Imlifidase: Is it the Magic Wand in Renal Transplantation?

Potential kidney transplant patients with HLA-specific antibodies have reduced access to transplantation. Their harmful effects are mediated by the Fc portion of IgG, including activation of the complement system and Fc receptor-initiated cytotoxic processes by circulating leucocytes. Avoiding antibody incompatibility is the conventional approach, but for some patients this can mean extended waiting times, or even no chance of a transplant if there are no alternative, compatible donors. For these cases, pretransplant antibody removal may provide access to transplantation. Plasmapheresis is currently used to achieve this, with acceptable outcome results, but the process can take days to reduce the antibody levels to a safe level, so has limited use for deceased donors. There is now an alternative, in the form of an IgG-digesting enzyme, Imlifidase, which can be administered for in vivo IgG inactivation. Imlifidase cleaves human IgG, separating the antigen-binding part, F(ab')2 from Fc. Typically, within six hours of dosing, most, if not all, of the circulating IgG has been inactivated, allowing safe transplantation from a previously incompatible donor. For deceased donor transplantation, where minimizing cold ischaemia is critical, this six-hour delay before implantation should be manageable, with the compatibility testing processes adjusted to accommodate the treatment. This agent has been used successfully in phase 2 clinical trials, with good short to medium term outcomes. While a donation rate that matches demand may be one essential answer to providing universal access to kidney transplantation, this is currently unrealistic. IgG inactivation, using Imlifidase, is, however, a realistic and proven alternative.

Live-donor kidney transplant outcome prediction (L-TOP) using artificial intelligence.

Outcome prediction for live-donor kidney transplantation improves clinical and patient decisions and donor selection. However, the concurrently used models are of limited discriminative or calibration power and there is a critical need to improve the selection process. We aimed to assess the value of various artificial intelligence (AI) algorithms to improve the risk stratification index. We evaluated pre-transplant variables among 66 914 live-donor kidney transplants (performed between 01/12/2007-01/06/2021) from the United Network of Organ Sharing database, randomized into training (80%) and test (20%) sets. The primary outcome measure was death-censored graft survival. We tested four machine learning models for discrimination (time-dependent concordance index, CTD, and area under the ROC curve) and calibration (integrated Brier score, IBS). We used decision curve analysis to assess the potential clinical utility. Among the models, the deep Cox mixture model showed the best discriminative performance (AUC = 0.70, 0.68, and 0.68 at 5, 10, and 13 years post-transplant, respectively). CTD reached 0.70, 0.67, and 0.66 at 5, 10, and 13 years post-transplant. The IBS score was 0.09, indicating good calibration. In comparison, applying the Living Kidney Donor Profile Index (LKDPI) on the same cohort produced a CTD of 0.56 and an AUC of 0.55-0.58 only. Decision curve analysis showed an additional net benefit compared to the LKDPI, 'Treat all' and 'Treat None' approaches. Our AI-based deep Cox mixture model, termed Live-Donor Kidney Transplant Outcome Prediction outperforms existing prediction models, including the LKDPI, with the potential to improve decisions for optimum live donor selection by ranking potential transplant pairs based on graft survival. This model could be adopted to improve the outcomes of paired exchange programs.

Deceased-Donor Kidney Transplant Outcome Prediction Using Artificial Intelligence to Aid Decision-Making in Kidney Allocation.

In kidney transplantation, pairing recipients with the highest longevity with low-risk allografts to optimize graft-donor survival is a complex challenge. Current risk prediction models exhibit limited discriminative and calibration capabilities and have not been compared to modern decision-assisting tools. We aimed to develop a highly accurate risk-stratification index using artificial intelligence (AI) techniques. Using data from the UNOS database (156,749 deceased kidney transplants, 2007-2021), we randomly divided transplants into training (80%) and validation (20%) sets. The primary measure was death-censored graft survival. Four machine learning models were assessed for calibration (integrated Brier score [IBS]) and discrimination (time-dependent concordance [CTD] index), compared with existing models. We conducted decision curve analysis and external validation using UK Transplant data. The Deep Cox mixture model showed the best discriminative performance (area under the curve [AUC] = 0.66, 0.67, and 0.68 at 6, 9, and 12 years post-transplant), with CTD at 0.66. Calibration was adequate (IBS = 0.12), while the kidney donor profile index (KDPI) model had lower CTD (0.59) and AUC (0.60). AI-based D-TOP outperformed the KDPI in evaluating transplant pairs based on graft survival, potentially enhancing deceased donor selection. Advanced computing is poised to influence kidney allocation schemes.

Can eHealth applications improve renal transplant outcomes for adolescents and young adults? A systematic review.

BACKGROUND AND OBJECTIVES: Adherence to medical treatment following a kidney transplant is particularly challenging during adolescence and young adulthood. There is increasing evidence of the benefits of the use of computer and mobile technology (labelled as eHealth hereafter) including serious gaming and gamification in many clinical areas. We aimed to conduct a systematic review of such interventions designed to improve self-management skills, treatment adherence and clinical outcomes in young kidney transplant recipients aged 16 to 30 years. METHOD: The Cochrane Library, MEDLINE, EMBASE, PsychINFO, SCOPUS and CINAHL databases were searched for studies published between 01 January 1990 and 20 October 2020. Articles were short-listed by two independent reviewers based on pre-defined inclusion/exclusion criteria. Reference lists were screened and authors of published conference abstracts contacted. Two reviewers independently appraised selected articles, systematically extracted data and assessed the quality of individual studies (CASP and SORT). Thematic analysis was used for evidence synthesis; quantitative meta-analysis was not possible. RESULTS: A total of 1098 unique records were identified. Short-listing identified four eligible studies, all randomized controlled trials (n = 266 participants). Trials mainly focused on mHealth applications or electronic pill dispensers (mostly for patients >18 years old). Most studies reported on clinical outcome measures. All showed improved adherence but there were no differences in the number of rejections. Study quality was low for all four studies. CONCLUSIONS: The findings of this review suggest that eHealth interventions can improve treatment adherence and clinical outcomes for young kidney transplant patients. More robust and high-quality studies are now needed to validate these findings. Future studies should also extend beyond short-term outcomes, and consider cost of implementation. The review was registered with PROSPERO (CRD42017062469).

Hypoxia during maintenance hemodialysis-the critical role of pH.

Background: The impact and management of subclinical hypoxia during hemodialysis is a significant medical challenge. As key determinants of O2 availability and delivery, proposed mechanisms contributing to hypoxia include ischemia, alkalemia and pulmonary leukocyte sequestration. However, no study has comprehensively investigated and compared these interrelated mechanisms throughout a typical hemodialysis treatment week. This study aimed to comprehensively assess the physiological mechanisms that contribute to hypoxia during hemodialysis. Methods: In 76 patients, we measured arterial blood gases and pH at four time-points during hemodialysis (start, 15 min, 60 min, end) over the course of a standard treatment week. For the mid-week hemodialysis session, we additionally measured central hemodynamics (non-invasive cardiac output monitoring) and white blood cell count. Results: Linear regression modelling identified changes in pH, but not central hemodynamics or white blood cell count, to be predictive of changes in PaO2 throughout hemodialysis (e.g. at 60 min, ß standardized coefficient pH = 0.45, model R2 = 0.25, P < .001). Alkalemia, hypokalemia, decreased calcium and increased hemoglobin-O2 affinity (leftward shift in the oxyhemoglobin dissociation curve) were evident at the end of hemodialysis. pH and hemoglobin-O2 affinity at the start of hemodialysis increased incrementally over the course of a standard treatment week. Conclusion: These data highlight the important role of pH in regulating O2 availability and delivery during hemodialysis. Findings support routine pH monitoring and personalized dialysate bicarbonate prescription to mitigate the significant risk of alkalemia and subclinical hypoxia.

STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for MIBC patients. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy number variations, or cell cycle distribution. However, unbiased RNA sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a non-canonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.

Dynamic Behaviour of Donor Specific Antibodies in the Early Period Following HLA Incompatible Kidney Transplantation.

In HLA-incompatible kidney transplantation, monitoring donor-specific antibodies (DSA) plays a crucial role in providing appropriate treatment and increases kidney survival times. This work aimed to determine if early post-transplant DSA dynamics inform graft outcome over and above other predictive factors. Eighty-eight cases were classified by unsupervised machine learning into five distinct DSA response groups: no response, fast modulation, slow modulation, rise to sustained and sustained. Fast modulation dynamics gave an 80% rate for early acute rejection, whereas the sustained group was associated with the lowest rejection rates (19%). In complete contrast, the five-year graft failure was lowest in the modulation groups (4-7%) and highest in the sustained groups (25-31%). Multivariable analysis showed that a higher pre-treatment DSA level, male gender and absence of early acute rejection were strongly associated with a sustained DSA response. The modulation group had excellent five-year outcomes despite higher rates of early rejection episodes. This work further develops an understanding of post-transplant DSA dynamics and their influence on graft survival following HLA-incompatible kidney transplantation.

CORRECTED ARTICLE: Effect of Dietary Potassium Restriction on Serum Potassium, Disease Progression, and Mortality in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet. METHODS: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses. RESULTS: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I2 = 0%). Higher (4,558 mg/d) versus lower (1,725 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14, 95% CI: [0.77, 1.70] I² = 57%). Higher (4,414 mg/d) compared with lower (1,670 mg/d) dietary potassium intake was not significantly associated with reduced mortality risk (HR: 0.80, 95% CI: [0.46, 1.41] I² = 78%). CONCLUSIONS: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia but whether this is associated with risk of death in those with CKD is uncertain. High-quality randomized controlled trials are needed.

Comparative Evaluation of Sclerostin Levels in Gingival Crevicular Fluid in the Treatment of Chronic Periodontitis Patients Using Diode Laser as an Adjunct to Scaling and Root Planing: A Clinico-biochemical Study.

AIMS: Sclerostin is an inhibitor of bone formation, and laser irradiation enhances osteoblast proliferation. The objective of this study was to assess and compare the gingival crevicular fluid (GCF) sclerostin level and clinical parameters of chronic periodontitis patients following the application of diode laser (810 nm) as an adjunct to scaling and root planing (SRP). SUBJECTS AND METHODS: Fifteen systemically healthy chronic periodontitis patients (age 35-55 years) with probing pocket depth ≥5mm were included in this split-mouth study. SRP and pocket irradiation with diode laser were done in the test group and SRP alone in the control group at baseline. Low-level laser therapy application and saline irrigation were done in both the groups, respectively, in the 2nd and 3rd visits. Two microliters of GCF samples was collected from both the groups at baseline before treatment and on the 90th day for the assessment of sclerostin concentration. RESULTS: This study showed a statistically significant reduction of clinical parameters in the test and control groups at the end of 3 months. Both the groups showed a statistically significant reduction of sclerostin levels in GCF after 3 months, in which the test group (125.80 ± 28.21 to 82.80 ± 9.31) showed a highly significant reduction (P = 0.000). CONCLUSIONS: The adjunctive use of laser had shown a beneficial effect in terms of clinical parameters and osteoblast proliferation by the reduction in the levels of sclerostin in GCF. From the observations of this study, it can be concluded that the therapeutic effectiveness of diode laser as an adjunct to SRP is having a beneficial effect and sclerostin can be used as a potent biomarker.

The Measurement of Food Insecurity in High-Income Countries: A Scoping Review.

The measurement of food insecurity is essential to monitor the prevalence, risk factors, consequences and effects of food insecurity and the interventions and policies implemented to tackle it. Yet, how best to apply it remains an unsettled issue due to the multifaceted and context-dependent nature of food insecurity. We report a scoping review of measures of food insecurity at the individual and household level in high-income countries with the final purpose of facilitating a catalogue of instruments to be used by both researchers and practitioners. The scoping review was conducted following the methodological framework of Arksey and O'Malley and the Joanna Briggs Institute guidelines. We included all types of documents published between 2000-2020 using instruments that estimate food insecurity at both individual and household level in high-income countries, and with respondents including adolescents, adults, and elderly. We identified a total of 23 measurement strategies being used in 33 peer-reviewed publications and 114 documents from the grey literature. Our results show that most measures focus on the access dimension of food insecurity and that further research is required to develop measures that incorporate aspects of quality of dietary intake and relevant individual, household and social conditions related to food insecurity.

HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation.

BACKGROUND: HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival. METHODS: One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. RESULTS: The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P < 0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode. CONCLUSIONS: One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.

Immunoglobulin isotype compositions of ABO specific antibodies are dependent on the individual patient blood group and blood group specificity: Results from a healthy donor cohort.

Antibodies specific for the blood group ABO system antigens are of clinical significance and immunological interest. Routine clinical methods typically employ direct or indirect haemagglutination methods to measure IgM and IgG, respectively. We have developed a simple, single tube method to quantify IgM, IgG, and IgA specific for A and B antigens in order to improve accuracy and reproducibility, and to investigate the relationships between ABO group antibody type, and antibody level. Plasma samples from 300 healthy blood donors were studied. Levels of IgM and IgG binding to reagent group A and B red cells were measure by agglutination (HA) and multi-colour flow cytometry (MC-FC). IgA was also measured by MC-FC. Our FC method was found to be significantly more reproducible than HA for the measurement of blood group A and B specific antibodies. We found statistically significant correlations between antibodies measured by GC-HA and MC-FC, but sufficient differences to indicate that these methods are not equivalent. By MC-FC, IgM, IgG and IgA levels and isotope profiles were found to be dependent on both the donor ABO type and the specificity of the antibody. This study demonstrated heterogeneity in the immunoglobulin class profiles of ABO-blood group specific antibodies within the healthy population. Differences in isotype profiles of ABO-blood group specific antibodies may indicate fundamental differences in the immune mechanisms that generate these antibodies. This is likely to be relevant to the clinical situations where management or diagnosis depend on ABO-specific antibody detection and measurement.

Cardiac stunning during haemodialysis: the therapeutic effect of intra-dialytic exercise.

BACKGROUND: Cardiovascular risk is elevated in end-stage renal disease. Left ventricular (LV) dysfunction is linked to repetitive transient ischaemia occurring during haemodialysis (HD). Cardiomyocyte ischaemia results in 'cardiac stunning', evidenced by regional wall motion abnormalities (RWMAs). Ischaemic RWMA have been documented during HD resulting in maladaptive cardiac remodelling and increased risk of heart failure. Intra-dialytic exercise is well tolerated and can improve quality of life and functional capacity. It may also attenuate HD-induced cardiac stunning. METHODS: This exploratory study aimed to assess the effect of intra-dialytic cycle ergometry on cardiac stunning. Twenty exercise-naïve participants on maintenance HD (mean ± SD, 59 ± 11 years) underwent resting echocardiography and maximal cardiopulmonary exercise testing. Subsequently, cardiac stunning was assessed with myocardial strain-derived RWMAs at four time points during (i) standard HD and (ii) HD with 30 min of sub-maximal intra-dialytic cycle ergometry at a workload equivalent to 90% oxygen uptake at the anaerobic threshold (VO2AT). Central haemodynamics and cardiac troponin I were also assessed. RESULTS: Compared with HD alone, HD with intra-dialytic exercise significantly reduced RWMAs after 2.5 h of HD (total 110 ± 4, mean 7 ± 4 segments versus total 77 ± 3, mean 5 ± 3, respectively; P = 0.008). Global cardiac function, intra-dialytic haemodynamics and LV volumetric parameters were not significantly altered with exercise. CONCLUSIONS: Intra-dialytic exercise reduced cardiac stunning. Thirty minutes of sub-maximal exercise at 90% VO2AT was sufficient to elicit acute cardio-protection. These data potentially demonstrate a novel therapeutic effect of intra-dialytic exercise.

Metastatic Anaplastic Lymphoma Kinase Rearrangement-Positive Adenocarcinoma of Occult Primary Mimicking Ovarian Cancer.

Lung cancer is a worldwide concern and is the leading cause of cancer-related death in the United States. Adenocarcinoma is the most common type of non-small cell lung cancer; however, unlike other types of lung cancer this disease is often seen in light tobacco smokers and non-smokers. The presence of driver mutations, such as the epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4 (EML-4)-anaplastic lymphoma kinase (ALK) rearrangement, appears to be more common in these patients. The presence of the ALK mutation provides a target for ALK-inhibiting agents, such as alectinib. Routine testing for driver mutations is the standard of care in the management of advanced non-small cell lung cancer. Lung cancer frequently metastasizes to distant sites such as the bone, brain, and the adrenal glands, but rarely to the ovaries. We present a young, female, patient who complained of shortness of breath and was found to have pulmonary emboli, extensive lymphadenopathy, and a right ovarian mass. Initial pathology from a cervical lymph node favored a gastrointestinal or an ovarian malignancy. However, immunohistochemical staining ultimately suggested an occult lung adenocarcinoma primary with ovarian metastasis. She had a left oophorectomy that demonstrated similar findings and was positive for the ALK mutation. She was treated with alectinib with good response though ultimately died from her disease. This case demonstrates the rare finding of an ALK-mutated lung adenocarcinoma with ovarian metastasis and, to our knowledge, it is the first with an occult lung adenocarcinoma primary. Driver mutation testing should be considered in metastasis from an occult primary when a pulmonary malignancy is suspected.