Antibody-mediated rejection is the leading cause of kidney graft dysfunction. The process of diagnosing it requires the performance of an invasive biopsy and subsequent histological examination. Early and sensitive biomarkers of graft damage and alloimmunity are needed to identify graft injury and eventually limit the need for a kidney biopsy. Moreover, other scenarios such as delayed graft function or interstitial fibrosis and tubular atrophy face the same problem. In recent years, interest has grown around extracellular vesicles, specifically exosomes actively secreted by immune cells, which are intercellular communicators and have shown biological significance. This review presents their potential as biomarkers in kidney transplantation and alloimmunity. AlthFor this reason, many transplant centers choose to perform biopsies only “by indication” when some classical parameters are altered, such as creatinine, proteinuria, or the existence of specific anti-Human Leukocyte Antigen (HLA) donor antibodies (DSA) . HoweverAmong these possible biomarkers, it is worth highlighting circulating extracellular vesicles (EVs), specifically, exosomes actively secreted by immune cells, which are intercellular communicators that carry microRNA, DNA, and proteins with biological significance as intercellular mediators .This review summarizes the current EVs literature in kidney transplantation and their use as biomarkers.2The discovery of EVs dates to the last century. Since then, several names have been attributed to them, and a sharp increase in scientific publications has been evidenced in the last decade . In 2014EVs are classified into three categories: exosomes, which are intraluminal vesicles contained in multivesicular bodies (MVBs) and released into the extracellular environment upon fusion of MVBs with the plasma membrane, microvesicles  budded from the plasma membrane, and apoptotic bodies, the largest of the known vesicles and released during programmed cell death when the plasma membrane blebs –12  help penetrate exosomes inside cells, invasion, and fusion, whereas heat shock proteins such as HSP70 and HSP90 are involved in antigen binding and presentation. Other proteins such as Alix, annexins, Rab, or TSG101 are associated with exosome release, membrane transport, and function. Notably, some of these proteins, such as CD63, CD81, HSP70, and TSG101, which are enriched explicitly in exosomes, are generally used as their marker proteins , 17, 18Lipids such as cholesterol and sphingomyelin enrich EV membranes and, as well as their essential structural role, can also be transferred between cells .The parent cell source and the properties of target cells determine EVs’ biodistribution, and their quantity in circulation is determined by the balance between production and clearance. Clearance occurs via interactions with target cells through endocytosis, phagocytosis, pinocytosis, or membrane fusion , and als3Up to now, there is no unique standardized protocol for EV isolation , and obtEVs can be isolated from many sources, including biological fluids and cell culture supernatants , 30. IniAccording to MISEV 2018, differential ultracentrifugation was the most common isolation technique . It consSince then, an assortment of techniques has been developed, such as field-flow fractionation (FFF), variations of size exclusion chromatography (SEC), ion exchange chromatography, microfiltration, fluorescence-activated sorting, novel immunoisolation techniques, and microfluidics or precipitation techniques using a plethora of commercial kits , 6.Further information on EV isolation is beyond the scope of this review. All these methods, along with their strengths and weaknesses, are extensively discussed elsewhere , 35.4EVs are involved in the regulation of physiological functions such as maintenance of homeostasis, enhanced coagulation –38, vessRegarding their role in immunology, EVs act in innate and adaptative immune systems. In the innate, their major role has been described as pro-inflammatory mediators secreted by activated macrophages, neutrophilic granulocytes, NK cells, or mast cells in scenarios such as infection –47, sepsRegarding adaptive immunity, EVs are a source of antigens for antigen-presenting cells (APC) such as macrophages, dendritic cells (DCs), and B cells. Depending on their cargo and parenting cells, they can induce immunogenic or tolerogenic responses , 42, 52.Besides promoting intercellular information exchange via their surface molecules, their role as carriers of soluble mediators such as cytokines has been described. These cytokines include interleukin 1β (IL-1 β), interleukin 1α (IL-1 α), interleukin 18 (IL-18), macrophage migration inhibitory factor (MIF), interleukin 32, membrane-bound tumor necrosis factor (TNF), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), interleukin 8 (CXCL8), fractalkine (CX3CL1), CCL2, CCL3, CCL4, CCL5, and CCL20, and transforming growth factor β (TGF β) , 61.5Nowadays, biomarkers of the different EVs in circulation have been assessed in plenty of publications. The most developed field is oncology, where tumor mass has been linked to the amount of tumor-derived circulating exosomes. In the field of kidney disease, some studies demonstrate the participation of exosomes in different processes, which include acute kidney failure, autoimmune kidney disease, diabetic kidney disease, glomerulonephritis, vasculitis, or thrombotic microangiopathies .Regarding transplantation, EVs in body fluids have been proposed as liquid biopsies. Mainly, publications focus on heart, lung, or pancreatic islet allografts. A profile of blood-derived EVs through multiplex flow cytometric assay using antibody-coated capture beads has been described in heart transplant recipients. A significant increase in the concentration of plasma-derived EVs in patients undergoing both acute cell and ABMR has been confirmed compared with subjects not undergoing them . In the In kidney transplant, a decrease of circulating microparticle levels and their procoagulant activity after graft has been described in comparison to the prior hemodialysis status, hypothesizing that microparticles could be associated with cardiovascular risk improvement after transplant , 68. Stu5.1In graft rejection, all the immune system components are involved in causing graft injury, including T and B lymphocytes, antibodies, endothelial cells, NK cells, macrophages, polymorphonuclear cells, or complement components .Qamri et al. analyzed early post-transplant changes in circulating endothelial CD31+/CD42b− microparticle (EMP) levels after kidney transplant in 213 kidney recipients and 14 kidney + pancreas recipients. In the first cohort, no changes in circulating EMP levels were observed when graft dysfunction was unrelated to acute rejection. However, when this dysfunction was due to an episode of acute rejection (confirmed through a graft biopsy), an elevation in circulating EMP was detected. At the time of stratification according to PTC C4d staining, in patients with the negative one, a faster decrease in EMP levels was observed in comparison with patients with positive PTC C4d staining. This led the authors to suggest that circulating EMP levels could inform about ongoing endothelial cell injury. Moreover, when analyzing the different etiologies of end-stage kidney disease, a trend was found toward a decline in post-transplant EMP levels in causes due to diabetes mellitus, obstructive/inherited kidney disease, and autoimmune disease .In another study by Peake et al., urinary exosomal mRNA from frequent kidney injury biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and kidney injury molecule-1 (KIM-1), together with the constitutively produced cystatin C, were compared with their corresponding synthesized urinary protein levels as well as with the creatinine reduction ratio (CRR) on post-operatory day 7. The results showed that, although urinary NGAL and IL-18 protein levels did correlate with CRR on day 7, this was not the case for mRNA inside urinary exosomes. The explanation for these findings lay in the selectivity for exosome packaging and does not have to be representative of the parenting cell .One year later, Sigdel et al. described 11 proteins to be enriched in the urinary exosomes of patients with biopsy-proven acute rejection; three of these proteins  had not been previously identified in healthy urine exosomal proteins .Park et al. reported a urine-based platform, iKEA , to detect rejection of kidney transplants through T-cell-derived EVs. This platform, based on a magneto-electrochemical sensing system, revealed a higher level of CD3-positive EVs in kidney rejection recipients, with an accuracy of approximately 91.1% .Tower et al. found a correlation between plasma C4d+, especially C4d+/CD144+ microvesicles, and the presence of ABMR and its severity and response to treatment in kidney recipients. Ninety-five kidney recipients with for-cause biopsies performed and twenty-three healthy volunteers were evaluated. After histopathologic examination of the graft biopsies, 28 patients with ABMR were found. In them, the density of C4d+/CD144+ microvesicles was 11-fold greater than in kidney transplant patients without ABMR and 24-fold greater than in healthy volunteers. The densities of C4d+ and C4d+/annexin V+ (C4d+/AVB+) microvesicles were also higher in ABMR recipients. Moreover, C4d+/AVB+ microvesicles correlated with ABMR biopsy severity. Lastly, in nine cases, treatment was associated with a reduction in the densities of C4d+/CD144+ and CD144+ microvesicles, which also showed them to be a treatment response monitoring tool .Zhang et al. selected 21 genes  whose mRNA transcript levels were increased in plasma exosomes of ABMR kidney recipients compared with cell-mediated rejection and/or no rejection. The authors also generated a gene score with the combination of the transcript levels of four of these genes , which was significantly higher in the ABMR group than the other groups .Yang et al. suggested a correlation between ABMR and follicular helper T cell (Tfh cell)-derived exosomes through their increase in the circulation of such patients compared with non-ABMR patients. Moreover, Tfh cell-derived exosomes promoted B cell proliferation and differentiation. Moreover, their study reported a decline in CTLA-4 expression on the Tfh cell-derived exosome surface in kidney transplant patients with ABMR. CTLA-4 is a leukocyte differentiation antigen and a transmembrane receptor on T cells, with an established role in alloantigen-driven T cell activation and various autoimmune diseases. CTLA-4 on exosomes inhibited human T cell activation by directly interacting with the molecules CD80 or CD86. Furthermore, intracellular CTLA-4 can inhibit Tfh cell differentiation, reduce IL-21 secretion, and inhibit B cell proliferation and differentiation into plasma cells .Regarding acute T cell-mediated rejection, Lim et al. identified several urinary exosomal biomarker candidates in an Asian population of kidney transplant patients using a proteomics approach. Validation of the findings by western blot assay proved that tetraspanin-1 and hemopexin were significantly higher in TCMR patients .Chen et al. established a circulating exosomal miRNA panel by extracting plasma exosomes from 58 kidney transplant recipients and 27 healthy controls. Exosomal miR-21, miR-210, and miR-4639 could discriminate between subjects with chronic kidney dysfunction and those with normal graft function. At one year follow-up, patients with a low calculated score from this three-miRNA panel revealed a stable recovery of allograft function .Lastly, our group has proposed using B-cells–derived EVs (BEVs) to check B cell proliferation in secondary lymphoid organs and bone marrow after desensitization. BEVs (CD19+ or HLA-II+) were associated with surviving B cells in lymph nodes retrieved upon surgery on patients who received desensitization with Rituximab, plasma exchanges, and immunoglobulins. After the administration of Rituximab, no B cells were circulating. CD19+ or HLA-II+ EVs may reflect the mass of surviving B cells in secondary lymphoid organs that may predispose them to subsequent rejection. This is suggested by the rebound of BEVs in patients who develop ABMR after desensitization .5.2DGF leads to a higher risk of acute rejection and progression to chronic graft dysfunction , 87–89. Among the first studies on exosomes and kidney dysfunction, Alvarez et al. evaluated if the different urine fractions  have different NGAL expression in 15 kidney allograft recipients (eleven living donors and four deceased donors) soon after transplantation. Western blot analysis showed that the average NGAL expression in the exosomal fraction was significantly higher in deceased donor patients from the first post-operatory day and that its expression lasted increased in patients with DGF compared with non-DGF patients .Dimuccio et al. showed lower levels of CD133-positive EVs in urine samples of transplanted patients. This decrease was evidenced from the first post-operatory day until day 7, when an increase was described. However, compared with patients with DGF, these last had a significant rise. Moreover, in patients with severe pre-transplant vascular injury of the allograft, CD133-positive EVs did not increase. The origin of CD133-positive EVs appeared restricted to glomeruli and proximal tubules. These data implicate CD133-positive cells in renal tissue regeneration after injury due to cold ischemia and IRI. Accordingly, no increase was observed in recipients with severe pre-transplant vascular damage, implying an inefficient regeneration of the graft tissue in these recipients .In another study, Wang et al. explored miRNA expression profiling in the DGF process. Fifty-two known and five conserved exosomal miRNAs expressed in kidney-transplanted patients with DGF were identified. Three co-expressed exosomal miRNAs: hsa-miR-33a-5p R-1, hsa-miR-98-5p, and hsa-miR-151a-5p, were further observed to be significantly upregulated in the peripheral blood of DGF patients. Moreover, hsa-miR-151a-5p was positively correlated with the patient’s first-week serum creatinine levels, blood urea nitrogen, and uric acid after transplantation .5.3In the field of kidney transplant, fibrosis serves as the final and irreversible stage of the pathogenic mechanisms that lead to the loss of allograft function . For thiSaejong et al. describe the potential use of microRNA (miR)-21 expression in plasma exosomes for non-invasive monitoring of high-grade IFTA in kidney transplant patients. There are already previous studies on the role of exosomal miR-21 as a fibrosis biomarker and its association with TGF-β, a cytokine known to be involved in fibrosis pathogenesis. In the study by Saejong, miR-21 from the plasma exosome fraction (but not from the whole plasma) could discriminate between low- versus high-grade IFTA. It is demonstrated that the released miR-21 decreases phosphatase and tensin homolog (PTEN), which causes the phosphorylation of Protein kinase B (AKT) signaling, in turn reducing the expression of E-cadherin and raising the expression of α-SMA and fibronectin in kidney tubules .More recently, Carreras-Planella et al. describe the search for kidney allograft dysfunction protein biomarkers related to four biopsy-proven diagnoses: IFTA, acute T-cell rejection, calcineurin inhibitors toxicity, and normal kidney function. The authors carried out a proteomic analysis of the urinary EVs (uEVs), discovering some EV-associated proteins that show different expressions depending on whether they come from pathological or normal kidney function allografts. Moreover, a change in the expression of vitronectin (VTN) was also evidenced in recipients with chronic IFTA, suggesting urinary VTN levels as another possible biomarker for monitoring fibrotic changes in kidney transplant patients. For the fibrosis process to occur, VTN must join the potent profibrotic glycoprotein PAI-1, although the precise mechanisms are arguable. VTN has been reported to increase PAI-1 activity in the renal tissue, hindering fibrinolysis. However, other studies described the opposite, highlighting a protective role against fibrosis .The same group also demonstrated the potential role of uEVs as biomarkers of chronic calcineurin inhibitor toxicity (CNIT). Their nephrotoxicity and role in kidney fibrosis are known and have been described in multiple studies and they are first-line agents in the immunosuppressive regimen of kidney transplantation. The problems we continue to face are CNIT diagnosis and management. In this study, the urine from kidney transplant recipients with CNIT diagnosis is compared with recipients with IFTA and without CNIT or normal allograft function . After data analysis, members of the uroplakin  and plakin families (periplakin and envoplakin) were significantly upregulated in the CNIT group, suggesting a central role in CNIT development. The binding of uroplakin proteins covers the urothelium’s surface to prevent urine influx from the lumen, also covering the renal pelvis, ureters, urinary bladder, and prostatic urethra. Periplakin and envoplakin function as cell-linker proteins. The upregulation of these proteins in the CNIT recipient’s uEV suggests that the toxic effect of CNI on the urothelium may increase their citolinker activity .Lastly, Costa de Freitas et al. also evaluated the expression of different urinary exosome-derived miRNAs (exo-miRs) in transplant patients on a tacrolimus regimen. As a result, a difference in the expression of 16 exo-miRs was observed. Among them, the marked upregulation of miR-155-5p and downregulation of miR-223-3p and miR-1228-3p stand out. Moreover, it was found that the tacrolimus dose correlated with the expression of miR-155-5p and miR-223-3p, serum creatinine with the expression of miR-223-3p, and the number of blood leukocytes with miR-223-3p and miR-1228-3p .6EVs participate in intercellular communication in physiological and pathological processes, and in recent years, interest in them has grown as tools to monitor post-transplant evolution in a non-invasive way. Previous studies on diverse biological samples (blood or urine) include a wide range of pathologies such as kidney graft rejection , DGF, IFTA, and drug toxicity. The limitations we have to consider are that the studies published and presented here do not often include multiple centers, the number of patients included is low, and the results have yet to be validated in larger cohorts. Appropriate method validation studies need to be improved, and the isolation protocol needs standardization to avoid the co-isolation of various vesicles or differences in contamination levels. The most modern technologies will likely offer new opportunities in this field; for instance, the Imaging Flow Cytometry (IFCM)-based methodology for the direct detection (without prior isolation) of donor-derived EVs (dd-EVs) in the plasma of kidney transplant patients based on Human Leukocyte Antigen (HLA) mismatch  or furthDespite the promising published data, nowadays, we cannot use EVs as a definitive decision tool. Future studies are required before their analysis could facilitate the decision process in routine clinical practice. We still need basic parameters such as creatinine, proteinuria, or specific anti-HLA donor antibodies, and EV analysis may not replace the invasiveness of graft biopsy as the gold standard.Future studies will extend our knowledge of the role of EVs as biomarkers in the kidney transplant field. A combination of biomarkers could help us decide whether a biopsy should be done and may have a supportive role when interpreting data provided by an allograft biopsy.Conceptualization, EC-P, MR-B, EB-M, JR, and DC; resources, EC-P, MR-B, EB-M, JR, and FD; writing—original draft preparation, EC-P and DC; writing—review and editing, IR and DC; supervision, IR. All authors contributed to the article and approved the submitted version.


Global collaboration is the cornerstone of current scientific advancement in nephrology. Within the realm of nephrology, the regions of Asia and Australasia have emerged as hotbeds of innovation, research, and clinical excellence. With a rich diversity of patient populations, unique healthcare challenges, and a strong commitment to advancing renal care, Asia and Australasia have become recognized for their contributions to global excellence in nephrology.In recent years, the field of nephrology in Asia and Australasia has undergone a remarkable transformation, leading to groundbreaking discoveries, improved patient outcomes, and a positive impact on public health. These achievements have been the result of concerted efforts by healthcare providers, researchers, and allied professionals who have strived to tackle the challenges posed by kidney diseases in the region.One of the key drivers of excellence in nephrology in Asia and Australasia has been the advancement of research and clinical practice. Researchers and clinicians in the region have made significant contributions to various aspects of nephrology, including hereditary nephropathy, renal pathology, glomerulonephritis classification, prognosis, and the development of new treatments. These advancements have not only deepened our understanding of kidney diseases but have also translated into tangible improvements in patient care, diagnosis, and treatment options.Guo et al. investigated the clinical and pathological characteristics of patients with IgA nephropathy (IgAN) with and without associated minimal change disease (MCD). The study found that patients with MCD-IgAN had lower levels of serum galactose-deficient immunoglobulin A1 (Gd-IgA1) than those with non-MCD-IgAN but presented with higher levels than healthy participants. In comparison to non-MCD-IgAN, complement C3 activation in the circulation and the renal location was substantially weaker in MCD-IgAN. The authors suggest that IgAN with MCD might be MCD with coincidental IgA deposition. This study provided valuable insights into the clinical and pathological characteristics of patients with IgAN with and without MCD.In this Research Topic, the study by Liu et al. investigated the relationship between serum phosphate levels and mortality in 23,283 septic patients. The study found that both hypo- and hyperphosphatemia were independent risk factors for mortality, and that dynamic changes in phosphate levels were also associated with increased mortality risk. There is a U-shaped association between serum phosphate levels and the risk of mortality in septic patients.In a second study, Zhang et al. provided an overview of the potential therapeutic effects of plant-derived compounds in treating autosomal dominant polycystic kidney disease (ADPKD), which is the leading hereditary kidney disease. The article highlighted the limitations of current drugs used to treat ADPKD and suggested that plant-derived compounds may offer a promising alternative. Plant-derived compounds, including saikosaponin-d, Ganoderma triterpenes, curcumin, ginkgolide B, steviol, resveratrol, Sparganum stoloniferum Buch.-Ham, Cordyceps sinensis, triptolide, quercitrin, naringin, cardamonin, gambogic acid, and olive leaf extract, have shown potential in delaying the development of cysts or improving renal function in ADPKD. These plant-derived compounds act on various signaling pathways involved in the pathogenesis of ADPKD, such as the RAS/MAPK pathway and intracellular calcium levels, and may serve as promising candidates for future therapeutic interventions.A review by Nagai et al. discussed the relationship between urban design and CKD. The prevalence of CKD has increased in Japan due to the aging population, and lack of physical activity is a major preventable risk factor for mortality in adults. Rural city planning in Japan can improve renal health outcomes by promoting walking, bicycling, and the use of public transportation, which can increase daily physical activity levels and access to specialized medical care. Moreover, multidisciplinary education without medication for obese populations can positively impact obesity through increased physical activity, and recreational walking is a dominant contributor to increasing step counts.Despite the impressive strides made in nephrology, Asia and Australasia continue to face unique challenges in managing kidney diseases. The prevalence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) remains high in these regions, driven by factors such as an aging population, increasing rates of diabetes and hypertension, and lifestyle changes. Limited healthcare resources, inadequate infrastructure, and disparities in access to specialized care pose significant hurdles to effective kidney disease management. The study by To further overcome these challenges and enhance the level of care, collaborative approaches have emerged as vital components of achieving global excellence in nephrology. Regional alliances, research consortia, and professional networks have facilitated the sharing of knowledge, expertise, and best practices among nephrology communities in Asia and Australasia. By fostering multidisciplinary collaborations between clinicians, researchers, epidemiologists, geneticists, and allied healthcare professionals, these initiatives have catalyzed innovation, accelerated research progress, and promoted the development of region-specific policies and guidelines.In summary, the region of Asia and Australasia has emerged as a powerhouse of global excellence in nephrology, demonstrating remarkable advancements, overcoming challenges, and fostering collaborative approaches to enhance patient care. By leveraging research and addressing the evolving burden of kidney diseases, Asia and Australasia will continue to make significant contributions on a global scale to the field of nephrology and improve the lives of individuals affected by kidney diseases.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Patient Blood Management (PBM), endorsed by the World Health Organisation is an evidence-based, multi-disciplinary approach to minimise inappropriate blood product transfusions. Kidney transplantation presents a particular challenge to PBM, as comprehensive evidence of the risk of transfusion is lacking. The aim of this study is to investigate the prevalence of post-transplant blood transfusions across multiple centres, to analyse risk factors for transfusion and to compare transplant outcomes by transfusion status.This analysis was co-ordinated via the UK Transplant Registry within NHS Blood and Transplant (NHSBT), and was performed across 4 centres. Patients who had received a kidney transplant over a 1-year period, had their transfusion status identified and linked to data held within the national registry.Of 720 patients, 221(30.7%) were transfused, with 214(29.7%) receiving a red blood cell (RBC) transfusion. The proportion of patients transfused at each centre ranged from 20% to 35%, with a median time to transfusion of 4 (IQR:0-12) days post-transplant. On multivariate analysis, age , gender , ethnicity , and dialysis dependence pre-transplant , were associated with transfusion. A risk-adjusted Cox proportional hazards model showed transfusion was associated with inferior 1-year patient survival  and allograft survival , and inferior allograft function.RBC transfusions are common and are independently associated with inferior transplant outcomes. We urge that further research is needed to understand the mechanisms behind the outcomes, to support the urgent development of transplant-specific anaemia guidelines. Patient blood management (PBM) embodies an evidence-based, multi-disciplinary approach to minimise inappropriate blood product transfusions, in turn improving patient outcomes and reducing overall healthcare costs , 2. It ide novo allosensitisation and rejection, contributing to premature allograft loss , the British Transplant Society (BTS) and the HLA matched Red Cell Working Group in the UK. Four transplant centres in the UK participated: Cambridge, London - Imperial College Renal and Transplant Centre, Oxford and London – Guy’s Hospital. The study was co-ordinated via the UK Transplant (UKT) Registry within NHSBT.st April 2016 and 31st March 2017 were included. NHS Blood and Transplant employees in the blood transfusion laboratories at each centre were sent the relevant list of local transplant recipients via the UKT Registry, who then confirmed transfusion status. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) expects blood product traceability, that is the ability to trace each individual product from the donor to its destination in 100% of cases. Each laboratory collected the same baseline information, which included: the transfusion status , the date of the first transfusion, the type of transfusion and the total amount of units received within the given timeframe. Of note, no patient was transfused in the month prior to transplant. The responses from each haematology laboratory were then returned to NHSBT for amalgamation, allowing the transfusion cohort to be assessed in the context of nationally collected data, which includes recipient demographics , pre-emptive status, level of sensitisation and mismatch level), donor information  and outcomes , graft survival and patient survival).All patients who received a kidney alone transplant at one of the 4 participating centres between 1The analysis was performed within NHSBT as part of a service evaluation, and as used routinely collected data, institutional approval was obtained. The study has been reported in line with the STROBE  guidelines for observational studies.p < 0·05 was considered statistically significant. Data were analysed using IBM SPSS Statistics for Macintosh version 25 (IBM).Differences in donor and recipient characteristics between transfused and non-transfused groups were examined using the Kruskal-Wallis test or the Chi-square test. Number and percentage of missing variable data were detailed in the appropriate tables and complete case analysis was employed. Kaplan-Meier survival estimates were used to demonstrate death censored graft survival and patient survival; univariate differences between groups were examined using the log-rank test. A binary logistic regression model was used to report independent donor and recipient characteristics associated with odds of transfusion. A Cox proportional hazards model was used to assess the risk-adjusted association between transfusion status and death censored allograft and patient survival; risk adjusted for dialysis at transplant, waiting time, recipient age, cold ischaemic time, donor age. Two-sided tests were conducted and Seven hundred and twenty patients received a kidney transplant across the 4 centres between 2016 and 2017. Of these, 221/720 (30.7%) were transfused; 189 (26.3%) received a red blood cell (RBC) transfusion alone, 7 (1.0%) platelets alone and 25 (3.5%) received both blood and platelet transfusions. There was inter-centre variation in the proportion of patients transfused, ranging from 20% to 35%, p=0.005. The median time to transfusion was 4 (IQR:0-12) days post-transplant, and the median number of units transfused was 2 (IQR:2-5) units of blood and 1 (IQR:1-3) pool of platelets.Kidney donor characteristics associated with transfusion included deceased donor status and increasing donor age, Recipient variables which were found to be associated with transfusion on univariate analysis included gender, ethnicity, age at transplant, pre-emptive status, time on the wait list and degree of HLA sensitisation, The median cold ischaemic time was longer in the transfused group compared with the non-transfused group at 11.5 (IQR:8.8–16.4) versus 9.5 (IQR:4.8–14.5) hours respectively, p<0.0001. The proportion of patients with immediate graft function was also less in the transfused group at 132 (60%) compared with the non-transfused group in whom 424 (85%) had immediate graft function, p<0.0001.On multivariate analysis, donor and recipient factors which were associated with transfusion included recipient age, gender, ethnicity, and dialysis dependence at the time of transplant, whilst the only independent kidney donor characteristics associated with the need for a post-transplant transfusion was a history of hypertension, Further details on indications for transfusion was available from one centre, and maybe found in the Patient survival at 12 months post-transplant was inferior in the transfused group at 93.5% (95%CI 88.3-96.5) compared with 99.3% (95%CI 97.7-99.8) in the non-transfused group, p<0.0001, Analysing the survival outcomes by type of transfusion received, patients who had both blood and platelets transfused had the worst 12 month patient and allograft survival at 81.2% (95%CI 51.9-93.6) and 68.8% (95%CI 45.5-83.8) respectively; which was significantly worse than patients receiving blood transfusions alone, who had a 12 month patient and allograft survival of 95.5% (95%CI 90.3-98.0), p=0.03 and 91.2% (95%CI 85.8-92.6) respectively, p=0.0015, The final analysis involved assessing the independent impact of transfusion on the 12-month patient and allograft survival by performing a risk-adjusted Cox proportional hazards model. Variables adjusted in the model included the need for dialysis at the time of transplant, the transplant wait time, recipient age, kidney donor age and cold ischaemic time. Patient survival at 12 months was inferior in recipients who had received a post-transplant transfusion compared with non-transfused patients, HR 7.94 (95%CI 2.08-30.27), p=0.002, In this multicentre study we have demonstrated that post-transplant transfusions are common, with significant variation in rates across the different centres. Multivariable analysis of clinical characteristics associated with transfusions identified that recipient characteristics had a greater impact on transfusion risk than kidney donor characteristics. Furthermore, we have shown that transfusions, which mainly occur in the early post-transplant period are associated with inferior allograft function, allograft survival and patient survival at 12 months post-transplant, which is maintained even after adjusting for clinical characteristics recognised to be associated with poor allograft outcomes. Therefore, independent of the potential impact on allosensitisation, these data provide evidence that the transplant community needs to address these inequalities and explore the mechanisms behind the adverse outcomes to inform interventions which may improve patient health and transplant longevity.The underlying principles or 3 pillars of PBM relate to the detection and management of anaemia, minimisation of blood loss including optimisation of coagulation, and optimising patient specific tolerance of anaemia , 20, 21.We found that the requirement for blood transfusions predominantly occurs in the early post-transplant period, which is supported by other reports , 9, 24. Recombinant erythropoietin (rEPO) and iron therapy have been and remain the cornerstones of the treatment of renal anaemia. However, rEPO use is not without risk, with data from clinical trials demonstrating an increased risk of cardiovascular events when normal haemoglobin or haematocrit thresholds are passed –29. Morede novo HLA and donor specific antibody (DSA) development in the literature (Even in patients fully optimised pre-transplant, the need for blood transfusions will never be eradicated, and although not addressed in this study, the medium- and long-term impact of transfusion induced allosensitisation in kidney transplant risk is still an area of concern that warrants further investigation independently. The transplant community recognises that the prevention of allosensitisation is vital, given the lack of effectiveness of therapeutic interventions, both for desensitisation and treatment of antibody mediated rejection. We acknowledge that an issue remains of the conflicting evidence of the relevance of post-transplant transfusions on terature , 34, 35.terature . We hypoterature , 37. Givde novo DSA. Given the median time to transfusion was 4 days post-transplant, we did not employ a time-varying coefficient model, which is recognised as a further potential limitation. Key data on haemoglobin and iron levels are unavailable, and further information on causes of graft loss and death, may have helped to delineate cause from association. However, the multicentre nature of this study has highlighted the high frequency of transfusions is a common complication, and the impact of graft and patient survival at 12 months more consequential than previously considered. It needs to be acknowledged that this is not the first study to show an association of transfusion with graft and patient outcomes, however, it’s strength is the multicentre approach, incorporating analyses on both donor and recipient characteristics using granular data to report on multiple clinical outcomes including allograft function (This study would have been strengthened with additional data related to immunosuppression type, rejection and function , 18, 38.To summarise, PBM applied to general surgical procedures has been shown to reduce the need for transfusions and improve patient outcomes by lowering morbidity and mortality , 2. In tm.willicombe08@imperial.ac.uk.The data analysed in this study is subject to the following licenses/restrictions: The datasets generated and analysed during the current study are not publicly available due to analysis being performed as part of a service evaluation within NHSBT of routinely collected clinical data. Requests to access these datasets should be directed to The data in this manuscript was acquired as part of routine clinic care, and analysed as part of a service evaluation, and obtained institutional approval from NHSBT under clinical governance arrangements, which does not need research ethics committee review under Health Research Authority guidance . As the SH, MW, FR, CB and DR conceptualised the study. All authors contributed to the research methodology. SR, DF, MM, DR, FR and LM participated in data acquisition. LM performed the data analysis. SH, MW, FR, DR wrote the initial draft. All authors reviewed and edited the manuscript.


Hypertension is a significant global public health issue. Exercise has long been regarded as a fundamental component in the prevention and treatment of hypertension . Daily pExercise intervention for the prevention and management of hypertension” presents information on the cardiovascular effects of various forms of exercise through original and review articles. The exercises analyzed include deep breathing exercises, Liuzijue training, and inspiratory muscle training. Additionally, the influence of leisure time resistance activities and the variability of 24-h acute blood pressure responses to exercise are examined. All these studies provide different insights into the therapeutic effects of exercise in individuals with hypertension.The Research Topic “Tavoian and Craighead explored the use of deep breathing exercises in work settings as a strategy to reduce blood pressure levels and manage work-related stress. They summarized the physiological and psychological effects of deep breathing to support its implementation in the workplace, which is often characterized by frequent episodes of mental health conditions. The authors presented promising real-world evidence that supports the plausibility of deep breathing interventions in this context.The therapeutic role of deep breathing exercises, which is a broad term encompassing several types of non-resisted, paced breathing strategies such as yogic breathing or Pranayama, diaphragmatic breathing, and abdominal breathing, in reducing blood pressure was discussed in two literature reviews. Herawati et al. summarized the currently available information on the advantages of breathing exercises in decreasing blood pressure in patients with hypertension. The review included 20 studies with a mean PEDro score of 7.4, in which resting blood pressure and heart rate were the most frequently assessed outcomes. The results of the studies exhibited wide variability, with systolic blood pressure declining by 4–54.22 mmHg, and diastolic blood pressure dropping by 3–17 mmHg with deep breathing exercises. Based on the available evidence, it is suggested that this exercise strategy holds merit in improving cardiovascular parameters in hypertensive patients. However, further studies are warranted to understand the optimal exercise protocols and the underlying mechanisms behind these effects.The scoping review conducted by Carpes et al. aimed to measure inter-individual variations in 24-h blood pressure after a single bout of various exercise modalities in older adults with hypertension. They investigated the mean changes in 24-h blood pressure in participants with hypertension after aerobic, combined, resistance, and isometric handgrip exercise sessions related to a non-exercising control session. The prevalence of responders in the total 24-h ranged from 22% to 37% for systolic and from 26% to 53% for diastolic blood pressure after different exercise modalities. Authors concluded that various exercise modalities might acutely reduce 24-h blood pressure in older adults with hypertension, although a high inter-individual variability has been observed. These responses are important because the chronic hypotensive effect of physical training appears to be related to the sum of the acute blood pressure reduction that occurs after an exercise session.The original article developed by Zheng et al. conducted a systematic review with meta-analysis, founding important results. This review summarized findings from eight randomized controlled trials totaling 215 patients. Expressive alterations were found in some cardiovascular outcomes, highlighting a reduction of 12.55 mmHg  and 4.77 mmHg  in systolic and diastolic blood pressure, respectively. In addition, a subgroup analysis showed superior blood pressure reductions in low intensity IMT compared to medium-high intensity inspiratory muscle training. Even with positive cardiovascular findings, the authors presenting inspiratory muscle training as an auxiliary approach in the clinical exercise context for hypertension management.Evaluating the effects of inspiratory muscle training on the blood pressure of patients with hypertension, Wu et al. aimed to compare the effectiveness of Liuzijue training  with traditional aerobic training on blood pressure, endothelial function, and gut microbiota composition in hypertensive patients. Results showed that Liuzijue training was more effective in lowering blood pressure levels in 57% of participants, compared to 25% in the traditional aerobic training group. Liuzijue training also appeared to improve immune homeostasis by reducing pro-inflammatory markers and promoting a healthier gut microbiota balance. The study suggests a potential link between immune factors and gut microbiota, which could be the mechanism behind Liuzijue training’s ability to lower blood pressure levels. However, further research is necessary due to the limited patient sample size.A study conducted by Park et al. analyzed the role of physical activity and the regular practice of resistance exercise in the prevention of hypertension in a community-based cohort of 5,075 adults. After a follow-up of almost 8 years on average, it was found that those who had high levels of physical activity decreased their risk of developing hypertension in 30% compared to those with low levels of physical activity. The addition of the regular practice of resistance exercise to high levels of physical activity further prevented the development of hypertension only in women, while the practice of resistance training alone, without satisfactory leisure-time physical activity did not affect the incidence of hypertension. This study emphasizes the importance of meeting the global recommendations of physical activity and the relevant potential of resistance training in cardiovascular prevention. Future studies are required to investigate the sex differences and training intensity in resistance training related antihypertensive effects.Finally, Overall, the research discussed in this Research Topic underscores the importance of exercise as a major component in preventing and managing hypertension. It highlights the effectiveness of various exercise strategies in improving cardiovascular parameters, reducing blood pressure, and potentially preventing the development of hypertension.


Hypertension is a common and important risk factor for cardiovascular disease which is the leading cause of death among the general population and travelers. Data on hypertension among travelers are very limited due to the scarcity of research reports in this specific population. Therefore, this study aimed to determine the prevalence of hypertension among adult travelers and the stability of blood pressure control during international trips using a mobile automated blood pressure device.This was a cross-sectional descriptive study conducted at the Thai travel clinic, Hospital for Tropical Diseases in Bangkok, Thailand. All adult travelers completed a questionnaire which included demographic data, medical history, medication use, trip characteristics and hypertension awareness and knowledge. Standard two time blood pressure measurements were performed at the clinic to detect possible undiagnosed hypertension. Travelers with pre-existing hypertension were also invited to monitor their blood pressure level before and during their trip for a total of 14 days by using an automated blood pressure device and reporting the readings back to the study team.p < 0.001). Eleven travelers agreed to monitor their blood pressure, Most  had stable blood pressure control during their trip. One participant had > 10 mmHg higher blood pressure during the trip, however this was not clinically significant. All participants remained well, and acute symptoms secondary to hypertension were not reported.During July and October 2022, a total of 1,359 adult travelers visited the Thai Travel Clinic before their international trip. The overall prevalence of hypertension was 28.8%, including those with pre-existing hypertension (6.7%) and those with newly diagnosed hypertension (22.2%). Travelers with newly diagnosed hypertension were significantly younger than travelers with pre-existing hypertension (38.5 years vs. 55.6 years, Up to 28.8% of adult travelers seen in pre-travel consultations had hypertension. Most of them were unaware of their blood pressure condition. Vital signs including blood pressure should be evaluated in all pre-travel visits in order to prevent undiagnosed severe hypertension that might lead to hypertensive crisis.The online version contains supplementary material available at 10.1186/s40794-023-00199-5. Hypertension is a very common and significant medical problem worldwide. It is estimated that up to 26.4% of the global adult population had hypertension in 2000, and this prevalence is estimated to increase to 29.2% by 2025 , 2. UncoAlthough international travel has been disrupted by the corona virus disease of 2019 pandemic, a recent report from the United Nations World Tourism Organization (UNWTO) showed that international travel has rebounded to 80% of pre-pandemic levels in the first quarter of 2023. It is estimated that international arrivals will recover to 95% of pre-pandemic levels by the end of this year [There is limited research reporting the prevalence of hypertension among travelers which varies between 5.2 to 18.6% depending on the population studied –13. HoweTherefore, we conducted this study aiming to determine the prevalence of hypertension among adult travelers and to determine their blood pressure variation during travel using an automated blood pressure device.This study was conducted in the Thai Travel Clinic, Hospital for Tropical Diseases, Bangkok, Thailand. Medical records of adult travelers (age ≥ 18 years) who visited the study site from July 2022 to October 2022 were reviewed. Records contained two parts, including a questionnaire section, which was completed by travelers before consultation, and a medical record section, which was filled by doctors and nurses at the clinic. Each record contained data on age, gender, nationality, destination, purpose of the trip, pre-existing medical conditions (if any), current medications (if any), vital signs .All travelers were asked to rest before undergoing blood pressure measurement at the clinic. Travelers who had a history of hypertension as an underlying disease, regardless of the current blood pressure level and medical management status, were considered as having pre-existing hypertension. Travelers who had no history of hypertension but had two readings at the clinic with a systolic blood pressure (SBP) higher than 140 mmHg and/or diastolic blood pressure (DBP) higher than 90 mmHg after resting for 5 min were considered as having newly diagnosed hypertension (new hypertension).All travelers who had hypertension (pre-existing and new) were invited to complete an additional questionnaire regarding hypertension. Information included lifestyle habit, smoking, alcohol consumption, physical activity, and salt intake was collected. Basic knowledge about hypertension, such as positive and negative factors for hypertension control and the possible complications of hypertension, was also included in the questionnaire see .Travelers with pre-existing hypertension were invited to monitor their blood pressure levels while traveling. Participants were requested to measure their blood pressure by using an automated blood pressure device two times a day—in the morning, before a meal, and at night, before going to bed.An automated blood pressure device is used to measure and display arterial blood pressure through automated inflation and deflation of a cuff applied to an extremity. The method used to estimate blood pressure with an automated device is the detection of arterial flow through oscillometry. In this method, pulses sensed through the cuff are filtered, amplified, processed, and applied to an algorithm to estimate SBP and DBP. Participants could use any model of automated blood pressure device which was owned by them throughout their trip. Participants were advised that measurements should be taken while sitting on a chair with their feet on the floor, legs uncrossed, back supported, and with at least 5 min of relaxation before measurement. The fourteen-day data collection period was divided equally into before travel and during travel. Blood pressure levels were measured twice, with a 1–2-min interval between readings. Participants were required to measure their blood pressure levels at the same time every day during their travel, and were requested to submit their data to the investigator via email or using the official LINE® application, which is an online platform for communication with other individuals popular in Thailand.The study protocol and questionnaire were reviewed and approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University.This study calculated the sample size for estimating the prevalence of hypertension among travelers, considering a prevalence rate of 13% and a desired precision of 5%. The expected sample size required for this estimate was determined to be at least 174 participants. For the secondary objective, the sample size was calculated to be at least 11, based on a desired precision of 5% and assuming a mean blood pressure difference of 10 mmHg and a standard deviation of 10 mmHg among travelers. The level of significance was set at 0.05 and the power at 0.80. A two-tailed Z-test was used with a Z-value of 1.96. Statistical analysis was performed using Statistical Products and Service Solutions (SPSS) software version 25.0. Categorical data were presented as numbers and percentages with a 95% confidence interval. Pearson's Chi-square test was used for comparing categorical data in the characteristics of hypertensive travelers, with a p-value below 0.05 considered statistically significant.Instability of blood pressure during the trip was defined as a ≥ 10 mmHg change in mean SBP or mean DBP or mean arterial pressure (MAP) before and during travel or a SBP of ≥ 170 mmHg or DBP of ≥ 100 mmHg with a 20% change from the mean SBP or DBP.2 (SD ± 4.2). Up to 62.8% of them were Thai travelers, followed by North American/European (22.2%) and other non-Thai Asian travelers (11.8%). The main reason for travel was tourism (40.8%), followed by business/working (36.7%). Detailed demographic data are shown in Table Between July and October 2022, 1,359 adult travelers visited the Thai Travel Clinic before their international trip. Fifty-four percent of them were males, and the overall median age was 34 years (range 18–67 years). Their mean body mass index was 23.61 kg/mp < 0.005). The average body mass index (BMI) in travelers with hypertension was also significantly higher than the normal blood pressure group . Further details are shown in Table Among 1,359 travelers, 91 (6.7%) reported hypertension as their pre-existing disease, while 301 of 1359 travelers (22%) were considered to have newly diagnosed hypertension. The overall prevalence of hypertension was found to be 28.8%. The mean age of travelers with hypertension was significantly higher than travelers with normal blood pressure . The mean SBP in newly diagnosed hypertension was higher than travelers with pre-existing hypertension , while the mean DBP in both groups were not different.Travelers with newly diagnosed hypertension were significantly younger than travelers with pre-existing hypertension . This finding was also found in diabetes mellitus (DM), with 23.5% of travelers with pre-existing hypertension had DM while 2.6% of travelers with newly diagnosed hypertension had DM. However, no differences were observed between the two groups in term of salt intake, smoking, and physical exercise. Detailed traveler characteristics are shown in Table Travelers with pre-existing hypertension reported dyslipidemia as a comorbidity more frequently when compared to travelers with newly diagnosed hypertension  adhered to the research protocol and reported their blood pressure data to the study team.Among 11 participants, all of them were Thai, with an overall mean age of 56.9 years. Five of them were male 45.5%), while six of them were female (54.5%). Nearly all participants  had at least one medication for hypertension. Their mean SBP, DBP and MAP in the morning before the trip were similar to their mean SBP, DBP, MAP during the trip. When considering individual blood pressure levels, there was only one traveler (participant no 9) with a high SBP in the morning and evening which matched our criteria for instability of blood pressure (mean SBP change ≥ 10 mmHg) during the trip. However, no subject had a very high blood pressure episode (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg) during the trip. No acute events related to hypertension  were reported from the travelers during this trip. Further details about the variability of blood pressure values of all participants are shown in Tables 5.5%, whiTo our knowledge, this is the first study focused on the prevalence of hypertension among travelers in Thailand. In our study, the overall prevalence of hypertension was 28.84%. Interestingly, this prevalence was much higher than other reports. A previous study from a travel clinic in Marseille, France, reported a prevalence of 4.6%, while a study from Galway, Ireland revealed a self-reported prevalence of 2.9% , 15. TheIt is reasonable to suggest that the prevalence of newly diagnosed hypertension in our study was overestimated due to the “White Coat Hypertension” phenomenon. This phenomenon is characterized by an elevated blood pressure reading in a medical facility, while the individual’s ambulatory blood pressure remains within the normal range . MoreoveAlthough the prevalence of newly diagnosed hypertension in our study 22.15%) was likely to be overestimated, we could not totally ignore this prevalence. If we assume the effect of a single clinic visit and white coat hypertension was around 50% overestimated, at a conservative estimate, we can still observe an 11% prevalence of newly diagnosed hypertension in our group (mean age 38.5 years). This value is comparable to the prevalence in the general population in the same age group. Recent reports from the National Center for Health Statistics, United States showed that people aged 18–39 years had a 22.4% prevalence of hypertension , while a.15% was It is also important to note that, according to the World Health Organization, up to 46% of adults with hypertension are unaware that they have the condition, as healthy individuals may not have their blood pressure measured for many years . Travel The prevalence of travelers with pre-existing hypertension in our study was 6.7%. Our prevalence was higher when compared to that reported from France (4.6%) and Ireland (2.9%) , 15. OneAmong the 11 participants that agreed to participate in the blood pressure monitoring arm of the study, we found that most of them had well controlled blood pressure before and during the trip. There was no significant change in SBP, DBP, MAP throughout the trip. Although their blood pressure in the morning was slightly higher than in the evening, this was not clinically relevant (less than 10 mmHg). This finding may be due to the phenomenon known as the “morning surge of blood pressure”. This has been documented in various reviews as a normal aspect of human physiology due to the effect of circadian rhythm, which can cause high blood pressure levels in the morning , 26. AnoAlthough it is reasonable to assume that during international travel, travelers might have difficulty controlling their blood pressure due to several reasons, we could not demonstrate that in our study. Over 90% (10/11) travelers had stable blood pressure control during the trip, while only one participant had clinically insignificant higher blood pressure (≥ 10 mmHg). Moreover, all participants remained well, and no hypertension-related clinical events were reported during the trip.Nevertheless, it is important to keep in mind that international travel can be stressful due to a variety of reasons including airport stress, lack of sleep, jet lag, and language/communication barriers, all of which can negatively impact blood pressure control. Dietary habits may also adversely impact blood pressure regulations, especially when consuming foods and beverages high in salt, caffeine, and alcohol. Those factors can contribute to an increase in blood pressure levels , 27, 28.Travelers with pre-existing hypertension should have their blood pressure under control before the trip and continue taking their own antihypertensive drug(s) throughout the trip. Failure to take medication is always the main reason that makes blood pressure uncontrollable. Severely high BP or marked variation of blood pressure during the trip can lead to serious or even fatal consequences.There are several limitations to this study. Firstly, newly diagnosed cases of hypertension were determined based on high blood pressure readings taken at two separate timepoints within a single visit, which may lead to overestimation when compared to using multiple measurements over several visits or using ambulatory blood pressure monitoring. Secondly, participants enrolled in the second arm of the study were a unique group with well-controlled blood pressure before the trip, very good compliance with their doctor’s advice, and use of their own blood pressure measurement device. The results relating to blood pressure stability during the trip in this group might not, therefore, be generalisable to other hypertensive travelers.Our study found that hypertension was common among adult travelers, with an overall prevalence of 28.8%. Most travelers with hypertension were unaware of their high blood pressure level before visiting our travel clinic. Travelers with pre-existing hypertension in our study had relatively stable blood pressure throughout the trip. However, given that hypertension is an important risk factor for serious cardiovascular events or stroke, travel medicine practitioners should always assess travelers’ blood pressure in a pre-travel health consultation. In the next phase of our study, focusing on monitoring blood pressure, we aim to enhance the reliability of our findings by increasing the participant sample size. We will aim to use the same model of automated blood pressure device throughout the study to ensure consistency and accuracy. These steps will help us obtain more applicable results regarding blood pressure monitoring among travelers.Additional file 1.


This retrospective study investigated factors that influence the occurrence of decreased systolic and diastolic blood pressure including sociodemographic and economic factors, hypertension duration, cigarette consumption, alcohol consumption, duration of smoking, type of cigarettes, exercise, salt consumption, sleeping pills consumption, insomnia, and diabetes. These factors were applied to predict the reality of systolic and diastolic decrease using the machine learning algorithm Naïve Bayes, artificial neural network, logistic regression, and decision tree.The increase in blood pressure, both systolic and diastolic, is very harmful to the health because uncontrolled high systolic and diastolic blood pressure can cause various diseases such as congestive heart failure, kidney failure, and cardiovascular disease. There have been many studies examining the factors that influence the occurrence of hypertension, but few studies have used machine learning to predict hypertension.The machine learning models performed well and can be used for predicting whether a person with hypertension with certain characteristics will experience a decrease in their systolic or diastolic blood pressure after treatment with antihypertensive drugs. The increase in blood pressure both systolic and diastolic is very harmful to the health because high blood pressure can cause various diseases such as congestive heart failure, kidney failure, and cardiovascular disease –4. Systo2, and if a person is obese, then weight loss becomes important, alcohol consumption should be limited, and smoking should be stopped immediately as it can cause plaque buildup in the artery walls and leads to high blood pressure [Thus, lowering SBP and DBP is very important. This can be achieved by antihypertensive drugs, lifestyle modifications such as aerobic exercise, low salt (sodium) diet, and maintaining a healthy weight balance. Excessive weight, especially in the abdomen, can cause an increase in blood pressure between 18.5 to 24.9 kg/mpressure , 18. Adepressure .Machine learning (ML) is a well-known artificial intelligence (AI) technology that is developing very rapidly and is now the most popular in the fourth industrial revolution (industry 4.0). Applying machine learning to many tasks that usually require several stages of calculations using statistics can be achieved more rapidly , 21. IslThis retrospective study was conducted to develop a model to predict whether a patient who has a history of smoking has decreased systolic and diastolic pressure after taking medicines. The study involved 100 hypertension male patients from the Gamping 1 and Gamping 2 Health Center, Sleman Regency, Yogyakarta, who had a smoking history. This study was approved by the Health Research Ethics Commission of the Yogyakarta Ministry of Health (No. e-KEPK/POLKESYO/0646.1/X/2022).X) are explained further in detail later and the output variables (y1) were a decrease in SBP and (y2) for DBP. The output variable, called the target feature, was binomial data. The model prediction algorithms used were NB (Naïve Bayes), ANN , LoR (logistic regression), and DT (decision tree).The datasets were classified or grouped using machine learning into input and output features. The input features  was decreased SBP after taking antihypertensive drugs, y2 is the decrease in DBP, and the feature predictors (X) were smoking-related information, sociodemographic status, hypertension, and several other conditions related to blood pressure . The response variable . The ANN was designed using the MLP Classifier .The participants ranged in age between 25 and 74 years (mean 52 years), and most participants were 55 − 64 years and over 65 years (48%), retired, and had suffered from hypertension for an average of 6.49 years  Tables  and 2.TBefore taking any medication, their average systolic pressure was 158 mmHg, and diastolic pressure was 98 mmHg. After taking medication, their blood pressure decreased to 151 mmHg for systolic and 87 mmHg for diastolic pressure Table .The participants had smoked for an average of 10 years, and most quit after seeking medical treatment. Around 98% smoked cigarettes and 2% smoked e-cigarettes  for the decrease in SBP and (y2) for DBP.Of the features obtained from the 100 randomized medical records, the ten factors most correlated in order with a decreased SBP after taking antihypertensive drugs were age, duration hypertension, occupation, height, diabetes, weight, duration of smoking, exercise, the number of cigarettes smoked per day, and a high salt diet. In comparison, the factors most correlated to the decrease in DBP were age, the duration of smoking, salt consumption, occupation, exercise, the use of sleeping pills, insomnia, weight, consumption of alcohol, and height Table ; Table 6The machine learning performance of NB, DT, ANN, and LoR was good as evidenced by the high precision (≥90%), accuracy (≥84%), and sensitivity (≥80%) for SBP and DBP Table .Table 7The results show that the antihypertensive drugs used in this study do not necessarily reduce SBP and DBP. This is in line with research conducted by Marco et al. investigating the mean decrease in SBP and DBP achieved by antihypertensive drugs which showed that several sociodemographic factors such as sex, ethnicity, and obesity are associated with the antihypertensive response .The machine learning performed well in predicting whether a person with hypertension with certain characteristics would experience a decrease in SBP and DBP after taking antihypertensive drugs. Machine learning can be used for very large datasets and is an effective predictor when used with the features determined as affecting blood pressure. According to the performance indicators of precision, accuracy, precision and recall, and sensitivity, logistic regression has the most stable performance, followed by the decision tree, artificial neural network, and Naïve Bayes. Both the artificial neural network and logistic regression were equally good at predicting a decreased SBP, whereas logistic regression was better at predicting a decreased DBP.This is the first study to investigate the decreased SBP and DBP of male hypertensive patients with a history of smoking history using machine learning models. This is a real condition study as the participants were hypertensive males selected from the public health center (puskesmas) medical records between July and November 2022.The sample was relatively small, so the machine learning models should be trained and tested using larger datasets and more features to confirm these results and increase the accuracy of the predictions. Not all blood pressure data in this study was measured using enumerators because the participants were prescribed hypertension treatment by their doctors.The machine learning models Naïve Bayes, artificial neural network, logistic regression, and decision tree can be used to predict the decrease in SBP and DBP in hypertensive patients who are taking antihypertensive drugs. Since the decrease in SBP and DBP can be influenced by many factors not considered in this study such as patient compliance with taking drugs, obesity, and types of drugs, future research involving larger datasets and more features is needed.


Simultaneous pancreas and kidney transplantation is the optimum treatment for patients with type 1 diabetes and renal failure, providing survival benefit over deceased donor kidney transplant alone. Here the authors demonstrate that utilization of donation after circulatory death pancreases is a safe approach to expanding the donor pool with equivalent results to donation after brainstem death transplantation. They also demonstrate that pancreas transplantation after normothermic regional perfusion is feasible, but it will require ongoing prospective study to ensure that the benefits seen for liver transplantation do not come at the expense of pancreas transplant outcomes. In liver transplantation, normothermic regional perfusion leads to superior outcomes compared with sDCDThe aim of this study was to evaluate a decade of a DCD pancreas transplant programme and a cohort of DCD pancreas transplants performed with or without normothermic regional perfusion.All consecutive simultaneous pancreas and kidney transplantations performed at Addenbrooke’s Hospital, Cambridge, UK from 1 August 2008 to 31 July 2018 were included in this study. Full methodology is provided in detail in the A total of 211 patients  were included. The donor, recipient and transplant characteristics are summarized in Fig. 1a). Death-censored pancreas and kidney graft survival at 5 years was 83.9 and 93.2 per cent respectively, with no significant difference between sDCD and DBD cohorts .Patient survival at 1, 3, 5 and 10 years was 99.0, 96.6, 93.4 and 84.3 per cent respectively, with no significant difference between those receiving DBD or sDCD grafts . There was no significant difference in the serum creatinine, estimated glomerular filtration rate (eGFR) or glycated haemoglobin (HbA1c) at 1 year between groups . Rates of graft losses, thrombosis, length of stay, reoperation and episodes of rejection are included in the supplementary results (Delayed graft function (DGF) occurred in 33.3 per cent of renal grafts and 3.5 per cent of pancreatic grafts . Serum lipase, but not amylase, levels were also significantly lower in the normothermic regional perfusion cohort compared with sDCD (Lower levels of both amylase and lipase were seen in recipients of grafts from DBD compared with sDCD donors (,,Given the waiting list mortality and known survival benefits of simultaneous pancreas and kidney transplantation compared with renal transplant alone for diabetic patientsznab212_Supplementary_InformationClick here for additional data file.


Impaired kidney function is often associated with acute decompensation of chronic heart failure and portends a poor prognosis. Unfortunately, current data have demonstrated worse survival in patients with acute kidney injury than in patients with chronic kidney disease during durable LVAD placement as bridge therapy. Furthermore, end-stage heart failure patients undergoing combined heart-kidney transplantation have poorer short- and long-term survival than heart transplants alone. We evaluated the kidney function recovery in our heart failure population awaiting heart transplantation at our institution, supported by temporary Mechanical Circulatory Support (tMCS) with Impella 5.5. The protocol (#22004000) was approved by the Mayo Clinic institutional review board, after which we performed a retrospective review of all patients with acute on chronic heart failure and kidney disease in patients considered for only heart and kidney combined organ transplant and supported by tMCS between January 2020 and February 2021. Hemodynamic and kidney function trends were recorded and analyzed before and after tMCS placement and transplantation. After placement of tMCS, we observed a trend towards improvement in creatinine, Fick cardiac index, mixed venous saturation, and glomerular filtration rate (GFR), which persisted through transplantation and discharge. The average duration of support with tMCS was 16.5 days before organ transplantation. The median pre-tMCS creatinine was 2.1 mg/dL (IQR 1.75–2.3). Median hematocrit at the time of tMCS placement was 32% (IQR 32–34), and the median estimated glomerular filtration rate was 34 mL/min/BSA (34–40). The median GFR improved to 44 mL/min/BSA (IQR 45–51), and serum creatinine improved to 1.5 mg/dL (1.5–1.8) after tMCS. Median discharge creatinine was 1.1 mg/dL (1.19–1.25) with a GFR of 72 (65–74). None of these six patients supported with tMCS required renal replacement therapy after heart transplantation. Early adoption of Impella 5.5 in this patient population resulted in renal recovery without needing renal replacement therapies or dual organ transplantation and should be further evaluated. The progressive nature of heart failure and limited survival during end stages necessitates advanced therapies. These options may include consideration for transplantation or bridge therapies. Traditional bridge-to-transplant options have included continuous inotrope therapy or implantation of durable left ventricular assist devices (LVAD). Unfortunately, current data have demonstrated worse survival in patients with acute kidney injury than in patients with chronic kidney disease during LVAD placement as bridge therapy2.Impaired kidney function is often associated with acute decompensation of chronic heart failure and portends a poor prognosis4. Furthermore, end-stage heart failure patients undergoing combined heart-kidney transplantation have poorer short- and long-term survival than heart transplants alone5.Based on national data from the Organ Procurement and Transplantation Network (OPTN), there have been 2561 simultaneous heart/kidney transplantations in the United States since 1988. In 2021, a total of 349 simultaneous heart/kidney transplantations were performed. Of these transplantations, it is unclear how many would have had potentially reversible kidney injury with optimization of the cardiorenal axis. In patients with New York Heart Association (NYHA) class 3–4 and American Heart Association (AHA) stage C-D heart failure, worsening kidney function often prompts the consideration to start kidney replacement therapy, a factor that is directly linked to worse outcomes in the acute setting9.We evaluated the kidney function recovery in a chronic heart failure population awaiting heart transplantation at our institution supported by temporary Mechanical Circulatory Support (tMCS) with Impella 5.5. Our observations showed a sustained improvement in kidney function where kidney transplantation was not required in a subset of patients with the Impella 5.5 axillary tMCS device. This has not been routinely seen with cardiogenic shock patients supported before durable LVAD, inotrope therapy, or ECMOe performed a retrospective review of all patients with acute on chronic heart failure and kidney disease in patients considered for only heart and kidney combined organ transplant and supported by Impella 5.5 between January 2020 and February 2021. Hemodynamic and kidney function trends were recorded and analyzed before and after Impella 5.5 placement and transplantation.The protocol (#22004000) was approved by the Mayo Clinic institutional review board. All methods were performed in accordance with the relevant guidelines and regulations. W29.Our institutional protocols and multi-disciplinary approach to management has been described in previous publications and is summarized belowDuring our review period, 57 patients underwent heart transplantation, of which 20 patients with cardiogenic shock utilized the Impella 5.5 with Smart Assist, intended as a bridge to organ transplantation (35%). The presented series of six patients were the only individuals during this timeframe who were worked up for heart and kidney transplant while supported with Impella 5.5 Fig. . The kidHere, we describe six patients who demonstrated marked kidney function improvement, eventually undergoing heart-only transplantation, who were supported with the Impella 5.5 with SmartAssist. The resultant support of patients with the Impella device likely allowed for improved hemodynamic and cardiorenal optimization—without an increased risk of hemolysis or device-related complications and avoiding renal replacement therapies in the perioperative period.29. Progressive left ventricular failure, based on the assessment by Fick cardiac index, escalating needs of vasoactive support, or worsening end-organ markers  and clinical factors  prompted the utilization of tMCS with Impella 5.5 placement intended as bridge therapy.All patients supported with the Impella 5.5 with Smart Assist were co-managed with transplant critical care, transplant cardiology, and cardiothoracic surgery. Daily multi-disciplinary rounds were performed to provide cohesive care. For those patients being considered for heart-kidney transplantation, transplant nephrology was consulted. Our institutional practice for Impella 5.5 candidacy in the setting of progressive cardiogenic shock refractory to single or dual inotrope therapy has been previously describedImage assessment of Impella placement was conducted with a once-a-week trans-thoracic echocardiogram to assess for right heart failure and device positioning within the left ventricle.Hemodynamic assessment after Impella placement was performed using pulmonary artery catheters maintained for a minimum of 24 h, with the total duration of placement ultimately determined by the treatment team. Early device removal strategies were favored, given the increased risk of deep venous thrombosis formation and the need to maintain right internal jugular vein patency for post-transplant endomyocardial biopsy access.The standard purge solution in this group was heparin-based. Systemic anticoagulant strategies utilized heparin infusion to mitigate the risk of device-related thrombotic events. Bivalirudin was substituted for patients with concern for the development, or prior history, of heparin-induced thrombocytopenia (HIT) or allergy to heparin products. A target prothrombin time (PTT) was maintained between 50 and 70. Daily lactate dehydrogenase was assessed for thrombus formation and hemolysis. Plasma-free hemoglobin was rarely checked due to our institution's 1-week delay in results as a send-out test.Impella care was standardized as follows:Patient care and adjustment of guideline-directed medical therapies in this population were based on the treating physician’s discretion. Diuretic dosing was individualized based on central venous pressure monitoring, physical examination, lab values, and daily weights. Inotrope therapies were guided by daily mixed venous saturation assessment through a peripherally inserted central catheter (PICC) venous blood gas and Fick calculation of cardiac output and index. A weekly discussion of patients listed for heart or heart-kidney transplantation occurred within the multi-specialty selection conference. Patients awaiting organ transplantation supported with tMCS were reviewed for de-escalation, escalation, or alternative support needs.Informed consent was waived by the Mayo Clinic IRB (#22004000) due to the retrospective nature of this study. The Mayo Clinic IRB approved a waiver of HIPAA authorization in accordance with applicable HIPAA regulations.2 (IQR 1.64–1.8) while on single or dual vasoactive support (Table The median age was 67 (IQR 58–69), with 1 female and 5 male patients. The average BMI was 31 (IQR 29–33). In our cohort, blood groups included O 4), A (1), and B (1). Pre-admission data 1 year prior to admission are summarized in Table , A (1), 2 (IQR 2.6–2.8). Mixed venous saturation of 64% (IQR 62–65) compared to 56% before Impella placement. Cardiac power output, a surrogate of right ventricular function, increased to 0.9 W (pre-impella median of 0.6 W). After Impella placement, median hematocrit was 30% (IQR 32–35), unchanged from the pre-device state. Average lactate dehydrogenase did not indicate concern for hemolysis in any patients.The average duration of support with tMCS was 16.5 days before organ transplantation. After placement of the Impella 5.5 device, we observed a trend towards improvement in creatinine, Fick cardiac index, mixed venous saturation, and glomerular filtration rate (GFR), which persisted through transplantation and discharge Figs. , 3, 4, 5One patient was transplanted as a UNOS status 1 exception due to right ventricular failure, with the other five as UNOS Status 2. The median intraoperative cardiopulmonary bypass time was 162 min (IQR 162–183 min), and the median cold ischemic time was 205 min (IQR 202–224). The median duration of support with Impella was 18 days (IQR 17–26), with a post-transplant ICU length of stay of 5 days. The median hospital length of stay from admission to discharge was 42 days (IQR 38–47). The median discharge creatinine was 1.1 mg/dL (1.19–1.25) with a GFR of 72 (65–74), Fig. We present six patients being considered for heart and kidney transplant out of 20 supported with Impella 5.5 for progressive cardiogenic shock as a bridge to transplantation. These six patients demonstrated renal recovery to the point where our multi-disciplinary team was comfortable avoiding renal transplantation. Within all 20 patients reviewed during this timeframe, we found similar trends in renal function improvement , and sympathetic nervous system result in increased central venous (CVP) and intra-abdominal pressures11. Kidney congestion stems from elevated intra-abdominal and CVP, low cardiac output, and tubuloglomerular feedback. The increase in venous pressure compounds inadequate blood flow across the vasculature within the kidneys. As a result of slower flow in the ascending loop of Henle, renin release increases from the juxtaglomerular cells in the afferent arterioles. This results in sodium retention, worse congestion, and decreased urine output. Another factor that contributes to cardiorenal syndrome is oxidative stress. Oxidative stress is the product of an imbalance between oxidants and antioxidants, resulting in the inability of the body to metabolize elevated levels of reactive oxygen species (ROS)12. Increased levels of angiotensin II due to the activation of RAAS produces ROS and amplifies oxidative stress in patients with heart failure and kidney disease13. Furthermore, increased angiotensin II compounds the stress on the right ventricle and pulmonary vasculature by increasing pulmonary afterload.Cardiorenal syndrome involves the dysfunction between the heart and kidneys and the disease progression associated with the interdependence of these organs14. Additionally, large bodies such as the Acute Kidney Injury Group have worked to guide the clinical and therapeutic definition of renal recovery and broaden the understanding of underlying renal injury and recovery physiology, molecular markers, and predictors of renal recovery with some difficulty16.There is a lack of evidence surrounding renal recovery in patients with chronic kidney failure in cardiogenic shock supported with tMCS19. Acute decompensated heart failure and the progressive decline to cardiogenic shock with both right and left heart failure and systemic congestion eventually lead to multi-organ dysfunction20. The literature surrounding renal disease and outcomes with mechanical circulatory support in heart failure patients focuses on durable LVAD and acute or chronic kidney failure21. The Centers for Medicare and Medicaid Services have clearly stated that irreversible renal disease is an absolute contraindication to the placement of durable LVAD. However, a study of Medicare beneficiaries by Walther et al. in 2018 discussed the use of LVAD in patients requiring renal replacement therapy due to a combination of acute and chronic kidney disease22. As expected, the survival outcomes of this data were poor, reporting a 1-year mortality of 61.5% in patients undergoing LVAD placement with known renal failure. Older generation tMCS devices such as the Impella CP and 2.5 or even current generation ECMO use are associated with increased hemolysis, directly related to irreversible renal damage from pigment nephropathy, due to a combination of factors: pump size (Impella CP/2.5), pump flow (ECMO), and red blood cell shear stress among all three–independent of systemic anticoagulant usage26. Our own and other published data show this is rarely seen with the Impella 5.530. Furthermore, it is imperative to understand the acute decompensation of heart failure progressing to cardiogenic shock, necessitating escalation to vasoactive support followed by tMCS placement, highlights a population with an acute on chronic renal insult. As we show in Fig. 16.We do know, however, that intracardiac chamber filling pressures have long been described as critical markers of renal dysfunction and increased mortalityWe used Impella 5.5 support to manage cardiogenic shock in patients with a long-standing history of heart failure and stage 3 worse chronic kidney disease. The use of the Impella 5.5 device in this group was based on the inability to offload the left ventricle, the need for escalation of inotrope support, or progressive decline as evidenced by clinical and laboratory data, including worsening kidney function. Patients were evaluated for heart and kidney transplantation based on individual characteristics, which were driven by worsening kidney function despite an escalation in vasoactive support prior to Impella placement. The intent of early escalation to Impella 5.5 is to prevent the onset of cardiometabolic shock and irreversible end-organ damage.As outlined in our supplemental data, we found multiple patients who experienced optimization in renal function, indicating that Impella support has a stepwise improvement upon cardiac output beyond standard vasoactive support. Furthermore, there is a demonstrated decrease in bi-ventricular filling pressures and a probable effect upon the mitigation of worsening acute neurohormonal surge in shock.Reconsideration for obviating the need for renal transplantation in these six patients occurred due to marked improvement in GFR and avoidance of initiation of renal replacement therapies. Within our case series, baseline GFR in all of our patients was < 60 mL/min/BSA, with more than half moderate CKD stage 3b or worse. This drove an early team-based approach to consider heart-kidney transplantation due to the risk of worse outcomes with post-cardiopulmonary bypass-related renal injury.This improvement was demonstrated through improved GFR, preservation of right heart function, and sustained renal improvement without requiring renal replacement therapy before or after heart-only transplantation. These results are a significant improvement over other short or long-term mechanical circulatory support options we outlined. The use of Impella has the potential to improve patient outcomes and lead to sustained renal recovery and stabilization in heart failure cardiogenic shock.Furthermore, these patients tolerated the standard induction immunotherapy (thymoglobulin or basiliximab) without delaying the initiation of the calcineurin inhibitor, tacrolimus. All patients had initiation of tacrolimus within the first 96 h after extubation. Daily post-transplant complete blood counts were evaluated for potential thrombocytopenia . This finding is significant because induction immunotherapy can allow for a safe delay in initiating calcineurin inhibitor therapy to avoid renal injury. The fact that the patients did not experience kidney injury and could tolerate the standard immunotherapy regimen after heart transplantation suggests that their renal function had improved and stabilized despite undergoing the stress of cardiopulmonary bypass and expected vasoplegia after organ transplantation.In our limited case series, we found clinically significant improvement in kidney function in patients awaiting heart transplantation supported with the Impella 5.5 with SmartAssist. Patient-specific data highlights the broader impact of Impella 5.5 support in patients with AKI on CKD and cardiogenic shock—allowing for 1. Optimization of hemodynamic support , 2. Biventricular functional alignment , and 3. Splanchnic and renal venous decongestion .This data is presented as hypothesis-generating. We look to examine a new pathway for renal recovery/stabilization in cardiogenic shock with the support of the Impella device. Factors influencing renal function that are not under full control in the intensive care setting include accurate capture of urine output  and duration or utilization of invasive catheters for intracardiac filling pressure assessment. During our review of these six patients, urine output remained unchanged before or after Impella use. We also worked to quantify total diuretic dose and albumin/colloid blousing to balance the effect of competing factors in modifying renal function—however, no trends were highlighted. This may be due to practice variations amongst critical care or nephrology providers at different times during patient care. Overall, however, the general dosing of diuretics was 2.5 mg IV once or twice daily of bumetanide with intermittent use of 250 or 500 mg of IV Chlorothiazide before and after Impella support.Impella 5.5 use in our patient population resulted in renal recovery across all patients, with a further improvement in six patients who had significant renal dysfunction but eventually obviated the need for renal transplantation. Given the minimally invasive placement via axillary cutdown, limited hemolysis profile, and biventricular offloading—the Impella 5.5 with SmartAssist presents a new paradigm in optimization for patients with advanced kidney disease awaiting organ transplantation in cardiogenic shock. Further studies with larger cohorts should be considered.Supplementary Figure 1.