Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Incidence, Risk Factors, and Outcomes of De Novo Malignancy following Kidney Transplantation.

Introduction: Post-transplant malignancy is a significant cause of morbidity and mortality following kidney transplantation often emerging after medium- to long-term follow-up. To understand the risk factors for the development of de novo post-transplant malignancy (DPTM), this study aimed to assess the incidence, risk factors, and outcomes of DPTM at a single nephrology centre over two decades. Methods: This retrospective cohort study included 963 kidney transplant recipients who underwent kidney transplantation between January 2000 and December 2020 and followed up over a median follow-up of 7.1 years (IQR 3.9-11.4). Cox regression models were used to identify the significant risk factors of DPTM development, the association of DPTM with graft survival, and mortality with a functioning graft. Results: In total, 8.1% of transplant recipients developed DPTM, and the DPTM incidence rate was 14.7 per 100 patient-years. There was a higher mean age observed in the DPTM group (53 vs. 47 years, p < 0.001). The most affected organ systems were genitourinary (32.1%), gastrointestinal (24.4%), and lymphoproliferative (20.5%). Multivariate Cox analysis identified older age at transplant (aHR 9.51, 95%CI: 2.60-34.87, p < 0.001) and pre-existing glomerulonephritis (aHR 3.27, 95%CI: 1.10-9.77, p = 0.03) as significant risk factors for DPTM. Older age was significantly associated with poorer graft survival (aHR 8.71, 95%CI: 3.77-20.20, p < 0.001). When age was excluded from the multivariate Cox model, DPTM emerged as a significant risk factor for poor survival (aHR 1.76, 95%CI: 1.17-2.63, p = 0.006). Conclusion: These findings underscore the need for tailored screening, prevention, and management strategies to address DPTM in an aging and immunosuppressed kidney transplant population.

Hepatocardiorenal syndrome in liver cirrhosis: Recognition of a new entity?

Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome (HRS), outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context. In the absence of established heart disease, cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease. It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities. Despite the clinical description of these potential cardiac-related complications of the liver, the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS. Yet from a physiological sense, temporality (prior onset) of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients. In this review, we discuss current concepts surrounding how the heart may influence the development and progression of HRS, and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting. The temporality of heart and kidney dysfunction in HRS will be discussed. For a subgroup of patients who receive portosystemic shunting, the dynamics of cardiorenal interactions following treatment is reviewed. Continued research to determine the unknowns in this topic is anticipated, hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.

Clostridioides difficile Infection in Kidney Transplant Recipients.

Clostridioides difficile (C. difficile) is a bacterial organism that typically infects the colon, which has had its homeostasis of healthy gut microbiota disrupted by antibiotics or other interventions. Patients with kidney transplantation are a group that are susceptible to C. difficile infection (CDI) and have poorer outcomes with CDI given that they conventionally require long-term immunosuppression to minimize their risk of graft rejection, weakening their responses to infection. Recognizing the risk factors and complex pathophysiological processes that exist between immunosuppression, dysbiosis, and CDI is important when making crucial clinical decisions surrounding the management of this vulnerable patient cohort. Despite the clinical importance of this topic, there are few studies that have evaluated CDI in the context of kidney transplant recipients and other solid organ transplant populations. The current recommendations on CDI management in kidney transplant and solid organ transplant recipients are mostly extrapolated from data relating to CDI management in the general population. We provide a narrative review that discusses the available evidence examining CDI in solid organ transplant recipients, with a particular focus on the kidney transplant recipient, from the epidemiology of CDI, clinical features and implications of CDI, potential risk factors of CDI, and, ultimately, prevention and management strategies for CDI, with the aim of providing areas for future research development in this topic area.

Delivering Personalized, Goal-Directed Care to Older Patients Receiving Peritoneal Dialysis.

Background: An aging population living with chronic kidney disease and progressing to kidney failure, subsequently receiving peritoneal dialysis (PD) is growing. A significant proportion of these patients are also living with multi-morbidities and some degree of frailty. Recent practice recommendations from the International Society of Peritoneal Dialysis advocate for high-quality, goal-directed PD prescription, and the Standardized Outcomes of Nephrology-PD initiative emphasized the need for an individualized, goal-based care approach in all patients receiving PD treatment. In older patients, this approach to PD care is even more important. A frailty screening assessment, followed by a comprehensive geriatric assessment (CGA) prior to PD initiation and when dictated by change in relevant circumstances is paramount in tailoring PD care and prescription according to the needs, life goals, as well as clinical status of older patients with kidney failure. Summary: Our review aimed to summarize the different dimensions to be taken into account when delivering PD care to the older patient - from frailty screening and CGA in older patients receiving PD to employing a personalized, goal-directed PD prescription strategy, to preserving residual kidney function, optimizing blood pressure (BP) control, and managing anemia, to addressing symptom burden, to managing nutritional intake and promoting physical exercise, and to explore telehealth opportunities for the older PD population. Key Messages: What matters most to older PD patients may not be simply extending survival, but more importantly, to be living comfortably on PD treatment with minimal symptom burden in a home environment and to minimize treatment complications.

The Role of PLA2R in Primary Membranous Nephropathy: Do We Still Need a Kidney Biopsy?

Membranous nephropathy (MN) is the most prevalent cause of nephrotic syndrome amongst the non-diabetic adult population. A fifth of idiopathic nephrotic syndrome cases can be attributed to MN, rising to more than 40% in older patients over 60 years. Most MN cases are classified as being of a primary cause, where there is absence of a secondary disease process explaining its manifestation. Traditionally, the standard approach of diagnosing MN involves performing a kidney biopsy as histological evaluation offers not only conclusive evidence of the diagnosis but also provides valuable information regarding disease chronicity and the presence of any other kidney histopathological features. Nevertheless, kidney biopsy is an invasive procedure which poses risks for the patient including bleeding and pain and bears greater costs for the health system. The identification of the phospholipase A2 receptor (PLA2R) antigen in 2009 was a landmark discovery, one which has evolved our understanding of the disease processes in MN and subsequently our management approach of this condition. Antibodies against PLA2R (PLA2RAb) have since emerged as an attractive non-invasive test option to be applied for the diagnosis and prognostication of primary MN. However, much debate and unknowns remain about the accuracy and reliability of testing for PLA2RAb across various primary MN scenarios. We provide a review summarizing the historical journey of PLA2R in relation to its significance in primary MN and, more importantly, evidence emerging over the years which contemplated the role of PLA2RAb as a diagnostic and prognostic tool in primary MN.

COVID-19 Infection and Vaccination and Its Relation to Amyloidosis: What Do We Know Currently?

Amyloidosis is a complex disorder characterized by deposited insoluble fibrillar proteins which misfold into ß-pleated sheets. The pathogenesis of amyloidosis can vary but can be the result of immune dysregulation that occurs from sustained high inflammatory states, often known as AA amyloidosis. Multi-organ involvement including hepatic, gastrointestinal, renal, cardiac and immunological pathological manifestations has been observed amongst individuals presenting with amyloidosis. The recent global pandemic of severe acute respiratory syndrome coronavirus 2, also referred to as coronavirus 2019 (COVID-19), has been shown to be associated with multiple health complications, many of which are similar to those seen in amyloidosis. Though COVID-19 is recognized primarily as a respiratory disease, it has since been found to have a range of extra-pulmonary manifestations, many of which are observed in patients with amyloidosis. These include features of oxidative stress, chronic inflammation and thrombotic risks. It is well known that viral illnesses have been associated with the triggering of autoimmune conditions of which amyloidosis is no different. Over the recent months, reports of new-onset and relapsed disease following COVID-19 infection and vaccination have been published. Despite this, the exact pathophysiological associations of COVID-19 and amyloidosis remain unclear. We present a scoping review based on our systematic search of available evidence relating to amyloidosis, COVID-19 infection and COVID-19 vaccination, evaluating current perspectives and providing insight into knowledge gaps that still needs to be addressed going forward.

Physiological Associations between Vitamin B Deficiency and Diabetic Kidney Disease.

The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors-inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic.

Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

Norovirus acute gastroenteritis among US and European travellers to areas of moderate to high risk of travellers' diarrhoea: a prospective cohort study.

BACKGROUND: Acute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact among travellers is limited. METHODS: Prospective, multi-site, observational cohort study conducted 2015-2017, among adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms while travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive, and tested for other common enteric pathogens by Luminex xTAG GPP. RESULTS: Of the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks (95% CI: 22.4; 27.1). Twenty NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). Eighty percent of NoV-positive participants (vs. 38.9% in NoV-negative) reported at least moderate impact on travel plans. CONCLUSIONS: AGE is a prevalent disease among travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology.

Understanding and Expanding the Prospects for Electrosynthesis with Liquid Metal Electrodes.

ConspectusThis Account describes and summarizes the latest work from our laboratory on developing and maturing strategies based on low-temperature liquid metals as reaction environments for materials synthesis. The electrochemical liquid-liquid-solid (ec-LLS) crystal growth concept is a hybrid method that combines electrodeposition and melt crystal growth. Using liquid metals as both electrodes and solvents for the purpose of producing inorganic crystals and materials, a simple and environmentally friendly process is possible. The impetus is to address the key deficiency in the inorganic crystalline materials that are the basis of modern optoelectronics and renewable energy capture/conversion systems. Specifically, existing methods for synthesizing crystalline inorganic materials for these purposes are largely energy- and resource-intensive, with a substantial impact on the environment when scaled. A long-term goal of our work with ec-LLS is to realize a materials synthetic process that is matured without requiring intensive resources or negatively impacting the environment. To this end, the factors that both limit and govern ec-LLS processes must be identified and understood. To date, questions regarding the factors that affect crystal nucleation and growth, form factors, and overall composition remain.Previous work established concretely ec-LLS as a versatile method for synthesizing and producing crystalline semiconductors at low temperatures as either particles, nanowires, or microwires. Subsequent experiments have focused on two tiers. First, the microscopic details of the liquid metal and its interfaces that dictate materials synthesis and crystal growth must be identified. Second, strategies that widen the attainable material form factors to facilitate device architectures must be realized. Hence, this Account describes results aimed at answering three questions: (1) What are the consequences of reaching supersaturation by an electrochemical rather than a thermal driving force for crystal growth in ec-LLS? (2) Can the location of nucleation and subsequent crystal growth be controlled? (3) Does the atomic structure of the liquid metal affect product formation in ec-LLS? The science described herein illustrates the value of in situ methods spanning transmission electron microscopy, X-ray diffraction, and X-ray reflectance for revealing the role that liquid metal composition and structure can play in ec-LLS. Additionally, we summarize work that shows for the first time that it is possible to produce both single-crystalline epitaxial films and complex intermetallic compounds through ec-LLS by tuning the cell design, electrochemical excitation waveform, and composition of the liquid metal electrodes.The cumulative findings described here substantially enrich our understanding of the ec-LLS concept while simultaneously motivating further questions moving forward. Is it possible to attain complete control over the crystalline quality and composition of ec-LLS products? Can the materials produced by ec-LLS provide tailored functional properties for targeted applications? Can the ec-LLS strategy be further refined to allow material synthesis and deposition at precise locations with deterministically chosen form factors? What synthetic pathways are accessible when even more sophisticated electrochemical waveforms and cell designs are used? Our hope is that this Account will spur additional researchers to help answer such questions.