Browsing by Subject "anemia"
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Item A Comparison of the Safety and Efficacy of HX575 (Epoetin Alfa Proposed Biosimilar) with Epoetin Alfa in Patients with End-Stage Renal Disease(Karger, 2017-11) Weir, M. R.; Pergola, P. E.; Agarwal, Rajiv; Fink, J.; Kopyt, N.; Singh, A.; Kumar, J.; Schmitt, S.; Schaffar, G.; Rudy, A.; McKay, J.; Kanceva, R.; Medicine, School of MedicineBackground: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia. Methods: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28). Results: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was –0.093 g/dL, with 90% CI (–0.23 to 0.04) entirely within the pre-specified equivalence limits (–0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies. Conclusions: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.Item Early Treatment of Acetabular Fractures via an Anterior Approach Increases Blood Loss but not Packed Red Blood Cell Transfusion(Wolters Kluwer, 2024-01) Mullis, Brian H.; Chang, Joshua H.; Shah, Nihar; Sabbagh , Ramsey S.; Yu, Qing; Archdeacon, Michael T.; Sagi, H. Claude; Natoli, Roman M.; Orthopaedic Surgery, School of MedicineOBJECTIVE: The objective of this study was to determine whether time from hospital admission to surgery for acetabular fractures using an anterior intrapelvic (AIP) approach affected blood loss. METHODS: Design: Retrospective review. Setting: Three level 1 trauma centers at 2 academic institutions. Patient Selection Criteria: Adult (18 years or older) patients with no pre-existing coagulopathy treated for an acetabular fracture via an AIP approach. Excluded were those with other significant same day procedures (irrigation and debridement and external fixation were the only other allowed procedures). Outcome Measures and Comparisons: Multiple methods for evaluating blood loss were investigated, including estimated blood loss (EBL), calculated blood loss (CBL) by Gross and Hgb balance methods, and packed red blood cell (PRBC) transfusion requirement. Outcomes were evaluated based on time to surgery. RESULTS: 195 patients were studied. On continuous linear analysis, increasing time from admission to surgery was significantly associated with decreasing CBL at 24 hours (−1.45 mL per hour by Gross method, P = 0.003; −0.440 g of Hgb per hour by Hgb balance method, P = 0.003) and 3 days (−1.69 mL per hour by Gross method, P = 0.013; −0.497 g of Hgb per hour by Hgb balance method, P = 0.010) postoperative, but not EBL or PRBC transfusion. Using 48 hours from admission to surgery to define early versus delayed surgery, CBL was significantly greater in the early group compared to the delayed group (453 [IQR 277–733] mL early versus 364 [IQR 160–661] delayed by Gross method, P = 0.017; 165 [IQR 99–249] g of Hgb early versus 143 [IQR 55–238] g Hgb delayed by Hgb balance method, P = 0.035), but not EBL or PRBC transfusion. In addition, in multivariate linear regression, neither giving tranexamic acid nor administering prophylactic anticoagulation for venous thromboembolism on the morning of surgery affected blood loss at 24 hours or 3 days postoperative (P > 0.05). CONCLUSION: There was higher blood loss with early surgery using an AIP approach, but early surgery did not affect PRBC transfusion and may not be clinically relevant. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.Item Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow(Ferrata Storti Foundation, 2017-11) Clinkenbeard, Erica L.; Hanudel, Mark R.; Stayrook, Keith R.; Appaiah, Hitesh Nidumanda; Farrow, Emily G.; Cass, Taryn A.; Summers, Lelia J.; Ip, Colin S.; Hum, Julia M.; Thomas, Joseph C.; Ivan, Mircea; Richine, Briana M.; Chan, Rebecca J.; Clemens, Thomas L.; Schipani, Ernestina; Sabbagh, Yves; Xu, Linlin; Srour, Edward F.; Alvarez, Marta B.; Kacena, Melissa A.; Salusky, Isidro B.; Ganz, Tomas; Nemeth, Elizabeta; White, Kenneth E.; Medical and Molecular Genetics, School of MedicineItem The Evolution of Target Hemoglobin Levels in Anemia of Chronic Kidney Disease(Elsevier, 2019-07) Bazely, Jonathan; Wish, Jay; Medicine, School of MedicineSince the introduction of erythropoiesis-stimulating agents (ESAs) into clinical practice in 1989, considerable effort has been put forth toward identifying the optimal treatment strategy for managing anemia of CKD. After initial treatment of only the most severely anemic patients, therapy was subsequently expanded to include most patients on dialysis and many nondialysis CKD patients. Many nephrology societies and regulatory agencies have sought to identify the most appropriate hemoglobin levels to which ESA therapy should be targeted. As increasing evidence became available about the impacts of ESAs on varying endpoints including morbidity, mortality, and quality of life, the guidelines put forth by such agencies evolved over time. We review the literature impacting these determinations through the past 3 decades and comment on how this informs the application of this knowledge to the care of patients today.Item Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation(Elsevier, 2021-11) Wish, Jay B.; Eckardt, Kai-Uwe; Kovesdy, Csaba P.; Fishbane, Steven; Spinowitz, Bruce S.; Berns, Jeffrey S.; Medicine, School of MedicineThe National Kidney Foundation convened an interdisciplinary international workshop in March 2019 to discuss the potential role of a new class of agents for the treatment of anemia in patients with chronic kidney disease (CKD): the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). International experts with expertise in physiology, biochemistry, structural chemistry, translational medicine, and clinical management of anemia participated. Participants reviewed the unmet needs of current anemia treatment, the biology of hypoxia-inducible factor, the pharmacology of prolyl hydroxylase inhibitors, and the results of phase 2 clinical trials of HIF-PHIs among patients with CKD, both those treated by dialysis and those not receiving kidney replacement therapy. The results of key phase 3 clinical trials of HIF-PHIs available as of the time of writing are also included in this report, although they appeared after the workshop was completed. Participants in the workshop developed a number of recommendations for further examination of HIF-PHIs, which are summarized in this report and include long-term safety issues, potential benefits, and practical considerations for implementation including patient and provider education.Item Mechanisms and mediators of hypertension induced by erythropoietin and related molecules(Oxford, 2018-10) Agarwal, Rajiv; Medicine, School of MedicineHypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin–angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce hypertension by provoking calcification and augmenting chronic intermittent hypoxia as occurs in sleep apnea. Others show that there may be an antihypertensive effect via kidney repair. Whether these drugs will alter the risk of hypertension compared with EPO remains to be seen.Item Not FIT for Use: Fecal Immunochemical Testing in the Inpatient and Emergency Settings(Elsevier, 2022-01) Bhatti, Umer; Jansson-Knodell, Claire; Saito, Akira; Han, Andrew; Krajicek, Edward; Han, Yan; Imperiale, Thomas F.; Fayad, Nabil; Medicine, School of MedicineBackground Fecal immunochemical testing (FIT) is widely used for colorectal cancer screening, its only indication. Its effect on clinical decision-making beyond screening is unknown. We studied the use of FIT in emergency and inpatient settings and its impact on patient care. Methods Using electronic medical records, we reviewed all non-ambulatory FITs performed from November 2017 to October 2019 at a tertiary care community hospital. We collected data on demographics, indications, gastroenterology consultations, and endoscopic procedures. Multivariate logistic regression was performed to determine the effect of FIT on gastroenterology consultation and endoscopy. Results We identified 550 patients with at least 1 FIT test. Only 3 FITs (0.5%) were performed for colorectal cancer screening. FITs were primarily ordered from the emergency department (45.3%) or inpatient hospital floor (42.2%). Anemia (44.0%), followed by gastrointestinal bleeding (40.9%), were the most common indications. FIT was positive in 253 patients (46.0%), and gastroenterology consultation was obtained for 47.4% (n = 120), compared with 14.5% (n = 43) of the 297 FIT-negative patients (odds ratio 3.28; 95% confidence interval, 2.23-4.82, P < .0001). A potential bleeding source was identified in 80% of patients with reported or witnessed overt gastrointestinal bleeding, a similar proportion (80.7%; P = .92) to patients who were FIT positive with overt gastrointestinal bleeding. Multivariate analysis showed that melena, hematemesis, and a positive FIT were associated with gastroenterology consultation (all P < .05), while only melena (odds ratio 3.34; 95% confidence interval, 1.48-7.54) was associated with endoscopy. Conclusions Nearly all emergency department and inpatient FIT use was inappropriate. FIT resulted in more gastroenterology consultation but was not independently associated with inpatient endoscopy.Item Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review(Elsevier, 2022-06) Bazeley, Jonathan W.; Wish, Jay B.; Medicine, School of MedicineIron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.Item Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: Role of K+ channels(Springer, 2017-11) Kiel, Alexander M.; Goodwill, Adam G.; Noblet, Jillian N.; Barnard, April L.; Sassoon, Daniel J.; Tune, Johnathan D.; Cellular and Integrative Physiology, School of MedicineThis study was designed to identify mechanisms responsible for coronary vasodilation in response to progressive decreases in hematocrit. Isovolemic hemodilution was produced in open-chest, anesthetized swine via concurrent removal of 500 ml of arterial blood and the addition of 500 ml of 37 °C saline or synthetic plasma expander (Hespan, 6% hetastarch in 0.9% sodium chloride). Progressive hemodilution with Hespan resulted in an increase in coronary flow from 0.39 ± 0.05 to 1.63 ± 0.16 ml/min/g (P < 0.001) as hematocrit was reduced from 32 ± 1 to 10 ± 1% (P < 0.001). Overall, coronary flow corresponded with the level of myocardial oxygen consumption, was dependent on arterial pressures ≥ ~ 60 mmHg, and occurred with little/no change in coronary venous PO2. Anemic coronary vasodilation was unaffected by the inhibition of nitric oxide synthase (l-NAME: 25 mg/kg iv; P = 0.92) or voltage-dependent K+ (K V) channels (4-aminopyridine: 0.3 mg/kg iv; P = 0.52). However, administration of the K ATP channel antagonist (glibenclamide: 3.6 mg/kg iv) resulted in an ~ 40% decrease in coronary blood flow (P < 0.001) as hematocrit was reduced to ~ 10%. These reductions in coronary blood flow corresponded with significant reductions in myocardial oxygen delivery at baseline and throughout isovolemic anemia (P < 0.001). These data indicate that vasodilator factors produced in response to isovolemic hemodilution converge on vascular smooth muscle glibenclamide-sensitive (K ATP) channels to maintain myocardial oxygen delivery and that this response is not dependent on endothelial-derived nitric oxide production or pathways that mediate dilation via K V channels.