4 Å structure of antibody:HLA complex, and also analyse HLA features important for other HLA-interacting molecules, to enhance our understanding of alloimmunity.

The current state-of-the-art technology employed to assess anti-human leukocyte antigen antibodies (Anti-HLA Ab) for donor-recipient matching and patient risk stratification in renal transplantation is the single antigen bead (SAB) assay. However, there are limitations to the SAB assay as it is not quantitative and due to variations in techniques and reagents, there is no standardization across laboratories. In this study, a structurally-defined human monoclonal alloantibody was employed to provide a mechanistic explanation for how fundamental alloantibody biology influences the readout from the SAB assay. Performance of the clinical SAB assay was evaluated by altering Anti-HLA Ab concentration, subclass, and detection reagents. Tests were conducted in parallel by two internationally accredited laboratories using standardized protocols and reagents. We show that alloantibody concentration, subclass, laboratory-specific detection devices, subclass-specific detection reagents all contribute to a significant degree of variation in the readout. We report a significant prozone effect affecting HLA alleles that are bound strongly by the test alloantibody as opposed to those bound weakly and this phenomenon is independent of complement. These data highlight the importance for establishing international standards for SAB assay calibration and have significant implications for our understanding of discordance in previous studies that have analyzed its clinical relevance.

Objectives To determine if contrast-enhanced CT imaging performed in patients during their episode of AKI contributes to major adverse kidney events (MAKE). Methods A propensity score–matched analysis of 1127 patients with AKI defined by KDIGO criteria was done. Their mean age was 63 ± 16 years with 56% males. A total of 419 cases exposed to CT contrast peri-AKI were matched with 798 non-exposed controls for 14 covariates including comorbidities, acute illnesses, and initial AKI severity; outcomes including MAKE and renal recovery in hospital were compared using bivariate analysis and logistic regression. MAKE was a composite of mortality, renal replacement therapy, and doubling of serum creatinine on discharge over baseline; renal recovery was classified as early versus late based on a 7-day timeline from AKI onset to nadir creatinine or cessation of renal replacement therapy in survivors. Results Sixty-two patients received cumulatively > 100 mL of CT contrast, 143 patients had > 50–100 mL, and 214 patients had 50 mL or less; MAKE occurred in 34%, 17%, and 21%, respectively, as compared with 20% in non-exposed controls ( p  = 0.008 for patients with > 100 mL contrast versus none). More contrast-exposed patients experienced late renal recovery (27% versus 20%) and longer hospital days (median 10 versus 8) than non-exposed patients (all p  < 0.01). On multivariate analysis, cumulative CT contrast > 100 mL was independently associated with MAKE (odds ratio 2.39 versus non-contrast, adjusted for all confounders, p  = 0.005); cumulative CT contrast under 100 mL was not associated with MAKE. Conclusions High cumulative volume of CT contrast administered to patients with AKI is associated with worse short-term renal outcomes and delayed renal recovery. Key Points • Cumulative intravenous iodinated contrast for CT imaging of more than 100 mL, during an episode of acute kidney injury, was independently associated with worse renal outcomes and less renal recovery. • These adverse outcomes including renal replacement therapy were not more frequent in similar patients who received cumulatively 100 mL or less of CT contrast, compared with non-exposed patients. • More patients with CT contrast exposure during acute kidney injury experienced delayed renal recovery.

Donor-specific antibodies (DSAs) targeting mismatched human leukocyte antigen (HLA) molecules are one of the principal threats to long-term graft survival in solid organ transplantation. However, many patients with long-term circulating DSAs do not manifest rejection responses, suggesting a degree of heterogeneity in their pathogenicity and related functional activity. Immunologic risk stratification of transplant recipients is complicated by challenges intrinsic to defining alloantibody responses that are potentially pathogenic versus those that are not. Thus, a comprehensive understanding of how human alloantibodies target and interact with donor HLA molecules is vital for the development and evaluation of new strategies aimed at reducing antibody-mediated rejection responses. In this study, we employ hydrogen–deuterium exchange–mass spectrometry (HDX–MS), molecular dynamics (MD) simulations, and advanced biochemical and biophysical methodologies to thoroughly characterize a panel of human monoclonal alloantibodies and define the influence of Fc-region biology, antibody binding kinetics, target antigen density, and structural characteristics on their ability to potentiate the forms of immune effector mechanisms that are strongly implicated in transplant rejection. Our findings have significant implications for our understanding of the key biological determinants that underlie the pathogenicity or lack thereof of human alloantibodies.

Acute kidney injury (AKI) develops in 4% of hospitalized patients and is a marker of clinical deterioration and nephrotoxicity. AKI onset is highly variable in hospitals, which makes it difficult to time biomarker assessment in all patients for preemptive care. The study sought to apply machine learning techniques to electronic health records and predict hospital-acquired AKI by a 48-hour lead time, with the aim to create an AKI surveillance algorithm that is deployable in real time. The data were sourced from 20,732 case admissions in 16,288 patients over 1 year in our institution. We enhanced the bidirectional recurrent neural network model with a novel time-invariant and time-variant aggregated module to capture important clinical features temporal to AKI in every patient. Time-series features included laboratory parameters that preceded a 48-hour prediction window before AKI onset; the latter's corresponding reference was the final in-hospital serum creatinine performed in case admissions without AKI episodes. The cohort was of mean age 53 (SD 25) years, of whom 29%, 12%, 12%, and 53% had diabetes, ischemic heart disease, cancers, and baseline eGFR <90 mL/min/1.73 m , respectively. There were 911 AKI episodes in 869 patients. We derived and validated an algorithm in the testing dataset with an AUROC of 0.81 (0.78-0.85) for predicting AKI. At a 15% prediction threshold, our model generated 699 AKI alerts with 2 false positives for every true AKI and predicted 26% of AKIs. A lowered 5% prediction threshold improved the recall to 60% but generated 3746 AKI alerts with 6 false positives for every true AKI. Representative interpretation results produced by our model alluded to the top-ranked features that predicted AKI that could be categorized in association with sepsis, acute coronary syndrome, nephrotoxicity, or multiorgan injury, specific to every case at risk. We generated an accurate algorithm from electronic health records through machine learning that predicted AKI by a lead time of at least 48 hours. The prediction threshold could be adjusted during deployment to optimize recall and minimize alert fatigue, while its precision could potentially be augmented by targeted AKI biomarker assessment in the high-risk cohort identified.

Background Patients with chronic kidney disease (CKD) have poor health-related quality of life (HRQoL). The association of CKD-related complications such as anemia and mineral and bone disorders (MBD) with HRQoL in pre-dialysis patients is not well-studied. As such, this study aimed to determine the association of anemia and MBD with HRQoL in pre-dialysis patients. Methods This was a cross-sectional study involving 311 adult pre-dialysis patients with stage 3–5 CKD from an acute-care hospital in Singapore. Patients’ HRQoL were assessed using Kidney Disease Quality of Life Short Form (KDQOL-SF™) and EuroQol 5 Dimensions–3 levels (EQ5D-3L). HRQoL between patients with and without anemia or MBD were compared by separate hierarchical multiple linear regression analyses using various HRQoL scales as dependent variables, adjusted for sociodemographic, clinical and psychosocial variables. Results After adjusting for MBD, anemia was associated with lower HRQoL scores on work status (WS), physical functioning (PF) and role physical [β (SE): −10.9 (4.18), p  = 0.010; −3.0 (1.28), p  = 0.018; and −4.2 (1.40), p  = 0.003, respectively]. However, significance was lost after adjustments for sociodemographic variables. Patients with MBD had poorer HRQoL with respect to burden of kidney disease, WS, PF and general health [(β (SE): −7.9 (3.88), p  = 0.042; −9.5 (3.99), p  = 0.018; −3.0 (1.22) p  = 0.014; −3.6 (1.48), p  = 0.015, respectively]. Although these remained significant after adjusting for sociodemographic variables, significance was lost after adjusting for clinical variables, particularly pill burden. This is of clinical importance due to the high pill burden of CKD patients, especially from medications for the management of multiple comorbidities such as cardiovascular and mineral and bone diseases. Conclusions Neither anemia nor MBD was associated with HRQoL in our pre-dialysis patients. Instead, higher total daily pill burden was associated with worse HRQoL. Medication reconciliation should therefore be routinely performed by clinicians and pharmacists to reduce total daily pill burden where possible.

IntroductionObesity may be a risk factor for kidney donors to develop reduced renal function. The Framingham heart study suggested that visceral adipose tissue (VAT) confers a more adverse metabolic profile compared with subcutaneous adipose tissue (SAT). Asians tend to have a higher VAT composition and it is unclear if their kidney function is affected differently. We hypothesized that Asian living kidney donors who have visceral obesity are at a higher risk of renal function deterioration 1 year after donation.MethodsBetween 2011 and 2014, we retrospectively evaluated data from 73 consecutive patients (52% male; mean age 44.9 ± 11.7 years) before they underwent donor nephrectomy and at their 1 year routine follow-up. VAT and SAT were measured at the level of the umbilicus on pre-operative computerized tomography (CT). Visceral obesity (VO) was defined as a VAT > 100 cm [2] and patients were then further divided and compared in two subgroups: VAT > 100 and < 100 cm [2]. Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m [2]) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pre-operatively and 1 year post-operatively.ResultsBoth subgroups had similar baseline kidney function (P = NS) pre-operatively. At the 1 year follow-up, patients with VO experienced a more significant decline of renal function (109 ± 9 to 89 ± 8 mL/min per 1.73 m2), compared to those without VO (111 ± 12 to 96 ± 11 mL/min per 1.73 m2, P = 0.013). VO was associated with a body mass index (BMI) > 25 kg/m2 (P < 0.001), male gender (P < 0.001) and older age at the time of donor nephrectomy (48.0 vs 39.5 years, P = 0.01). The presence of hypertension or hyperlipidaemia pre-operatively, choice of surgical approach, and post-operative complication rates, did not differ significantly between the subgroups.ConclusionsVisceral obesity as defined by VAT > 100 cm2 at the level of the umbilicus on cross-sectional imaging, may have a significant impact on early renal function after donor nephrectomy. Adiposity markers, as measured by cross-sectional CT imaging, may be incorporated into routine pre-operative kidney donor workup.

Haematuria has a prevalence of 12% in the postrenal transplant patient population. It heralds potentially dangerous causes which could threaten graft loss. It is important to consider causes in light of the unique, urological, and immunological standpoints of these patients. We review the literature on common causes of haematuria in postrenal transplant patients and suggest the salient approach to the evaluation of this condition. A major cause of haematuria is urinary tract infections. There should be a higher index of suspicion for mycobacterial, fungal, and viral infection in this group of immunosuppressed patients. Measures recommended in the prevention of urinary tract infections include early removal of foreign bodies as well as prophylactic antibiotics during the early transplant phase. Another common cause of haematuria is that of malignancies, in particular, renal cell carcinomas. When surgically managing cancer in the setting of a renal transplant, one has to be mindful of the limited retropubic space and the need to protect the anastomoses. Other causes include graft rejections, recurrences of primary disease, and calculus formation. It is important to perform a comprehensive evaluation with the aid of an experienced multidisciplinary transplant team.

IntroductionWhile hospitalist and internist inpatient care models dominate the landscape in many countries, geriatricians and internists are at the frontlines managing hospitalized older adults in countries such as Singapore and the United Kingdom. The primary aim of this study was to determine outcomes for older patients cared for by geriatricians compared with non-geriatrician-led care teams.Materials and MethodsA retrospective cohort study of 1,486 Internal Medicine patients aged ≥75 years admitted between April and September 2021 was conducted. They were either under geriatrician or non-geriatrician (internists or specialty physicians) care. Data on demographics, primary diagnosis, comorbidities, mortality, readmission rate, Hospital Frailty Risk Score (HFRS), Age-adjusted Charlson Comorbidity Index, Length of Stay (LOS), and cost of hospital stay were obtained from the hospital database and analyzed.ResultsThe mean age of patients was 84.0 ± 6.3 years, 860 (57.9%) females, 1,183 (79.6%) of Chinese ethnicity, and 902 (60.7%) under the care of geriatricians. Patients under geriatrician were significantly older and had a higher prevalence of frailty, dementia, and stroke, whereas patients under non-geriatrician had a higher prevalence of diabetes and hypertension. Delirium as the primary diagnosis was significantly higher among patients under geriatrician care. Geriatrician-led care model was associated with shorter LOS, lower cost, similar inpatient mortality, and 30-day readmission rates. LOS and cost were lower for patients under geriatrician care regardless of frailty status but significant only for low and intermediate frailty groups. Geriatrician-led care was associated with significantly lower extended hospital stay (OR 0.73; 95% CI 0.56–0.95) and extended cost (OR 0.69; 95% CI 0.54–0.95).ConclusionGeriatrician-led care model showed shorter LOS, lower cost, and was associated with lower odds of extended LOS and cost.