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.

Evaluation of a Novel Dermal Cooling System for the Treatment of Benign Pigmented Lesions in Asians.

OBJECTIVE: Our study aimed to evaluate the efficacy of this novel dermal cooling system (DCS) in reducing pigmentation in benign pigmented lesions in Asian patients and its potential side effects. METHODS: It was a prospective open-label single-center study. Asian patients, with the presence of benign pigmented lesions mainly including lentigines, melasma, nevus spilus, ephelides, café au lait, and seborrheic keratosis were recruited for a novel DCS. The DCS provided localized cooling of the epidermal layer below freezing but was less intense than cryotherapy. Each patient received DCS at Week 0 and repeated at 4-week intervals up to 10 sessions. Global aesthetic improvement scores (GAIS) by blinded physicians and subjects were recorded at 2, 6, and 12 months posttreatment follow-up. RESULTS: Eighty-one patients were recruited with a total of 305 sessions performed and 1716 lesion sites treated. At 2-month posttreatment, 76.5% and 58.6% treatment sites showed obvious to marked improvement respectively and the improvement sustained at 6 and 12 months. Only minor adverse events were reported. Erythema and edema were the most commonly anticipated effects immediately after treatment. The pain was minimal. Postinflammatory hyperpigmentation was only reported in 2.2% (38/1716) treated sites. CONCLUSION: To our knowledge, this study was the first study to demonstrate that this novel DCS was an effective, safe, and well-tolerated treatment for benign pigmented lesions in Asians.

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.

A review of the topical management of acne and its associated sequelae in the Asia-Pacific region with a spotlight on trifarotene.

Acne, a highly prevalent skin disease, can be particularly bothersome for patients of Asian background because of its impact on self-confidence and social interactions. In addition to active acne lesions, some patients may develop sequelae such as scarring, macular/postinflammatory hyperpigmentation, or erythema. The tendency of Asian skin to develop sequelae because of its increased susceptibility to irritation, cultural preferences for lighter skin phototypes, and differences in skincare regimens may all contribute to the increased burden of acne. Moreover, many Asia-Pacific countries do not have their own guidelines for acne management, and those that do often have no schedule in place for regular updates. In this article, we provide a critical review of the published guidance for the management of acne and its sequelae in the Asia-Pacific region, identifying gaps in current recommendations that could be addressed to enhance standards of acne care in Asia-Pacific countries. Along with highlighting the importance of a comprehensive skincare regimen to increase treatment efficacy and adherence, we discuss topical retinoids and retinoid combination options in the acne armamentarium that may be beneficial for sequelae prevention and management, such as adapalene 0.3% ± benzoyl peroxide 2.5%, tretinoin 0.05%, tazarotene 0.1%, and trifarotene 0.005%. In particular, trifarotene 0.005% has been observed to significantly reduce acne scar counts in a Phase 4 study. The recent data highlight the need to establish up-to-date guidance for acne and acne sequelae management in Asia-Pacific countries to provide optimal care to Asian patients.

Echocardiographic parameters of cardiac structure and function in the diagnosis of acute myocarditis in adult patients: A systematic review and meta-analysis.

BACKGROUND: Transthoracic echocardiography (TTE) plays a key role in the initial work-up of myocarditis where the identification of pathologic structural and functional changes may assist in its diagnosis and management. The aim of this systematic review was to appraise the evidence for the utility of echocardiographic parameters of cardiac structure and function in the diagnosis of myocarditis in adult populations. METHODS: A systematic literature search of medical databases was performed using PRISMA principles to identify all relevant studies assessing TTE parameters in adult patients with myocarditis (1995-2020; English only; PROSPERO registration CRD42021243598). Data for a range of structural and functional TTE parameters were individually extracted and those with low heterogeneity were then meta-analyzed using a random-effects model for effect size, and assessed through standardized mean difference (SMD). RESULTS: Available data from six studies (with a pooled total of 269 myocarditis patients and 240 controls) revealed that myocarditis can be reliably differentiated from healthy controls using echocardiographic measures of left ventricular (LV) size and systolic function, in particular LV end-diastolic diameter, LV ejection fraction (LVEF) and LV global longitudinal strain (LV-GLS) (p ≤ .01 for all). LV-GLS demonstrated the highest overall effect size, followed by LVEF and LVEDD (SMD: |0.46-1.98|). Two studies also demonstrated that impairment in LV-GLS was associated with adverse cardiovascular outcomes in this population, irrespective of LVEF. CONCLUSIONS: LV-GLS demonstrated the greatest overall effect size and therefore ability to differentiate myocarditis populations from healthy controls. GLS was also shown to be a predictor of adverse cardiovascular outcomes, in this population. HIGHTLIGHTS: What is already known on this subject? Myocarditis is a disease process that is often a diagnosis of exclusion, as it frequently mimics other acute cardiac pathologies. Transthoracic echocardiography is traditionally the initial imaging modality used for noninvasive structural assessment in populations with myocarditis. What might this study add? This study demonstrates that left ventricular (LV) global longitudinal strain, LV ejection fraction and LV end-diastolic diameter can differentiate between myocarditis patients and healthy controls. LV-GLS demonstrated the greatest overall effect size when comparing these two populations, in comparison to the other measures. How might this impact on clinical practice? This study demonstrates that assessment of myocardial deformation indices allows for sensitive discrimination between myocarditis patients from healthy controls. Routine assessment of LV-GLS may serve as an important diagnostic tool in the acute care setting.

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.

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.

The use of fractional radiofrequency in Asian patients to improve skin texture.

BACKGROUND AND OBJECTIVES: Fractional radiofrequency devices have been demonstrated to improve skin texture, such as smoothness, rhytides, brightness, and atrophic acne scars, by increasing dermal thickness, dermal collagen content, and dermal fibrillin content. The objective of the study is to assess the efficacy and adverse effects of this device on Asian patients of skin type III and IV with skin textural changes. MATERIALS AND METHODS: The study was designed as a prospective, open-labeled single-arm study, which was conducted with 20 Chinese patients aged 21-60 years and having irregularities in their skin texture, rhytides, and acne scars. The patients received six treatments at intervals of 4 weeks. Treatment was initiated with the maximum energy tolerated, which was then adjusted during the course of treatment if the patients felt excessive discomfort. A total of two passes were delivered in each session. Physician assessment results and standardized photographs were collected at the baseline, after all treatment visits, and at 1, 2, and 6 months after the final treatment visit. RESULTS: A total of 17 patients completed the study according to the established protocol. At the 6-month follow-up, 71% of patients were satisfied and 24% of patients were very satisfied with the received treatments, and the treatment physician reported varying degrees of improvement based on the global assessment scale in 60% of the subjects. While the anticipated side effects, such as erythema, edema, pinpoint bleeding, scab formation, and flare of acne, were noted in the patients, no serious adverse effects occurred. CONCLUSION: The use of fractional radiofrequency improves skin texture and is safe for use in Asian patients of skin type III and IV. No long-term serious adverse effects were noted.

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 impact of body mass index on cardiac structure and function in a cohort of obese patients without traditional cardiovascular risk factors.

Background: Obesity has been linked with alterations in hemodynamic, autonomic, and hormonal pathways in the body, leading to a spectrum of cardiovascular changes. We sought to evaluate the effects of obesity on structural and functional changes of the heart in the absence of cardiac disease and associated risk factors. Methods: We identified healthy outpatients without any cardiovascular disease or risk factors from our institution's echocardiography database (2017-2020). Patients were stratified by body mass index (BMI; normal: 18.5-25 kg/m2; overweight: 25-30 kg/m2; class 1 obesity: 30-35 kg/m2; class 2 obesity: 35-40 kg/m2; class 3 obesity: >40 kg/m2). Traditional and advanced echocardiographic parameters of cardiac chamber size and function including left ventricular global longitudinal strain (LV-GLS), left atrial reservoir strain (LASr), and right ventricular free wall strain (RV-FWS) were examined. The optimal cut-off BMI for discriminating LV-GLS (>-17.5%), LASr (<23%), and RV-FWS (>-23%) impairment was calculated using ROC curves. Results: 307 patients were assessed (41.5 ± 13.3yrs; 36.5%male; LVEF 61.3 ± 4.8%). No significant differences in indexed chamber volumes or LVEF were appreciated across BMI groups (p > 0.05 for all). LV-GLS, LASr, and RV-FWS were all significant on one-way ANOVA for differences from the group mean (all p < 0.01). Jonckheere-Terpstra test confirmed a significant trend of lower absolute LV-GLS, LASr and RV-FWS values across the rising BMI groups. On ROC curve analysis, a BMI value of 29.9 kg/m2, 35.1 kg/m2, and 37.3 kg/m2 were associated with LASr (AUC: 0.75), RV-FWS (AUC: 0.72), and LV-GLS (AUC: 0.75) impairment respectively. Conclusion: Obesity is linked with subclinical reduction of cardiac function in otherwise healthy subjects without cardiovascular risk factors, with reduction of left atrial function occurring at lower BMI, followed by the right and left ventricular function.

Characterization of Subclinical Cardiac Dysfunction by Speckle Tracking Echocardiography in Patients With Non-severe Acute-Phase Myocarditis.

Subclinical changes in left ventricular (LV) function have been demonstrated in patients with acute-phase myocarditis (AM) despite normal LV ejection fraction. The impact of AM on right ventricular (RV) and left atrial (LA) function has not been well described. This study aimed to assess for subclinical chamber dysfunction by speckle tracking echocardiography and its clinical relevance in this population. Patients with a diagnosis of AM (as per the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases) admitted to our institution from 2013 to 2018 were assessed. Patients with elevated serum troponin, normal coronary assessment, and normal LV ejection fraction on transthoracic echocardiogram were included. Clinical and echocardiographic parameters were compared with healthy age-, gender- and risk-factor matched controls. Global longitudinal strain assessed through speckle tracking echocardiography was performed using vendor independent software (v4.6; TomTec Arena, Munich, Germany). The final cohort consisted of 80 patients (40 AM patients and 40 controls). No significant differences in baseline clinical characteristics were observed between groups. Of the echocardiographic parameters, AM patients had lower LV-global longitudinal strain (p <0.01), lower RV free-wall strain (p = 0.02) and lower peak LA strain (p <0.01). There were no differences in traditional echocardiographic measures of LV, RV, and LA function appreciated between groups. The presence of multichamber involvement was associated with peak Troponin levels (p <0.01). In conclusion, our study demonstrates the presence of global subclinical myocardial dysfunction in patients with AM. Additionally, the presence of multichamber involvement was significantly associated with degree of myocardial necrosis.

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.

Myopia Control Efficacy and Long-Term Safety of a Novel Orthokeratology Lens (MESOK Study)-A Randomized Controlled Clinical Trial Combining Clinical and Tear Proteomics Data.

Myopia control efficacy and long-term safety of the Breath-O-Correct orthokeratology (OK) lens was evaluated in a 2-year randomized, single vision (SV) spectacle lens-controlled, single-blind clinical trial combining clinical and tear proteomics data. A total of 71 children (43 OK, 9.8 ± 1.3 years; 28 SV, 9.5 ± 1.4 years) completed the 2-year study. Axial length (AL), cycloplegic refraction, clinical safety parameters (best-corrected visual acuity, central cornea thickness, corneal endothelial health, ocular surface disease index), and quantitative tear proteomics were evaluated by masked examiners. Mean 2-year-normalized AL elongations in the OK and SV groups differed significantly (p = 0.03) and were 0.37 ± 0.37 mm and 0.60 ± 0.41 mm, respectively. OK-mediated myopia control efficacy was 37.1%. No significant difference was found in clinical safety parameters of both groups (p > 0.10), except for a thinner central corneal thickness in the OK group (p = 0.01). Proteomics revealed modest OK lens-mediated effects on immune response proteins, including an increased abundance of haptoglobin at 6 and 12 months and a decreased abundance of two proteins (neutrophil defensin 3 and histone 4) at 6 months. The changes were further validated using a high-resolution multiple-reaction monitoring (MRMHR) mass spectrometry. In summary, the Breath-O-Correct OK lens significantly reduced AL elongation in schoolchildren without adverse clinical effects or subclinical inflammatory responses.