Chronic Blood Research Articles

Diagnostic Approach and Pathophysiological Mechanisms of Anemia in Chronic Liver Disease—An Overview

Hematological abnormalities are frequently linked to chronic liver disease of any etiology. About 75% of patients with advanced chronic liver disease experience anemia. The causes of anemia are complex and multifactorial, particularly in cirrhotic patients. Acute and long-term blood loss from the upper gastrointestinal tract, malnutrition, an enlarged spleen brought on by portal hypertension, hemolysis, and coagulation issues are the main causes of anemia. Alcohol, a common cause of chronic liver disease, determines anemia through direct toxicity on the bone marrow, with the suppression of hematopoiesis, through vitamin B6, B12, and folate deficiency due to low intake and malabsorption. In patients with chronic hepatitis C virus infection, antiviral drugs such as pegylated interferon and ribavirin can also cause significant anemia. The use of interferon has been linked to bone marrow toxicity, and hemolytic anemia brought on by ribavirin is a well-known dose-dependent side effect. Within six months of the infection with hepatitis B, hepatitis C, and Epstein–Barr viruses, aplastic anemia associated with hepatitis is seen. This anemia is characterized by pancytopenia brought on by hypocellular bone marrow. Esophageal varices, portal hypertensive gastropathy, and gastric antral vascular ectasia can all cause acute and chronic blood loss. These conditions can progress to iron deficiency anemia, microcytic anemia, and hypochromic anemia. Another common hematologic abnormality in liver cirrhosis is macrocytosis, with multifactorial causes. Vitamin B12 and folate deficiency are frequent in liver cirrhosis, especially of alcoholic etiology, due to increased intestinal permeability, dysbiosis, and malnutrition. Many chronic liver diseases, like viral and autoimmune hepatitis, have a chronic inflammatory substrate. Proinflammatory cytokines, including tumor necrosis factor and interleukin 1, 6, and 10, are the main factors that diminish iron availability in progenitor erythrocytes and subsequent erythropoiesis, leading to the development of chronic inflammatory, normochromic, normocytic anemia.

Cost-effectiveness of ropeginterferon alfa-2b-njft for the treatment of polycythemia vera.

Aim: Patients with polycythemia vera (PV), a rare and chronic blood cancer, are at a higher risk for thromboembolic events, progression to myelofibrosis, and leukemic transformation. In 2021, ropeginterferon alfa-2b-njft (BESREMi®) was approved in the US to treat adults with PV. The purpose of this study is to estimate the cost-effectiveness of ropeginterferon alfa-2b-njft, used as a first- or second-line treatment, for the treatment of patients with PV in the US. Materials & methods: A Markov cohort model was developed from the healthcare system perspective in the United States. Model inputs were informed by the PROUD-PV and CONTINUATION-PV studies and published literature. The model population included both low-risk and high-risk patients with PV. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. Results: Over the modeled lifetime, ropeginterferon alfa-2b-njft provided an additional 0.4 higher quality-adjusted life years (QALYs) and 0.4life-years with an added cost of USD60,175, resulting in a cost per QALY of USD141,783. The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates. A younger patient age at baseline and a higher percentage of patients with low-risk disease improved the cost-effectiveness of ropeginterferon alfa-2b-njft. Conclusion: Ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea.

Molecular and environmental contributors to neurological complications in sickle cell disease.

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which affected hemoglobin polymerizes under hypoxic conditions resulting in red cell distortion and chronic hemolytic anemia. SCD affects millions of people worldwide, primarily in Sub-Saharan Africa and the Indian subcontinent. Due to vaso-occlusion of sickled red cells within the microvasculature, SCD affects virtually every organ system and causes significant morbidity and early mortality. The neurological complications of SCD are particularly devastating and diverse, ranging from overt stroke to covert cerebral injury, including silent cerebral infarctions and blood vessel tortuosity. However, even individuals without evidence of neuroanatomical changes in brain imaging have evidence of cognitive deficits compared to matched healthy controls likely due to chronic cerebral hypoxemia and neuroinflammation. In this review, we first examined the biological contributors to SCD-related neurological complications and then discussed the equally important socioenvironmental contributors. We then discuss the evidence for neuroprotection from the two primary disease-modifying therapies, chronic monthly blood transfusions and hydroxyurea, and end with several experimental therapies designed to specifically target these complications.

Hemoglobin S target of

Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10-year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83-99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.

Iron Chelation and Antioxidant Properties of Withania somnifera (Ashwagandha) Restore Fertility in Men and Women

Abstract: Withania somnifera (Ashwagandha) is one of the most renowned and revered medicinal plants in the Indian Ayurvedic system of medicine. Ashwagandha Rasayanas (tonics), capsules, tablets, and powdered herbs (churna) have been used for curing a wide variety of ailments, including reproductive problems, and for improving fertility in men and women as well as erectile dysfunction (ED) in men. Iron accumulation in reproductive organs is caused by excessive dietary intake of iron, dysregulation of iron transporters, chronic blood transfusions, and hemochromatosis. Iron overload produces oxidative stress and causes atrophy of ovaries and testes and hypogonadism, which leads to infertility in men and women. Emerging evidence from preclinical and clinical studies suggests that excessive iron-induced infertility results from dysfunction of the hypothalamic-pituitary-gonadal axis and consequently perturbs the secretion of sex hormones (GnRH, FSH, LH, estrogen, progesterone, and testosterone). The focus of this review is to summarize the pathophysiology of iron-overload toxicity of reproductive organs and the reversal of male/female infertility and libido with Ashwagandha. The bioactive ingredients of Ashwagandha appear to restore iron–overload infertility by acting on iron chelation and capturing iron free radicals (Fe+++) produced by the Fenton reaction. Many synthetic drugs have been tried for treating iron overload infertility, but the outcome has been inconsistent. Considering the high cost of these drugs, Ashwagandha may be a safer and more costeffective phytomedicine to cure iron-overload infertility and enhance libido in humans. Collectively, the iron chelation and antioxidant effects of Ashwagandha seem to reverse iron-overload infertility in men and women by improving testicular and ovarian functions.

Expert Insights: Phase III Clinical Trials in Non-Transfusion-Dependent (ENERGIZE) and Transfusion-Dependent (ENERGIZE-T) α- and β-Thalassaemia

The thalassaemias are a heterogeneous group of inherited chronic blood disorders associated with impaired haemoglobin (Hb) synthesis, resulting in ineffective erythropoiesis, haemolysis, and the development of lifelong anaemia. The pathophysiology of thalassaemia is due, in part, to increased energy demand to clear globin aggregates and reactive O2 species, and maintain overall red blood cell (RBC) health, coupled with insufficient adenosine triphosphate (ATP) production. For this article, interviews were conducted by EMJ in December 2022 with two key opinion leaders. Kevin Kuo is a Clinician-Investigator and Staff Haematologist at the University Health Network, Toronto, Canada, and Associate Professor in the Division of Hematology, Department of Medicine, University of Toronto, Canada. Maria Cappellini is Professor of Medicine in the Department of Clinical Sciences and Community, University of Milan, Italy. Both haematologists have over 50 years of expertise and clinical experience between them in treating patients with thalassaemia. The two experts provided insights into two ongoing Phase III clinical trials for both α- and β-thalassaemia. These trials are investigating the effect of mitapivat, a first-in-class, small molecule pyruvate kinase activator, in patients across the full range of thalassaemia subtypes. The ENERGIZE trial is investigating mitapivat in patients with non–transfusion-dependent thalassaemia (NTDT), and the ENERGIZE-T trial is investigating mitapivat in patients with transfusion-dependent thalassaemia (TDT).

Patient perspectives of 'Watch and Wait' for chronic haematological cancers: Findings from a qualitative study.

Chronic blood cancers are incurable, and characterised by unpredictable, remitting-relapsing pathways. Management often involves periods of observation prior to treatment (if required), and post-treatment, in an approach known as 'Watch and Wait'. This study aimed to explore patient experiences of 'Watch and Wait'. In-depth interviews with 35 patients (10 accompanied by relatives) with chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma or myeloma. Data were analysed using descriptive qualitative techniques. Patient views of Watch and Wait ranged along a continuum, from immediate acceptance, to concern about treatment deferral. Significant ongoing anxiety and distress were described by some, due to the uncertain pathways associated with Watch and Wait. Infrequent contact with clinical staff was said to exacerbate this, as there was limited opportunity to ask questions and seek reassurance. Patients indicated that the impact of their malignancy could be underestimated by clinicians; possibly due to them comparing chronic and acute subtypes. Most patients lacked knowledge of blood cancers. Support from clinicians was considered greater among treated patients, possibly due to increased contact, and many drew on relatives for aid. Most patients were satisfied with their time-allocation with haematology staff, although experiences could be improved by greater access to clinical nurse specialists, counselling services, and community-based facilities. Experiences varied. Anxiety about unpredictable futures could be more distressing than any physical symptoms and have a greater impact on quality of life. Ongoing assessment could facilitate identification of difficulties, and is particularly important among individuals without supportive networks.

Factors Associated with Elevated Transcranial Doppler Ultrasound Velocities in Children With Sickle Cell Anemia in Mwanza, Tanzania

Background: Stroke occurs in 11% of patients with SCA before 20 years of age. In Northwestern Tanzania, the prevalence of stroke among children living with SCA under the age 15 years is 16.9%, of which might be attributed to the absence of routine screening for the risk of stroke by using Transcranial Doppler Ultrasound (TCD). Screening with TCD allows preventive measures such as chronic blood transfusion to be done which has led to the reduction of stroke by 92%. Methods: This was a prospective analytical cross sectional study which enrolled 267 SCA children aged 2 to 16 years attending Bugando Medical Centre Pediatric Sickle Cell Clinic from July 2019 to June 2020. Assessment of factors associated with elevated TCD included a clinical history of stroke in sibling, death in sibling, temperature, oxygen saturation in room air, blood pressure, hemoglobin level and total white blood cell count. TCD was done by accessing transtemporal window and recording the highest time average mean of maximum velocity (TAMMV) of major vessels mainly, middle cerebral artery (MCA) and distal internal carotid artery (dICA). Results: The median age of enrolled was 6.6 (IQR: 4-9) years. The prevalence of elevated TCD (&gt; 170 cm/s) was found to be 21% (56/267). By multivariate logistic regression, low oxygen saturation in room air, p - value = 0.037, OR 1.08 [95% CI 1.00-1.17] and low hemoglobin level, p - value = 0.001, OR 1.76 [95% CI 1.26-2.45] were statistically significantly associated with elevated TCD among children living with SCA. Conclusion: The high prevalence of elevated TCD velocity, with low hemoglobin and low oxygen saturation in room air as associated factors under multivariate logistic regression, warrants routine TCD screening for children with SCA aged 2 to 16 years.

Antibiofilm activity of bromelain from pineapple against Staphylococcus aureus

Bromelain is a set of proteolytic enzymes usually obtained from pineapple (Ananas comosus). Although bromelain has distinguished therapeutic properties, little is known about its proteolytic potential against opportunistic pathogens related to wound healing complications, such as Staphylococcus aureus. This study aimed to investigate the antibiofilm and antibacterial activity of bromelain in 43 clinical strains of S. aureus isolated from chronic wounds and blood cultures. Bromelain’s activity against S. aureus biofilm in vitro was assessed by analyzing biofilm formation in cultures grown in the presence of 1% bromelain and biofilm destruction after the addition of 1% bromelain to mature biofilms. Proteinase K and sodium metaperiodate were also added to mature biofilms in parallel to compare their activity with that of bromelain and, together with exopolysaccharide and protein production rate assays, to determine the chemical composition of the biofilm extracellular matrix of selected strains of S. aureus. Bromelain was also evaluated for its DNase activity and impact on cellular hydrophobicity and auto-aggregation. Mueller-Hinton agar dilution was used to determine bromelain minimal inhibitory concentration (MIC). Biofilm assays showed that 1% bromelain significantly inhibits S. aureus biofilm formation (p = 0.0157) by up to 4-fold and destroys its mature biofilms (p &lt; 0.0001) by up to 6.4-fold, both compared to the control grown without bromelain. Biofilms of methicillin-resistant S. aureus strains isolated from chronic wounds were the most affected by bromelain treatment. No antibacterial activity was detected with bromelain MIC assays and the proteolytic activity of bromelain was identified as the main antibiofilm mechanism of the enzyme, though its DNase activity may also contribute. The epithelial therapeutic properties of bromelain combined with its antibiofilm activity against S. aureus make it a promising alternative to compose the therapeutic arsenal for the control of S. aureus biofilms in the context of wound care.

A study on transfusion-transmitted infections and other complications amongst children with beta-thalassaemia major attending a tertiary care institution in Kolkata

Abstract Background: Chronic blood disorders such as beta-thalassaemia major require continuous blood transfusions, which results in complications such as transfusion-transmitted infections (TTIs), iron overload, skeletal deformities, endocrinal and cardiac and hepatic disorders. This study aimed at assessing proportion of TTIs, other complications and factors associated with their occurrence amongst children with beta-thalassaemia major. Methods: This cross-sectional study was conducted amongst children with beta-thalassaemia majo attending a tertiary care institution in Kolkata One hundred and ninety two children were selected amongst participants who fulfilled the inclusion criteria. Parents of study participants were interviewed using pre-designed, pre-tested, semi-structured schedule. Results: TTIs were evident in 8.3% of the study participants. Amongst them, hepatitis C, malaria and hepatitis B were present amongst 3.6%, 2.6% and 2.1%, respectively. No cases of human immunodeficiency virus infection and syphilis were found. Elevated serum ferritin levels (53.6%), Chipmunk facies (5.2%), hypothyroidism (2.1%), cardiomyopathy and diabetes mellitus (0.5% each) were noted. A significant association was observed between iron chelation therapy and serum ferritin level amongst these children (P = 0.042). Conclusions: Various transfusion-related complications are still prevalent amongst children suffering from beta-thalassaemia major.

Optimizing IFN alpha therapy against Myeloproliferative Neoplasms.

Myeloproliferative Neoplasms (MPNs) are hematological malignancies that result from acquired driver mutations in hematopoietic stem cells (HSCs), causing overproduction of blood cells and an increased risk of thrombo-hemorrhagic events. The most common MPN driver mutation affects the JAK2 gene (JAK2V617F ). Interferon alpha (IFNα) is a promising treatment against MPNs by inducing a hematological response and molecular remission for some patients. Mathematical models have been proposed to describe how IFNα targets mutated HSCs, indicating that a minimal dose is necessary for long-term remission. This study aims to determine a personalized treatment strategy. First, we show the capacity of an existing model to predict cell dynamics for new patients from data that can be easily obtained in clinic. Then, we study different treatment scenarios in silico for three patients, considering potential IFNα dose-toxicity relations. We assess when the treatment should be interrupted, depending on the response, the patient's age, and the inferred development of the malignant clone without IFNα. We find that an optimal strategy would be to treat the patients with a constant dose so that the treatment could be interrupted as fast as possible. Higher doses result in earlier discontinuation but also higher toxicity. Without knowledge of the dose-toxicity relationship, trade-off strategies can be found for each patient. A compromise strategy is to treat patients with medium doses (60-120 μg/week) for 10-15 years. Altogether, this work demonstrates how a mathematical model calibrated from real data can help build a clinical decision-support tool to optimize long-term IFNα therapy for MPN patients. Significance Statement Myeloproliferative Neoplasms (MPNs) are chronic blood cancers. Interferon alpha (IFNα) is a promising treatment with the potential to induce a molecular response by targeting mutated hematopoietic stem cells. MPN patients are treated over several years, and there is a lack of knowledge concerning the posology strategy and the best timing for interrupting therapy. The study opens avenues for rationalizing how to treat MPN patients with IFNα over several years, promoting a more personalized approach to treatment.

Gatekeepers in research: the experience of recruiting carers of people with chronic blood cancers.

Gatekeepers play a crucial role in successfully recruiting participants to nurse-led qualitative research, particularly in clinical settings. To present the authors' experience of recruiting and conducting qualitative interviews during the COVID-19 pandemic with the carers of patients who have chronic haematological malignancies, and the effects that gatekeepers had on recruitment. The authors had to adapt and adjust their research plan because of difficulties in accessing their target population. Establishing and maintaining relationships with gatekeepers and a Patient and Public Involvement (PPI) panel was integral in successfully collecting data. Ongoing reflexivity and feedback from supervisors, gatekeepers and PPI members in addition to developing research experience can help researchers to overcome challenges in recruiting difficult-to-access populations. Researchers need to be prepared for challenges to their research plans and carefully consider the options available for addressing these challenges. Reaching out to others is integral in expanding researchers' ideas.

1069-P: Digital Platform Users Managing Three Chronic Conditions—Diabetes, Hypertension, and Overweight—Experience Better Outcomes than Those Who Manage One Condition, after Six Months

The coexistence of diabetes, hypertension, and overweight increases the risk for macrovascular and microvascular complications. This study followed users who managed multiple chronic conditions measures, blood glucose (BG), blood pressure (BP) and weight with a single integrated digital platform. The objective was to investigate BG levels and engagement to blood glucose monitoring system (BGMS) in users managing BG, BP and weight on a single platform compared to users managing only BG on the same platform. A retrospective data analysis was performed on users who were active during 2019-2022 and measured BG using Dario platform at least six months. The test group included users who measured BP and weight within 6 months from their first BG measurement; a matched control group was generated of users who measured BG only. BG levels were assessed by average BG (BG avg) and BGMS engagement was assessed by counting BG measurements per month. High-risk users were defined as those who started BG avg&amp;gt;180mg/dL in Month 1. The test group of 2,154 users showed significantly greater (1.7-fold) BGMS engagement than the control group of 14,954 users in Month 1 and Month 6 (p&amp;lt;0.01) (N=17,108). A test subgroup of 343 high-risk users who measured 3 conditions demonstrated significantly greater reduction versus matched control subgroup of 1,579 high-risk users measured BG only, after 6 months (17% vs.11%) (p&amp;lt;0.01). Moreover, the ratio of population that reduced their BG avg to lower than 180 mg/dL after 6 months (equivalent to A1C 8.0; HEDIS measure) was significantly higher in the test subgroup versus control subgroup in high-risk (by 30%; p&amp;lt;0.01). Monitoring several conditions may have the potential to offer a greater means for person with diabetes effectively manage glycemia. This study can illuminate the relative contribution of multi chronic conditions management driving behavioral change to successful diabetes outcomes. Disclosure Y.Hershcovitz: Employee; DarioHealth Corp. S.Budman: Employee; DarioHealth Corp. N.Yaniv: Employee; DarioHealth Corp. O.Manejwala: Employee; DarioHealth Corp., Stock/Shareholder; DarioHealth Corp.

Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification

Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (DIX) domain-containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with disrupted in schizophrenia 1 (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.

#6857 MATHEMATICAL MODEL FOR ADVERSE CARDIOVASCULAR EVENTS RISK ASSESSMENT IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Kidney transplantation is the most cardioprotective method of renal replacement therapy. Nevertheless, cardiovascular diseases are one of the main reason of mortality of with functioning kidney graft. The aim is creation of a mathematical model for adverse cardiovascular events risk assessment in kidney transplant recipients (KTR). Method The study included 237 kidney transplant recipients whose age was 47.1±10.8 years. For three years of observation 79 (33.3%) patients had adverse cardiovascular events (CVE) (acute coronary syndrome, life-threatening rhythm disturbance, complicated hypertensive crisis). The comparison group was 158 (66.7%) recipients without cardiovascular events. The study groups were comparable by gender, age and traditional cardiovascular risk factors. Results The proportion of patients with obesity and the graft glomerular filtration rate less than 30 ml/min/1.73 m2 were higher in KTR with CVE than in KTR without CVE –– 27.8% (n = 22) versus 12.7% (n = 20) and 12.7% (n = 10) versus 3.2% (n = 5), p&amp;lt;0.01. p&amp;lt;0.01. The erythrocytosis and an increased NT-proBNP blood level was more common in KTR with CVE than in KTR without CVE – 29.1% (n = 23) versus 16.5% (n = 26), p&amp;lt;0.05 and 27.8% (n = 22) versus 11.4% (n = 18), p&amp;lt;0.01. KTR with CVE had a longer duration of chronic kidney disease than KTR without CVE – 21.1±12.2 years versus 16.6±9.6 years, p&amp;lt;0.01. Triglycerides and low density lipoproteins blood levels of KTR with CVE were higher than those of KTR without CVE – 1.70 (1.30-2.50) mmol/L versus 1.45 (1.08-1.80) and 2.97±0.88 mmol/L versus 2.61±0.69 mmol/L, p&amp;lt;0.01, respectively. was more common in KTR with CVE than in KTR without CVE. The above factors were included in the mathematical model. $Y\; = \;\frac{1}{{\;1 + {e^{( {4,156 - 1,033X1 - 0,037X2 - 1,003X3 - 0,384X4 - 0,470X5 - 1,712X6 - 1,119X7} )}}}},$ X1 - body mass index &amp;gt; 30 kg/m2 (0 - no, 1 - yes), X2 - duration of chronic kidney disease (years); X3 - erythrocytosis (0 - no, 1 - yes), X4 - triglycerides blood level (mmol/l); X5 - low density lipoproteins blood level (mmol/l); X6 - glomerular filtration less than 30 ml/min/1.73 m2 (0 - no, 1 - yes), X7 - increased NT-proBNP blood level (0 - no, 1 - yes) The formula predicts low risk of CVE in kidney transplant recipients with an estimated value of Y&amp;lt;0.35, with Y≥0.35 - high risk. Conclusion Obesity, graft dysfunction erythrocytosis, an elevated NT-proBNP blood level, longer duration of chronic kidney disease, higher triglycerides and low density lipoproteins blood levels can be used to assess cardiovascular risk in kidney transplant recipients.

#4993 EFFECT OF ETELCALCETIDE TREATMENT ON ERYTHROPOIESIS-STIMULATING AGENTS (ESAS) REQUIREMENT IN HEMODIALYSIS PATIENTS: A SINGLE CENTER STUDY

Abstract Background and Aims Anemia is a common consequence of advanced chronic kidney disease (CKD). There are various causes of renal anemia like decreased production of and resistance to Erythropoietin, shortened survival of red blood cells and chronic blood loss. Secondary hyperparathyroidism is a potential cause of renal anemia in CKD patients due to direct effect on Erythropoietin synthesis, red cell survival and bone marrow fibrosis [1]. There are several reports of the beneficial effect of treatment of hyperparathyroidism on hemoglobin (Hb) levels. Etelcalcetide is a novel intravenous calcimimetic used for the treatment of secondary hyperparathyroidism in hemodialysis patients. However, there are very few reports of Etelcalcetide's effect on anemia management in hemodialysis patients. We aimed to study the effect of Etelcalcitide on ESAs requirement in our hemodialysis cohort. Method This is a retrospective study in Al Wakra Hospital hemodialysis unit conducted on patients with uncontrolled secondary hyperparathyroidism who needed to be started on Etelcalcetide. Mean Hb and mean ESAs dose were calculated for a period of 6 months before and 6 months after starting Etelcalcetide, while iPTH levels were measured at the beginning and 6 months after starting Etelcalcetide. Inclusion criteria: hemodialysis patients who are on Etelcalcetide for at least 6 months. Exclusion criteria: Patients’ age &amp;lt; 18 years, hemodialysis duration &amp;lt; 12 months and patients with acute blood loss. Results Out of 94 hemodialysis patients, 26 (27.6%) were on Etelcalcetide. 2 patients were excluded, one for acute hematuria and the other for erosive gastritis. 24 patients were included (13 females and 11 males). Mean age of the patients was 58.7 years. 15 patients were on Darbepoetin, 8 on Erythropoietin and 1 patient was switched from Darbepoetin to Erythropoietin due to poor response. There was no significant difference in mean Hb levels for all the patients before and after starting Etelcalcetide (10.6 g/dl and 10.8 g/dl, respectively). Out of 24 patients, 19 had reduction while 5 had increase in ESAs dose requirement. In total, the mean reduction of ESAs dose for all the patients was 17.3%. There was a mean of 33.4% reduction in ESAs requirement for the 19 patients while a mean of 44% increase in the requirement for the 5 patients. Mean iPTH for the cohort at the time of starting Etelcalcetide and 6 months after was 1036 pg/ml and 473 pg/ml respectively. The mean reduction of iPTH for those who had decreased ESAs requirement was 58% while it was 38.8% for those who had increased ESA requirement. Conclusion This study showed that control of severe secondary hyperparathyroidism with Etelcalcetide was associated with reduction in ESAs requirement in hemodialysis patients. The more the control of hyperparathyroidism, the more the reduction of ESAs requirement. These findings were observed also in a one case report [2]. We believe that our study has one of the largest number of patients to show such an observation, however larger controlled studies are needed to confirm these preliminary findings in the improvement of anemia after treatment of hyperparathyroidism by Etelcalcetide.

#4295 SPECTRUM OF GLOMERULAR AND VASCULAR KIDNEY PATHOLOGY ASSOCIATED WITH MYELOPROLIFERATIVE NEOPLASMS

Abstract Background and Aims Myeloproliferative neoplasms (MPN) are chronic blood disorders defined by an overproduction of clonal, differentiated hematopoietic cells. A high prevalence of chronic kidney disease (CKD) is described in patients with MPN. The glomerular histological pattern of MPN-related kidney disease, MPN-related glomerulopathy (MPN-RG), may not account for the entirety of CKD risk in this population, as it appears to be rare and has mostly been reported in patients with myelofibrosis. The inflammatory and prothrombotic state of clonal blood cells has been linked to a systemic vasculopathy in MPN patients, characterized by thromboses and microvascular disease. Thus, we put forward the hypothesis that intrarenal vessel injury may occur during MPN, and that vascular nephrosclerosis may be a common histological pattern in MPN patients presenting with kidney disease. Method We conducted an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four kidney pathology units. All adult patients with a history of MPN who underwent a kidney biopsy were included. We performed a systematic histological review of glomerular and vascular compartments. MPN-RG was defined as mesangial expansion and negative glomerular immunofluorescence studies, with at least one of the following: mesangial hypercellularity, or features of chronic glomerular thrombotic microangiopathy. Hematopoietic cells were detected using anti-glycophorin C, anti-myeloperoxidase, and anti-factor VIII immunohistochemistry (IHC). Chronic vascular lesions were evaluated using the Banff aah and cv lesion definitions and compared to matched adult native kidney biopsies. We used multivariable logistic regression models to assess determinants of vascular lesions, using the number of antihypertensive drugs as a proxy for hypertension severity. Results We included 47 MPN patients who underwent a kidney biopsy, including 16 patients with chronic myeloid leukemia, 14 with polycythemia vera, 10 with essential thrombocythemia and 7 with primary myelofibrosis. 14 cases (29.8%) met our definition of MPN-RG. MPN-RG was strongly associated with myelofibrosis (primary or secondary, P = 0.021) and poorer ESRD-free survival (P = 0.007). Positive IHC for circulating cells in the glomerular capillaries was not associated with glomerular injury but was positively correlated with blood leukocyte count (P = 0.004). Thirty-three patients (75.0%) had moderate-to-severe arteriosclerosis; 39 patients (84.8%) had moderate-to-severe arteriolar hyalinosis. Multivariable models including 188 control kidney biopsies revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension (Table 1 and Table 2). Conclusion We demonstrate the strong association between MPN-RG and myelofibrosis and confirm its poor renal prognosis. We argue that the finding of glomerular intracapillary hematopoietic cells should not be considered in the diagnosis of MPN-RG. Most notably, our results show that MPN represent a novel, independent risk factor for vascular nephrosclerosis, and establish a new link between MPN and CKD. These findings raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

Myeloproliferative neoplasms - blurring the lines between cancer and chronic inflammatory disorder.

Myeloproliferative Neoplasm (MPN) is a group of chronic blood cancers that arise from a hematopoietic stem cell (HSC) clone with somatic mutations causing constitutive activation of myeloid cytokine receptor signaling. In addition to elevated blood cell counts, MPN typically presents with increased inflammatory signaling and inflammation symptoms. Therefore, while being a clonally derived neoplasm, MPN has much in common with chronic non-cancerous inflammatory conditions, such as rheumatoid arthritis, lupus, and many more. MPN and chronic inflammatory disease (CID) share similar chronicity, symptoms, dependency on the immune system, environmental triggers, and treatments. Overall, we will highlight the similarities between an MPN and CID. We highlight that while MPN is classified as a cancer, its behavior is more aligned to that of a chronic inflammatory disease. We propose that MPN should inhabit a fluid/spectrum between auto-inflammatory disease and cancer.

DISTURBED ASSOCIATION BETWEEN PLACENTAL SODIUM CONTENT AND GLYCOSAMINOGLYCANS IN GESTATIONAL HYPERTENSION BUT NOT IN PRE-ECLAMPSIA

Objective: Glycosaminoglycans (GAGs) facilitate tissue sodium accumulation which plays an important role in regulation of sodium homeostasis, water balance and blood pressure. During pregnancy, GAGs are also highly expressed in placental tissue. We studied placental sodium concentration and GAG content from normotensive and hypertensive pregnancies to explore a link between placental sodium and blood pressure during pregnancy. Design and method: We performed a prospective case-control study in singleton pregnancies with normal blood pressure (nBP, n = 22), gestational hypertension (GH, n = 12) and pre-eclampsia (PE, n = 10). Two full thickness placental biopsies (central [near umbilical cord insertion] and peripheral) were collected after delivery for analysis of placental electrolyte concentration (ICP-OES) and GAG content (UPLC-MS/MS). Linear associations were explored with a linear regression analysis with correction for gestational age, mode of delivery and treatment with antihypertensive drugs. Results: Placental sodium concentration in GH was 10.1% (p = 0.01) lower in central and 9.4% (p = 0.04) lower in peripheral biopsies compared to nBP. Total peripheral heparan sulfate (HS) expression was 32.3% lower in GH compared to nBP (p = 0.04). Also, di-sulfated HS as percentage of total HS was lower in peripheral biopsies of GH compared to nBP (11.0% [IQR 10.0-11.4] vs 12.3% [IQR 11.3-14.5], p = 0.02). In PE, placental GAG and sodium content were not significantly different from nBP. Placental sodium concentration was linearly associated with percentage of di-sulfated HS (Fig A), while in central biopsies it was negatively associated with systolic BP (Fig B). Conclusions: We show that GH is accompanied by lower placental sodium content when compared to pregnancies with normal blood pressure. Also, lower placental sodium content during pregnancy is associated with lower placental GAG content and higher BP. This indicates that placental sodium homeostasis might be involved in chronic maternal blood pressure regulation.

Cardiac iron overload in pediatric oncology and bone marrow transplant survivors.

e22022 Background: Cardiovascular late effects are a leading cause of mortality and morbidity in childhood cancer and Bone Marrow Transplant (BMT) survivors. In patients receiving chronic red blood cell transfusions, excess iron may be deposited in the liver, heart, and pituitary gland. Iron overload cardiomyopathy is characterized as a restrictive physiology with early diastolic dysfunction ultimately progressing to end-stage dilated cardiomyopathy. Iron loading in the heart can also lead to arrhythmias and increase myocardial ischemia reperfusion injury due to increased formation of reactive oxygen species. It is not yet known whether high transfused packed red blood cell (PRBC) volumes in cancer and BMT patients leads to cardiac iron deposition, and whether iron-induced cardiac injury contributes to the known cardiovascular late effects in these patients. Methods: 83 childhood cancer and BMT survivors with elevated serum ferritin levels and subsequent liver Magnetic Resonance (MR) imaging were identified. 18 patients (21.7%) who had liver iron content of &gt; 12mg/g (mean 16.0 ± 7.36 mg/g) also underwent Cardiac MRI (CMR) to determine cardiac iron content. Results: Median transfused blood volume was 393 ml/kg [95% Confidence Interval (CI) 170-780 ml/kg]. All 18 patients had at least one echocardiogram showing normal ventricular ejection fractions [mean 65.1 ± Standard Deviation (SD) 3.53%] and normal shortening fractions (mean 35.4 ± 3.67%). All patients had myocardial iron content within normal ranges (T2* relaxation time mean 35.1 msec ± 7.1 [normal &gt;20 msec], mean ± SD iron content 0.63± 0.2 mg/g dry weight, range 0.5-1.1). There was no association of cardiac iron content with transfused blood volume, anthracycline dose (mg/m2) or liver iron content (Pearson Correlation Coefficients 0.27, 0.29 and 0.89 respectively). Conclusions: Childhood cancer and BMT patients receive multiple PRBC transfusions to treat symptomatic anemia. It is currently unknown whether excess iron deposition in the heart contributes to the cardiac effects of impaired diastolic function and ultimately systolic dysfunction. In this study, 11 of 18 patients (61.1%) with high levels of liver iron had at least 1 other risk factor for the development of future cardiac dysfunction (either anthracycline exposure, radiation to the chest or total body irradiation or both). Larger studies are needed to determine whether oncology patients with high levels of iron deposition in their liver are also at risk for clinically significant cardiac iron loading, and what risk factors may exist for elevated myocardial iron content.