The Vitamin D Metabolite Ratio (VMR) is a Biomarker of Vitamin D Status That is Not Affected by Acute Changes in Vitamin D Binding Protein.

BACKGROUND: 25-hydroxyvitamin D[25(OH)D] may be a poor marker of vitamin D status due to variability in levels of vitamin D binding protein (VDBP). The vitamin D metabolite ratio (VMR) is the ratio of 24,25-dihydroxyvitamin D[24,25(OH)2D3] to 25(OH)D3 and has been postulated to reflect vitamin D sufficiency independent of variability in VDBP. Therapeutic plasma exchange (TPE) is a procedure that removes plasma, including VDBP, and may lower bound vitamin D metabolite concentrations. Effects of TPE on the VMR are unknown. METHODS: We measured 25(OH)D, free 25(OH)D, 1,25-dihydroxyvitamin D[1,25(OH)2D], 24,25(OH)2D3, and VDBP in persons undergoing TPE, before and after treatment. We used paired t-tests to assess changes in these biomarkers during a TPE procedure. RESULTS: Study participants (n = 45) had a mean age of 55 ± 16 years; 67% were female; and 76% were white. Compared to pretreatment concentrations, TPE caused a significant decrease in total VDBP by 65% (95%CI 60,70%), as well as all the vitamin D metabolites-25(OH)D by 66% (60%,74%), free 25(OH)D by 31% (24%,39%), 24,25(OH)2D3 by 66% (55%,78%) and 1,25(OH)2D by 68% (60%,76%). In contrast, there was no significant change in the VMR before and after a single TPE treatment, with an observed mean 7% (-3%, 17%) change in VMR. CONCLUSIONS: Changes in VDBP concentration across TPE parallel changes in 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D3, suggesting that concentrations of these metabolites reflect underlying VDBP concentrations. The VMR is stable across a TPE session despite a 65% reduction in VDBP. These findings suggest that the VMR is a marker of vitamin D status independent of VDBP levels.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

Therapeutic plasma exchange in the intensive care unit: Rationale, special considerations, and techniques for combined circuits.

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique with proven efficacy in a variety of conditions, including in the intensive care setting. It is not uncommon for a critically ill patient to require more than one extracorporeal procedure in addition to TPE. This review focuses on the combination of TPE with other extracorporeal circuits in a critical care setting via a single vascular access (either in-series, parallel, or a hybrid mode) which is often referred to as performing procedures "in tandem." Authors performed literature review via pubmed.gov using search terms: plasma exchange, plasmapheresis, apheresis, tandem circuits, combined circuits, critical care, ICU, CRRT, hemodialysis, and ECMO. Thirty-eight English-language, peer-reviewed papers were appraised that satisfied the content of this review on techniques for combining circuits with plasma exchange, as well as describing the advantages of tandem procedures and potential complications that can arise. Performing these procedures simultaneously can be advantageous in reducing total procedure and staffing time, avoiding placement of additional central lines, reducing overall need for anticoagulation, and limiting multiple blood primes in certain populations. However, the described combined circuits are complex, associated with higher complications, and require a skilled team to understand and mitigate the potential complications associated with these combined procedures.

Comprehensive guide to managing a chronic automated red cell exchange program in sickle cell disease.

Sickle cell disease (SCD) is associated with significant morbidity and mortality, and limits both the quality and quantity of life. Transfusion therapy, specifically automated red cell exchange (aRCE), plays a key role in management of SCD and is beneficial for certain indications in the chronic, outpatient setting. The approach to maintain a successful chronic aRCE program for SCD is multifaceted. This review will highlight important considerations including indications for aRCE, patient selection, transfusion medicine pearls, vascular access needs, complications of therapy, aRCE prescription, and therapy optimization. Moreover, the importance of a multidisciplinary approach with frequent communication between the services involved cannot be overstated. Ultimately, the underlying goal of a chronic RCE program is to improve the quality of life and longevity of patients with SCD.

Extracorporeal photopheresis for the treatment of chronic graft versus host disease.

OBJECTIVES: Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP). METHODS: This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed. RESULTS: Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment. DISCUSSION: We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.

Therapeutic Plasma Exchange in the Critically Ill Patient: Technology and Indications.

Therapeutic plasma exchange (TPE) is frequently the most common Apheresis Medicine technique used for extracorporeal therapy of a wide variety of renal, neurological, hematological, and other clinical indications. Many of these clinical indications require intensive care during critical illness. Conventional TPE uses one of two main technical methods to achieve the goal of removing known disease mediators from the plasma: using centrifugal forces to separate and remove components of blood, or a membrane filtration method that separates plasma from the cellular components of blood. The following review discusses the basic principles of TPE, the technological aspects, and relevant clinical scenarios encountered in the intensive care unit, including relevant guidelines and recommendations from the American Society for Apheresis.

Adoptive transfer of neoantigen-specific T-cell therapy is feasible in older patients with higher-risk myelodysplastic syndrome.

BACKGROUND: Myelodysplastic syndromes (MDS) represent the most common type of acquired bone marrow failure in adults and is characterized by ineffective maturation of myeloid precursor cells and peripheral cytopenias associated with higher rates of infection, bleeding and transfusion dependence. In higher-risk patients with MDS who relapse or do not respond after standard hypomethylating agent (HMA) therapy, the 2-year survival rate is 15%. METHODS: Here the authors report the feasibility and safety of a novel experimental T-cell therapy called personalized adoptive cell therapy, which selects, immunizes and expands T cells against MDS-specific mutations and is targeted to patient-specific tumor cell neoantigens. Somatic mutations serve as the pathogenic drivers of cancer, including MDS, as these transformative genetic mutations may generate novel immunogenic proteins (i.e., neopeptides and possible neoantigens) that may be targeted therapeutically. RESULTS: The authors demonstrate that the adaptive immune system can be trained ex vivo to recognize neopeptides as neoantigens and that the infusion of culture-expanded, neoantigen-immunized autologous T cells has been feasible and safe in the three patients treated to date. DISCUSSION: The authors report on early results from their first-in-human phase 1 clinical trial that aims to assess the safety and tolerability of this novel form of adoptive T-cell immunotherapy for HMA-refractory patients with higher-risk MDS.

Update to the ASFA guidelines on the use of therapeutic apheresis in ANCA-associated vasculitis.

Since 1986, the American Society for Apheresis (ASFA) has published practice guidelines on the use of therapeutic apheresis in the Journal of Clinical Apheresis (JCA) Special Issue. Since 2007, updated guidelines have been published every 3 years to reflect current evidence based apheresis practice with the most recent edition (8th) published in 2019. With each edition, the guidelines are reviewed and updated based on any newly published literature since the last review. The PEXIVAS study, an international, randomized controlled trial comparing therapeutic plasma exchange (TPE) vs no TPE and standard vs reduced dose steroid regimen on the primary composite outcome of end stage renal disease or death in patients with ANCA-associated vasculitis (AAV), was published in February 2020. This study represents the largest study on the role of therapeutic apheresis in AAV published to date and prompted the JCA Special Issue Writing Committee to reassess the current AAV fact sheet for updates based on this newly available evidence. This interim fact sheet summarizes current ASFA recommendations for the evidence-based use of therapeutic apheresis in AAV and supersedes the recommendations published in the 2019 guidelines.

Peripheral vascular access for therapeutic plasma exchange: A practical approach to increased utilization and selecting the most appropriate vascular access.

BACKGROUND: Therapeutic plasma exchange (TPE) is used in the treatment of many diseases. At present, peripheral vascular access (PVA) is an underutilized method of vascular access in TPE. It should be considered more frequently due its relatively low risk for adverse events, particularly infections. METHODS: The Advancing Vascular Access in Apheresis Working Group met in December 2017 for an extensive review and discussion of vascular access for TPE and developed a "road map" providing detailed information regarding clinical situations in which PVA-based TPE would and would not be appropriate. RESULTS: The road map is consistent with current recommendations that PVA should be used in combination with TPE whenever possible. PVA should be considered for patients who do not have existing central lines and who are stable. The patient should have peripheral veins that will allow for adequate treatment and must be able to comply with the process of achieving and maintaining peripheral access. There should be expert clinical assessment of veins, and this evaluation may include ultrasound and/or near infrared evaluation. Conditions that would prompt a switch from PVA to an alternate method of venous access include loss of venous access, patient preference, or development of a requirement for very frequent treatment over a long period of time. CONCLUSIONS: While PVA is not suitable for all patients requiring TPE, it has significant safety advantages over other approaches and should be employed whenever possible.

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.

OBJECTIVE: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS). METHODS: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a). RESULTS: Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised Vpeak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a). CONCLUSION: ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death. TRIAL REGISTRATION: NCT00800800.

Prophylactic red blood cell exchange for ABO-mismatched hematopoietic progenitor cell transplants.

BACKGROUND: To enhance donor availability, almost half of hematopoietic progenitor cell transplants (HPCTs) cross ABO blood type boundaries. ABO-incompatible HPCTs are well tolerated; however, there is an increased risk of delayed hemolysis in patients with minor and bidirectional ABO mismatches. Delayed hemolysis generally occurs 1 to 2 weeks after HPCT and is related to production of alloantibodies directed against recipient ABO red blood cell (RBC) antigens by passenger donor lymphocytes. One previous study has suggested that prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCT reduces the risks of severe immune hemolysis, but this recommendation is controversial. STUDY DESIGN AND METHODS: Herein we describe our experience using prophylactic RBC exchange in patients with minor and bidirectional ABO-mismatched HPCTs who were deemed to be at high risk for immune hemolysis. We compare the group of patients that received prophylactic RBC exchange with a historical cohort of ABO-mismatched patients who underwent HPCT without prophylactic RBC exchange. RESULTS: Our study suggests that prophylactic RBC exchange in minor and bidirectional ABO-mismatched HPCT does not reduce severe immune hemolysis, nor does it improve 1-year survival, the number of RBC units transfused after transplant, or length of hospitalization after HPCT. CONCLUSION: This study failed to identify a clear role for selected prophylactic RBC exchange in patients who were deemed at risk for severe post-HPCT immune hemolysis.

The selective therapeutic apheresis procedures.

Selective apheresis procedures have been developed to target specific molecules, antibodies, or cellular elements in a variety of diseases. The advantage of the selective apheresis procedures over conventional therapeutic plasmapheresis is preservation of other essential plasma components such as albumin, immunoglobulins, and clotting factors. These procedures are more commonly employed in Europe and Japan, and few are available in the USA. Apheresis procedures discussed in this review include the various technologies available for low-density lipoprotein (LDL) apheresis, double filtration plasmapheresis (DFPP), cryofiltration, immunoadsorption procedures, adsorption resins that process plasma, extracorporeal photopheresis, and leukocyte apheresis.

Therapeutic apheresis for renal disorders.

This review summarizes the clinical evidence and practical details for the use of plasmapheresis and other apheresis modalities for each indication in nephrology. Updated information on the molecular biology and immunology of each renal disease is discussed in relation to the rationale for apheresis therapy and its place amid other available treatments. Autoantibody-mediated diseases, such as anti-GBM (anti-glomerular basement membrane) glomerulonephritis (GN), ANCA (antineutrophil cytoplasmic antibody)-related GN and the antibody-mediated type of TTP (thrombotic thrombocytopenic purpura), and alloantibody-mediated diseases such as kidney transplant sensitization and humoral rejection, can be treated by various plasmapheresis methods. These include standard plasmapheresis with a replacement volume, or plasmapheresis with online plasma purification using adsorption columns or secondary filtration. However, it should be noted that the pathogenic molecules implicated in FSGS (focal segmental glomerulosclerosis), myeloma cast nephropathy, and perhaps other diseases are too small to be removed by most online purification methods. A great majority of controlled trials and series on which evidence-based treatment recommendations are made were performed using centrifugal plasmapheresis; it is presumed that membrane-separation plasmapheresis is equally efficacious. For some rarer diseases, such as MPGN (membranoproliferative GN) type 2 with factor H abnormalities or C3Nef (C3 nephritic factor) autoantibodies, there are only a few case reports, but enough scientific understanding to warrant a trial of plasmapheresis in severe cases. Photopheresis, which is effective for cell-mediated rejection in heart and lung transplantation, has not yet found a place in the routine treatment of kidney transplant rejection.

Role of the USF1 transcription factor in diabetic kidney disease.

The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-ß1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/-), and homozygous (USF1 -/-) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 -/- diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-ß1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 -/- diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-ß1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.

Human dopamine ß-hydroxylase promoter variant alters transcription in chromaffin cells, enzyme secretion, and blood pressure.

BACKGROUND: Dopamine ß-hydroxylase (DBH) plays an indispensable role in catecholamine synthesis by converting dopamine into norepinephrine. Here, we characterized a DBH promoter polymorphism (C-2073T; rs1989787; minor allele frequency ~16%) that influences not only gene transcription but also enzyme secretion and blood pressure (BP) in vivo. METHODS: Plasma DBH activity was measured spectrophotometrically. DBH genetic effects on BP were tested in subjects with the most extreme BP values in a large primary care population. Functional effects of promoter variants were studied by site-directed mutagenesis in DBH promoter haplotype/luciferase reporter plasmids transfected into chromaffin cells. Sequence motifs were predicted from position weight matrices, and endogenous transcription factor binding was probed by Chromatin ImmunoPrecipitation (ChIP). RESULTS: The T-allele of common promoter variant C-2073T was contained in a promoter haplotype that associated with plasma DBH activity, a trait also predicted by that variant itself. Promoter haplotypes including C-2073T predicted BP in the population, and the effect was also referable to C-2073T itself. Computationally, C-2073 disrupted a predicted match for transcription factor c-FOS. Site-directed mutagenesis at C-2073T altered not only basal promoter activity, but also transactivation by c-FOS, as well as the chromaffin cell secretory stimuli nicotine or pituitary adenylate cyclase-activating polypeptide (PACAP). Endogenous c-FOS bound to the motif in chromatin. CONCLUSIONS: These results suggest that DBH promoter variant C-2073T is functional in vivo: this promoter variant seems to initiate a cascade of transcriptional and biochemical changes including augmented DBH secretion, eventuating in elevation of basal BP, and hence cardiovascular risk. The observations suggest new strategies for probing the pathophysiology, risk, and treatment of hypertension.

Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.

RATIONALE: Dopamine beta-hydroxylase (DBH) plays an essential role in catecholamine synthesis by converting dopamine into norepinephrine. Here we systematically investigated DBH polymorphisms associated with enzymatic activity as well as autonomic and blood pressure (BP)/disease phenotypes in vivo. METHODS AND RESULTS: Seventy genetic variants were discovered at the locus; across ethnicities, much of the promoter was spanned by a 5' haplotype block, with a larger block spanning the promoter in whites than blacks. DBH secretion was predicted by genetic variants in the DBH promoter, rather than the amino acid coding region. The C allele of common promoter variant C-970T increased plasma DBH activity, epinephrine excretion, the heritable change in BP during environmental stress in twin pairs, and also predicted higher basal BP in three independent populations. Mutagenesis and expression studies with isolated/transfected DBH promoter/luciferase reporters in chromaffin cells indicated that variant C-970T was functional. C-970T partially disrupted consensus transcriptional motifs for n-MYC and MEF-2, and this variant affected not only basal expression, but also the response to exogenous/co-transfected n-MYC or MEF-2; during chromatin immunoprecipitation, these two endogenous factors interacted with the motif. CONCLUSIONS: These results suggest that common DBH promoter variant C-970T plays a role in the pathogenesis of human essential hypertension: common genetic variation in the DBH promoter region seems to initiate a cascade of biochemical and physiological changes eventuating in alterations of basal BP. These observations suggest new molecular strategies for probing the pathophysiology, risk, and rational treatment of systemic hypertension.

Transcription factors in the pathogenesis of diabetic nephropathy.

Approximately a third of patients with diabetes develop diabetic kidney disease, and diabetes is the leading cause of end-stage renal disease in most developed countries. Hyperglycaemia is known to activate genes that ultimately lead to extracellular matrix accumulation, the hallmark of diabetic nephropathy. Several transcription factors have been implicated in glucose-mediated expression of genes involved in diabetic nephropathy. This review focuses on the transcription factors upstream stimulatory factors 1 and 2 (USF1 and 2), activator protein 1 (AP-1), nuclear factor (NF)-kappaB, cAMP-response-element-binding protein (CREB), nuclear factor of activated T cells (NFAT), and stimulating protein 1 (Sp1). In response to high glucose, several of these transcription factors regulate the gene encoding the profibrotic cytokine transforming growth factor beta, as well as genes for a range of other proteins implicated in inflammation and extracellular matrix turnover, including thrombospondin 1, the chemokine CCL2, osteopontin, fibronectin, decorin, plasminogen activator inhibitor 1 and aldose reductase. Identifying the molecular mechanisms by which diabetic nephropathy occurs has important clinical implications as therapies can then be tailored to target those at risk. Strategies to specifically target transcription factor activation and function may be employed to halt the progression of diabetic nephropathy.

United States male students who heavily consume alcohol in Mexico are at greater risk of travelers' diarrhea than their female counterparts.

BACKGROUND: The relationship between alcohol consumption and travelers' diarrhea has not been well studied. METHODS: A cohort of US college students (n=171), who attended 2001 or 2002 summer educational sessions in Guadalajara, Mexico, were followed prospectively to examine the frequency of alcohol consumption and the development of travelers' diarrhea. RESULTS: More male students reported consuming >5 drinks/day of drinking while in Mexico compared to female students (p <.001). Males who consumed >5 drinks/day of drinking while in Mexico were more likely to develop diarrhea than their female counterparts who drank the same amount (79% vs. 46%; p=.035). No association was found between the development of travelers' diarrhea and the consumption of fewer than 5 drinks per day in Mexico. Non-drinkers accounted for only 8% of the population and had a relatively high attack rate of diarrhea (69%). CONCLUSIONS: This study suggests that males who drink heavily are at high risk for developing travelers' diarrhea and may be a group of people to target for education about the moderation of use of alcohol while traveling. Nondrinkers also deserve further study in larger numbers to confirm an apparently high attack rate of diarrhea and to explore what risk factors might be involved.