Use Of Repo Research Articles

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis

AbstractUp to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

Development and validation of a method for analyzing the sialylated glycopeptides of recombinant erythropoietin in urine using LC–HRMS

Erythropoietin (EPO) is a glycoprotein hormone that stimulates red blood cell production. It is produced naturally in the body and is used to treat patients with anemia. Recombinant EPO (rEPO) is used illicitly in sports to improve performance by increasing the blood’s capacity to carry oxygen. The World Anti-Doping Agency has therefore prohibited the use of rEPO. In this study, we developed a bottom-up mass spectrometric method for profiling the site-specific N-glycosylation of rEPO. We revealed that intact glycopeptides have a site-specific tetra-sialic glycan structure. Using this structure as an exogenous marker, we developed a method for use in doping studies. The profiling of rEPO N-glycopeptides revealed the presence of tri- and tetra-sialylated N-glycopeptides. By selecting a peptide with a tetra-sialic acid structure as the target, its limit of detection (LOD) was estimated to be < 500 pg/mL. Furthermore, we confirmed the detection of the target rEPO glycopeptide using three other rEPO products. We additionally validated the linearity, carryover, selectivity, matrix effect, LOD, and intraday precision of this method. To the best of our knowledge, this is the first report of a doping analysis using liquid chromatography/mass spectrometry-based detection of the rEPO glycopeptide with a tetra-sialic acid structure in human urine samples.

Deconstructing the use of REPO 105 and Repo 108 Transactions Under SFAS 140: the Case of Lehman Brothers Holding Inc. and the Liability of Ernst &amp; Young

Prior to filing for bankruptcy in 2008, Lehman Brothers Holding Inc., [LBHI] relied upon select repurchase agreements denominated “Repo 105” and “Repo 108” for the purpose of re-casting its balance sheet to meet net leverage ratios required by money markets. SFAS 140, as then existing without the 2011 amendment, provided a mechanism to treat “ordinary borrowings” as “asset sales”. LBHI used SFAS 140 to justify Repo 105 and Repo 108 transactions to engineer its balance sheet. The accounting treatment resulted in the publication of misleading quarterly and annual Financial Statements relied upon by external users to make investment decisions. In 2011 and 2012, the Southern District of New York issued opinions in the consolidated LBHI litigation. The finding that LBHI correctly applied the criteria of SFAS 140 to justify “borrowings” as “asset sales” under Repo 105 and Repo 108 is fundamentally flawed. During the period 2000 until 2008, Ernst &amp; Young [E&amp;Y] served as the outside auditor of LBHI. Legal principles governing the obligations of auditors support a finding that E&amp;Y committed professional malpractice by issuing unqualified audit opinions knowing that LBHI failed to disclose its liabilities to repurchase transferred securities under Repo 105 and Repo 108 transactions. Economic analysis of non-contractual obligations [tort] supports a reformulation of the legal standard governing auditor liability to external users of audited financial statements containing materially misleading information. The reformulated standard allocates incentives to take precautions both to the audit firm and to the external user to achieve an efficient allocation of the cost of harm ensuing from defective information products.

Do higher capital standards always reduce bank risk? The impact of the Basel leverage ratio on the U.S. triparty repo market

Abstract While simpler than risk-based capital requirements, the leverage ratio may encourage bank risk-taking. This paper examines the activity of broker-dealers affiliated with bank holding companies (BHCs) and broker-dealers not affiliated with BHCs in the repurchase agreement (repo) market to test whether this may be occurring. Using data on the triparty repo market, the paper arrives at three findings. First, following the 2012 introduction of the supplementary leverage ratio (SLR), broker-dealer affiliates of BHCs decreased their repo borrowing but increased their use of repo backed by more price-volatile collateral. Second, the paper finds that regardless of whether a U.S. BHC-affiliated broker-dealer parent is above or below the SLR requirement, the announcement of the SLR rule has disincentivized those dealers affiliated with BHCs from borrowing in triparty repo. Finally, the paper finds an increase in the number of active nonbank-affiliated dealers in certain asset classes of triparty repo since the 2012 introduction of the supplementary leverage ratio. This illustrates how regulation can have competitive effects on the financial sector and may result in activities shifting among financial firms.

Supplementary Leverage Ratio and Repo Supply

While simpler than risk-based capital requirements, the leverage ratio may encourage bank risk-taking. This paper examines the activity of broker-dealers affiliated with bank holding companies (BHCs) and broker-dealers not affiliated with BHCs in the repurchase agreement (repo) market to test whether this may be occurring. Using data on the triparty repo market, the paper arrives at three findings. First, following the 2012 introduction of the supplementary leverage ratio (SLR), broker-dealer affiliates of BHCs decreased their repo borrowing but increased their use of repo backed by more price-volatile collateral. Second, the paper finds that regardless of whether a U.S. BHC-affiliated broker-dealer parent is above or below the SLR requirement, the announcement of the SLR rule has disincentivized those dealers affiliated with BHCs from borrowing in triparty repo. Finally, the paper finds an increase in the number of active nonbank-affiliated dealers in certain asset classes of triparty repo since the 2012 introduction of the supplementary leverage ratio. This illustrates how regulation can have competitive effects on the financial sector and may result in activities shifting among financial firms.

Do Higher Capital Standards Always Reduce Bank Risk? The Impact of the Basel Leverage Ratio on the U.S. Triparty Repo Market

While simpler than risk-based capital requirements, the leverage ratio may encourage bank risk-taking. This paper examines the activity of broker-dealers affiliated with bank holding companies (BHCs) and broker-dealers not affiliated with BHCs in the repurchase agreement (repo) market to test whether this may be occurring. Using data on the triparty repo market, the paper arrives at three findings. First, following the 2012 introduction of the supplementary leverage ratio (SLR), broker-dealer affiliates of BHCs decreased their repo borrowing but increased their use of repo backed by more price-volatile collateral. Second, the paper finds that regardless of whether a U.S. BHC-affiliated broker-dealer parent is above or below the SLR requirement, the announcement of the SLR rule has disincentivized those dealers affiliated with BHCs from borrowing in triparty repo. Finally, the paper finds an increase in the number of active nonbank-affiliated dealers in certain asset classes of triparty repo since the 2012 introduction of the supplementary leverage ratio. This suggests risks may be shifting outside the banking sector.

Are high cumulative doses of erythropoietin neuroprotective in preterm infants? A two year follow-up report.

BackgroundPreterm infants are at risk for neurodevelopmental sequelae even in absence of major cerebral lesions. The hypothesis that Human Recombinant Erythropoietin (rEpo) could improve the neurodevelopmental outcome in risk neonates has raised the highest interest in recent years.MethodsA group of preterm neonates born at a gestational age ≤ 30 weeks and free from major cerebral lesions or major visual impairment, were included in the study if they had a complete neurologic evaluation for at least 24 months of postmenstrual age. They were assigned to group I in the case they had been treated with rEpo or group II if untreated. The aim was to evaluate whether rEpo, given at the high cumulative doses utilized for hematologic purposes, is able to improve the neurodevelopmental outcome in preterm infants born at a gestational age ≤ 30 weeks. A group of 104 preterm neonates were studied: 59 neonates who received rEpo for 6.9 ± 2.4 weeks at a median cumulative dose of 6300 UI/Kg (6337 ± 2434 UI/Kg), starting at a median age of 4 days and 45 neonates who were born in the period preceding the routine use of rEpo. The neurodevelopmental quotient at 24 month postmenstrual age was assessed utilizing the Griffiths’ Mental Developmental Scales.ResultsOur results failed to show any difference in the Developmental Quotient at 24 month. Bronchopulmonary dysplasia, minor intraventricular hemorrhages and blood transfusions were the clinical features significantly related to the Developmental Quotient.ConclusionsOur results do not support the hypothesis that rEpo, administered with the schedule utilized for hematologic purposes, improve the neurodevelopmental outcome of preterm neonates, at least those preterm infants free from major impairments.

A Macro View of Shadow Banking: Levered Betas and Wholesale Funding in the Context of Secular Stagnation

The literature to date on shadow banking has focused on the wholesale funding and private money creation aspects of shadow banking. This paper draws attention to those aspects of shadow banking that involve levered betas and the provision of excess returns over fixed income benchmarks. Broadening the discussion from net to gross repo, the paper highlights the role of broker-dealers as matched-book money dealers that stand between cash pools in search for safety, and various kinds of leveraged bond portfolios across the asset management complex in search for yield. This broader perspective shows deep linkages between shadow banking and asset management, including not only hedge funds but also what are assumed to be unleveraged, “long-only” mutual funds. Whereas cash pools’ problem is the structural shortage of safe, short-term, public assets (a shortage of public money), real money investors’ problem is structural asset-liability mismatches driven by the secular decline of yields on safe, long-term, public assets relative to “sticky” return targets/expectations. The secular rise of levered betas (that is, the secular increase in the use of both cash and synthetic forms of leverage in bond portfolios) has been asset managers’ way of helping real money investors bridge structural asset-liability mismatches through the provision of “equity-like returns with bond-like volatility”. To that end, the use of repo and securities lending by bond portfolios across the asset management complex exceeds the use of repo by banks and broker-dealers to fund their own bond portfolios and inventories, respectively. The “sucking sound” of asset-liability mismatches driving the secular rise of levered betas, financed through the absorption of cash pools’ money demand – “the leveraged bids glut” – is a powerful alternative to Bernanke’s “global savings glut” and Shin’s “global banking glut” hypotheses for the decline in the Treasury term premium and the compression of mortgage and other spreads before the 2008 crisis. Crowding out private money by boosting the volume overnight Federal Reserve RRPs or of U.S. Treasury bills would fix cash pools’ problems, but deepen real money investors’ asset-liability mismatches. More even-handed policies include “Dealer of Last Resort” and fixing imbalances in present incomes and future (pension) promises – a joint application of these policies would complement the G20/FSB reform agenda to date to find a better balance between the economic benefits of deep and liquid markets, and the financial stability risks inherent in the (gross) balance sheet intensity of the provision of deep and liquid markets.

Erythropoietin use in CKD patients with cancer: to tread with caution?

Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation of the erythroid lineage. Recombinant Epo (rEpo) is frequently used in the prevention and treatment of anemia of chronic kidney disease (CKD) and in the treatment of anemia associated with cancer. The expression of the Epo receptor (EpoR) in certain cancer cells has raised the possibility that exogenous rEpo may have direct effects on tumor cells with potential for stimulation of proliferation and resistance to chemotherapy and possibly metastasis. With recent clinical trials reporting negative outcomes with rEpo in the treatment of cancer-related anemia, with increased mortality in those who received rEpo, it has become necessary for nephrologists to analyze and review the effect of use of rEpo in treatment of anemia of CKD in patients who may have current or previously treated malignancy. It is known that CKD patients have an increased prevalence of certain malignancies (Wong G et al. Association of CKD and cancer risk in older people. J Am Soc Nephrol. 2009;20(6):1341-1350). If a CKD patient develops cancer or has a previous history of cancer, there is a dilemma which faces the treating nephrologist with respect to the use of rEpo in this situation. So far this issue has been addressed infrequently in the nephrology literature, and the guidelines are unclear. This review describes Epo and EpoR biology, reviews use of rEpo for treatment of cancer-related anemia and makes a case to the nephrology community for the careful use of rEpo in CKD patients with cancer.

Urinary Erythropoietin Concentrations after Early Short-Term Infusion of High-Dose Recombinant Epo for Neuroprotection in Preterm Neonates

Background: High-dose recombinant human erythropoietin (rEpo) has first been administered in clinical trials for neuroprotection in very preterm neonates at high risk of brain injury and in (near-) term neonates with hypoxic-ischemic encephalopathy. However, recent trials in adults raised concerns about the safety of high-dose rEpo for neuro- and cardioprotection. Objectives: To evaluate the putative accumulation or renal leakage of Epo as a function of developmental stage after repetitive early short-term infusion of high-dose rEpo (3 × 3,000 U/kg within 42 h after birth; NCT00413946) for neuroprotection in very preterm infants. Methods: Epo concentrations were measured using the ELISA technique in the first two consecutive urine specimens after each rEpo infusion. Results: Renal Epo excretion was significantly higher in preterm infants with gestational ages <29 weeks than in more mature infants and reached up to 23% of the administered rEpo within 8 h after each infusion. The urinary Epo concentration did not increase after three repetitive infusions of high-dose rEpo. The ratio of urinary Epo to total protein concentrations was the same in infants with gestational ages <29 weeks and in those with gestational ages ≥29 weeks. Conclusions: Our data suggest that the higher renal Epo excretion in more immature infants may be attributed to a higher glomerular filtration leakage due to the lower maturation of the kidneys and argue against saturation kinetics after multiple doses of 3,000 U/kg rEpo. This information should be considered in future trials on the use of rEpo for neuroprotection in neonates.

Understanding the Presence and Function of Erythropoietin Receptors on Cancer Cells

The expression of erythropoietin (EPO) and the EPO receptor (EPOR) have been recognized in a variety of human cancers, including breast, prostate, colon, ovary, uterine, cervical, glioblastoma, and head and neck squamous cell carcinoma (HNSCC). A growing number of studies demonstrate functional EPO/EPOR signaling events in cancer cells that contribute to disease progression. These findings have been difficult to reconcile with the current clinical practice of treating or preventing anemia in cancer patients with recombinant EPO (rEPO). Anemia is a wellrecognized negative prognostic factor for cancer patients treated with radiation therapy and chemotherapy. EPO has been an appealing alternative to blood transfusion for these patients to increase hemoglobin levels and to improve quality of life by decreasing fatigue. In addition to the identification of EPO and EPOR on cancer cells, a number of recent clinical trials have heightened concerns regarding the potential effects of EPO on cancer progression. The Breast Cancer Erythropoietin Trial (BEST) examined rEPO treatment in nonanemic, metastatic breast cancer patients. This study was terminated early when a higher mortality rate was observed among the rEPO treatment group. In a previous report, Henke and colleagues performed a randomized, double-blind, multi-institutional trial comparing anemic head and neck cancer patients receiving radiation therapy with or without rEPO treatment. These authors reported that rEPO treatment corrected hemoglobin levels, but was associated with decreased locoregional cancer control and patient survival. Although there was some concern regarding study design and methodology, that study and the BEST trial raised legitimate concerns regarding current recommendations for the routine use of rEPO in cancer patients. In the study reported in this issue of the Journal of Clinical Oncology, Henke and colleagues examined the expression of EPOR in a subset of 154 patients from a single clinical center derived from their original multicenter population (351 patients). Expression of EPOR was assessed by immunohistochemistry and reviewed by two independent, blinded pathologists. Within their patient population, 104 patients (67.5%) demonstrated EPOR expression. Their findings demonstrated that decreased locoregional progression-free survival due to treatment with rEPO was significant only in patients with HNSCC that expressed EPOR. rEPO treatment did not impact outcome in patients who had tumors that did not express EPOR. Although originally identified as a cytokine that promoted RBC progenitor survival and differentiation, the role of EPO in normal cells has been dramatically redefined within the past decade. EPO/EPOR signaling regulates physiologic cyclic uterine angiogenesis. In the CNS, EPO is produced by astrocytes and EPOR is expressed by neurons. EPO appears to have a neuroprotective effect against ischemic injury. Similarly, rEPO protects cardiac myocytes against ischemic injury in preclinical studies. The ability of cancer cells to subvert the EPO/EPOR system should not be surprising. A significant number of oncogenes represent signaling molecules that have been appropriated by cancer cells to facilitate proliferation and survival. The overexpression of the epidermal growth factor receptor in HNSCC is crucial for growth, invasion, metastasis, and angiogenesis. A number of preclinical studies have demonstrated EPO-mediated activation of the mitogenactivated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–Akt, JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription), and nuclear factor-kappa B (NF B) signaling pathways in a variety of human cancers. Activation of these signaling cascades has been associated with cellular functions that promote tumor progression. rEPO appears to induce cancer cell proliferation and inhibit apoptosis. In addition, EPO stimulates not only chemotaxis of endothelial cells, but also migration and invasion of breast cancer and HNSCC cells. Pretreatment with rEPO protects some cancer cell lines from the cytotoxic effects of the chemotherapeutic agent, cisplatin. Thus, EPO/EPOR signaling appears to contribute to a wide variety of tumor-promoting functions in different cancer types. The contribution of the EPO/EPOR signaling axis to cancer progression is not completely straightforward. The influence of EPO/EPOR on different cancer types appears to be quite variable and remains incompletely understood. A number of different tumor cell lines do not demonstrate any proliferation response to rEPO. Similarly, certain cancer types undergo increased apoptosis or are more sensitive to fluorouracil treatment. Clearly, the complex biology of EPO/EPOR signaling in normal and cancer cells requires continued research. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 29 OCTOBER 1

Efficacy of Two Different Dosage Schedules for Administering Recombinant Human Erythropoietin (r-EPO) to Very Low Birth Weight (VLBW) Infants † 1379

Introduction:Although r-EPO has been effective in reducing transfusions in VLBW infants, effective dosage schedules have varied in both dose and frequency. To understand the effect of dose frequency, we compared absolute reticulocytes (abs-Retic) between 2 and 5 times/week dosage using the same r-EPO weekly dose, 500U/kg. Study Design: 80 VLBW infants were stratified into <28 weeks and 28-30 weeks gestational age groups and randomized to either 2 or 5 doses/week; 72 completed 4 weeks and 30(<28wks) completed 8 weeks of study. The primary outcome variable was abs-Retics at 4 weeks in all infants, and at 8 weeks in those <28 wks. To further estimate the effect of dose, secondary outcome variables were examined. These were hematocrits, transfusions, iatrogenic blood losses, and infections. Multiple regression analysis was used to evaluate the effect of dose frequency on secondary outcome variables. Results: By 4 weeks, abs-Retics were 27% higher and by 8 weeks 44% higher in the infants given r-EPO 5 times a week (p=0.046 and p=0.03)(see Table). Hematocrits and transfusions per infant were not different between the groups. 79% of the variance in the amount transfused could be accounted for by iatrogenic blood loss, and the latter primarily associated with days ventilated (65%) and days of antibiotics (3%). Episodes of sepsis and necrotizing enterocolitis were significantly associated with decreased abs-Retics and increased transfusions. Conclusions: (1) More frequent administration of r-EPO produced a better response in erythropoiesis using the same weekly dose. (2) The effect of the increased erythropoiesis on transfusions was overshadowed by the impact of iatrogenic blood losses on transfusions during mechanical ventilation and evaluation for sepsis.Speculation: The most effective use of r-EPO in VLBW infants may be to provide more frequent dosage during mechanical ventilation along with strategies to reduce iatrogenic blood losses, and to adjust to less frequent dosage as iatrogenic blood losses decrease.