HLA-DR/DQ eplet mismatch predicts de novo donor-specific antibody development in multi-ethnic Southeast Asian kidney transplant recipients on different immunosuppression regimens.

Eplet mismatch has been recognized as a more precise strategy for determining HLA compatibility by analyzing donor-recipient HLA differences at the molecular level. However, predicting post-transplant alloimmunity using single-molecule eplet mismatch categories has not been validated in Asian cohorts. We examined a cohort of Southeast Asian kidney transplant recipients (n = 234) to evaluate HLA-DR/DQ eplet mismatch as a predictor of de novo donor-specific antibody (dnDSA) development. HLA-DR/DQ single-molecule eplet mismatch was quantified using HLA Matchmaker, and we utilized previously published HLA-DR/DQ eplet mismatch thresholds to categorize recipients into alloimmune risk groups and evaluate their association with dnDSA development. Recognizing that the predominance of cyclosporine use (71%) may alter published eplet mismatch thresholds derived from a largely tacrolimus-based (87%) cohort, we evaluated cohort-specific thresholds for HLA-DR/DQ single-molecule eplet mismatch categories. Recipient ethnicities included Chinese (65%), Malays (17%), Indians (14%), and others (4%). HLA-DR/DQ dnDSA developed in 29/234 (12%) recipients after a median follow-up of 5.4 years, including against isolated HLA-DR (n = 7), isolated HLA-DQ (n = 11), or both (n = 11). HLA-DR/DQ single-molecule eplet mismatch risk categories correlated with dnDSA-free survival (p = 0.001) with low-risk recipients having a dnDSA prevalence of 1% over 5 years. The cohort-specific alloimmune risk categories improved correlation with HLA-DR/DQ dnDSA-free survival and remained significant after adjusting for calcineurin inhibitor and anti-metabolite immunosuppression (p < 0.001). We validated the performance of single-molecule eplet mismatch categories as a prognostic biomarker for HLA-DR/DQ dnDSA development in a cohort of predominantly Asian kidney transplant recipients after adjusting for different immunosuppression regimens.

Deceased donor kidney transplant policies in Asia - implications on practice and recommendations for the future.

Deceased donor kidney transplantation (DDKT) is common in high income Western countries with high transplantation rates. However, the utilization of deceased organs is suboptimal in Asia, due to a multitude of factors. Coherent policies are integral to the development of DDKT programs and deterrence of commercialization, but most are still at an infancy and formative stage in Asia. This review article identifies the glass ceiling effects of social, cultural, religious, political, and technical factors hampering the progress of DDKT in Asia. Additionally, it reviews the history of policy development in different countries and describes their idiosyncratic barriers and challenges. Lastly, it discusses innovative policy measures that can be undertaken to proliferate DDKT practice and curtail commercialization. The long-term ideal is to achieve regional equity and self-sufficiency, through a shared ethos of social and ethical responsibility that transcends and resonates with the different segments of the Asian community.

Analyzing COVID-19 Vaccine Responses in Transplant Recipients.

COVID-19 vaccination has significantly impacted the global pandemic by reducing the severity of infection, lowering rates of hospitalization, and reducing morbidity/mortality in healthy individuals. However, the degree of vaccine-induced protection afforded to renal transplant recipients who receive forms of maintenance immunosuppression remains poorly defined. This is particularly important when we factor in the emergence of SARS-CoV-2 variants of concern (VOCs) that have defined mutations that reduce the effectiveness of Ab responses targeting the Spike Ags from the ancestral Wuhan-Hu-1 variants employed in the most widely used vaccine formats. In this study, we describe a qualitative, longitudinal analysis of neutralizing Ab responses against multiple SARS-CoV-2 VOCs in 129 renal transplant recipients who have received three doses of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2). Our results reveal a qualitative and quantitative reduction in the vaccine-induced serological response in transplant recipients versus healthy controls where only 51.9% (67 of 129) made a measurable vaccine-induced IgG response and 41.1% (53 of 129) exhibited a significant neutralizing Ab titer (based on a pseudovirus neutralization test value >50%). Analysis on the VOCs revealed strongest binding toward the wild-type Wuhan-Hu-1 and Delta variants but none with both of the Omicron variants tested (BA1 and BA2). Moreover, older transplant recipients and those who are on mycophenolic acid as part of their maintenance therapy exhibited a profound reduction in all of the analyzed vaccine-induced immune correlates. These data have important implications for how we monitor and manage transplant patients in the future as COVID-19 becomes endemic in our populations.

Disparities in ethnicity and metabolic disease burden in referrals to nephrology.

Introduction: The profile of patients referred from primary to tertiary nephrology care is unclear. Ethnic Malay patients have the highest incidence and prevalence of kidney failure in Singapore. We hypothesised that there is a Malay predominance among patients referred to nephrology due to a higher burden of metabolic disease in this ethnic group. Methods: This is a retrospective observational cohort study. From 2014 to 2018, a coordinator and physician triaged patients referred from primary care, and determined co-management and assignment to nephrology clinics. Key disease parameters were collated on triage and analysed. Results: A total of 6,017 patients were studied. The mean age of patients was 64 ± 16 years. They comprised 57% men; 67% were Chinese and 22% were Malay. The proportion of Malay patients is higher than the proportion of Malays in the general population (13.4%) and they were more likely than other ethnicities to have ≥3 comorbidities, including diabetes mellitus, hypertension, hyperlipidaemia, coronary artery disease and stroke (70% vs. 57%, P < 0.001). Malay and Indian patients had poorer control of diabetes mellitus compared to other ethnicities (glycated haemoglobin 7.8% vs. 7.4%, P < 0.001). Higher proportion of Malay patients compared to other ethnicities had worse kidney function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 on presentation (28% vs. 24%, P = 0.003). More ethnic Malay, Indian and younger patients missed appointments. Conclusion: A disproportionately large number of Malay patients are referred for kidney disease. These patients have higher metabolic disease burden, tend to miss appointments and are referred at lower eGFR. Reasons underpinning these associations should be identified to facilitate efforts for targeting this at-risk population, ensuring kidney health for all.

Engineering immunosuppressive drug-resistant armored (IDRA) SARS-CoV-2 T cells for cell therapy.

Solid organ transplant (SOT) recipients receive immunosuppressive drugs (ISDs) and are susceptible to developing severe COVID-19. Here, we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients (n = 136) treated with different ISDs. We demonstrate that a combination of a calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and prednisone (Pred) treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response. Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection. To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients, we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor (TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta, Delta, Gamma, and Omicron variants. This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

Healthy aging and chronic kidney disease.

The world population is aging and the prevalence of noncommunicable diseases such as diabetes, hypertension, and chronic kidney disease (CKD) will increase significantly. With advances in medical treatment and public health, the human lifespan continues to outpace the health span in such a way that the last decade of life is generally spent in poor health. In 2015, the World Health Organization defined healthy aging as 'the process of developing and maintaining the functional ability that enables wellbeing in older age.' CKD is increasingly being recognized as a model of accelerated aging and is associated with physical performance decline, cognitive decline, falls and fractures, poor quality of life, loss of appetite, and inflammation. Frailty and dementia are the final pathways and key determinants of disability and mortality independent of underlying disease. CKD, dementia, and frailty share a triangular relationship with synergistic actions and have common risk factors wherein CKD accelerates frailty and dementia through mechanisms such as uremic toxicity, metabolic acidosis and derangements, anorexia and malnutrition, dialysis-related hemodynamic instability, and sleep disturbance. Frailty accelerates glomerular filtration decline as well as dialysis induction in CKD and more than doubles the mortality risk. Anorexia is one of the major causes of protein-energy malnutrition, which is also prevalent in the aging population and warrants screening. Healthcare systems across the world need to have a system in place for the prevention of CKD amongst high-risk older adults, focusing on screening for poor prognostic factors amongst patients with CKD such as frailty, poor appetite, and cognitive impairment and providing necessary person-centered interventions to reverse underlying factors that may contribute to poor outcomes.

Outcomes of Care by Geriatricians and Non-geriatricians in an Academic Hospital.

Introduction: While 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 Methods: A 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. Results: The 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). Conclusion: Geriatrician-led care model showed shorter LOS, lower cost, and was associated with lower odds of extended LOS and cost.

Multi-photon microscopy for the evaluation of interstitial fibrosis in extended criteria donor kidneys: A proof-of-concept study.

INTRODUCTION: To evaluate the initial use of label-free second harmonic generation (SHG) imaging with two-photon excitation (2PE) auto-fluorescence in multiphoton microscopy (MPM) for the quantification of collagen/fibrosis on preimplantation biopsies of extended criteria donors (ECD). MATERIALS AND METHODS: Twenty preimplantation core biopsies were extracted from 10 donor kidney samples, of which originated from seven donors. Kidney Donor Profile Index (KDPI) and Remuzzi scores of biopsies were calculated. Collagen parameters measured included quantification by the Collagen Area Ratio in Total Tissue (CART) and qualitative measurements by Collagen Reticulation Index (CRI). RESULTS: Biopsies classified with > 85% KDPI scores had significantly higher CART (p = .011) and lower CRI values (p = .025) than biopsies with ≤ 85% KDPI scores. Increase in CRI values correlated significantly with rise in recipient creatinine levels 1-year post-transplant (p = .027; 95% CI: 4.635-66.797). CONCLUSION: MPM is an evolving technology that enables the quantification of the amount (CART) and quality (CRI) of collagen deposition in unstained preimplantation biopsies of donor kidneys stratified by KDPI scores. This initial evaluation found significant differences in both parameters between donor kidneys with more or less than 85% KDPI.

Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury.

BACKGROUND: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. METHODS: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. RESULTS: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. CONCLUSION: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

Volvariella volvacea brain Abscess in an immunocompromised host-An emerging fungal pathogen in Asia.

Volvariella volvacea is a fungus found in tropical regions, commonly associated with straw mushrooms. This is a 50-year-old Singaporean female post living donor renal transplant who presented with fever, cough and headache. She was diagnosed to have Volvariella volvacea brain abscess. She was treated with combination anti-fungal therapy without surgical debridement and remains stable. The pathogenicity of this rare fungus in immunocompromised hosts is demonstrated here and is of significance particularly in Asia where ingestion of straw mushrooms may be a risk factor for invasive fungal disease.

Health Care Analytics With Time-Invariant and Time-Variant Feature Importance to Predict Hospital-Acquired Acute Kidney Injury: Observational Longitudinal Study.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 m2, 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. CONCLUSIONS: 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.

A meta-analysis on the prevalence of chronic kidney disease in liver transplant candidates and its associated risk factors and outcomes.

Pre-liver transplant (LT) chronic kidney disease (CKD) has emerged as a leading cause of post-operative morbidity. We aimed to report the prevalence, associated risk factors, and clinical outcomes in patients with pre-LT CKD. Meta-analysis and systematic review were conducted for included cohort and cross-sectional studies. Studies comparing healthy and patients with s pre-LT CKD were included. Outcomes were assessed with pooled hazard ratios. 15 studies were included, consisting of 82,432 LT patients and 26,754 with pre-LT CKD. Pooled prevalence of pre-LT CKD was 22.35% (CI: 15.30%-32.71%). Diabetes mellitus, hypertension, viral hepatitis, and non-alcoholic fatty liver disease, and older age were associated with increased risk of pre-LT CKD: (OR 1.72 CI: 1.15-2.56, P = 0.01), (OR 2.23 CI: 1.76-2.83, P < 0.01), (OR 1.09; CI: 1.05-1.13, P < 0.01), (OR 1.73; CI: 1.10-2.71 P = 0.03), and (MD: 2.92 years; CI: 1.29-4.55years; P < 0.01) respectively. Pre-LT CKD was significantly associated with increased mortality (HR 1.38; CI: 1.2-1.59; P < 0.01), post-LT end-stage renal disease and post-LT CKD. Almost a quarter of pre-LT patients have CKD and it is significantly associated with post-operative morbidity and mortality. However, long-term outcomes remain unclear due to a lack of studies reporting such outcomes.

A meta-analysis of the cumulative incidence, risk factors, and clinical outcomes associated with chronic kidney disease after liver transplantation.

Chronic kidney disease (CKD) remains a relatively common complication after liver transplantation (LT), and significantly impacts overall survival. We sought to assess the cumulative incidence, risk factors and mortality associated with post-LT CKD. CKD was defined as eGFR <60 ml/min/1.73 m2 as estimated by the Modified Diet in Renal Disease (MDRD) formula. Single-arm meta-analysis was done to evaluate the cumulative incidence of CKD at 1-, 3-, and 5-year timepoints post-LT. Risk factors for CKD were evaluated using hazard ratios (HR). Twenty-one studies involving 44 383 patients were included. Cumulative incidence of stage 3-5 CKD was 31.44% (CI 0.182-0.447), 36.71% (CI 0.188-0.546), and 43.52% (CI 0.296-0.574) at 1, 3, and 5 years after LT, respectively. Stage 5 CKD cumulative incidence increased from 0.274% (CI 0.001-0.005) at 1 year to 2.06% (CI 0.009-0.045) at 5 years post-LT. Age, female sex, diabetes, and peri-operative acute kidney injury (AKI) were significant risk factors for CKD. Stage 4-5 CKD was associated with a decrease in overall survival (HR 3.23, 95% CI 1.74-5.98, P < 0.01). CKD after LT is relatively common, and is associated with significantly reduced overall survival. Identification of patients at high risk of developing CKD allows physicians to prophylactically use renal-sparing immunosuppression which may be crucial in achieving desirable clinical outcomes.

Cumulative iodinated contrast exposure for computed tomography during acute kidney injury and major adverse kidney events.

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.