A clinical safety trial of stroma‐free hemoglobin

Savitsky, J. Philip; Doczi, J; Black, Jennifer; Arnold, John D.

doi:10.1002/cpt197823173

Cited by 349 publications

(149 citation statements)

References 3 publications

(5 reference statements)

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“…Early studies showed that transfusing stroma-free, unmodified, extracellular Hb into humans results in renal dysfunction, hypertension, and abdominal pain (87,94,126). Subsequent work indicated that free HbA tetramers dissociate into dimers when diluted into plasma.…”

Section: Engineering Principles For Rhboc Productsmentioning

confidence: 99%

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Varnado

Mollan

Birukou

et al. 2013

Antioxidants & Redox Signaling

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Significance: The worldwide blood shortage has generated a significant demand for alternatives to whole blood and packed red blood cells for use in transfusion therapy. One such alternative involves the use of acellular recombinant hemoglobin (Hb) as an oxygen carrier. Recent Advances: Large amounts of recombinant human Hb can be expressed and purified from transgenic Escherichia coli. The physiological suitability of this material can be enhanced using protein-engineering strategies to address specific efficacy and toxicity issues. Mutagenesis of Hb can (i) adjust dioxygen affinity over a 100-fold range, (ii) reduce nitric oxide (NO) scavenging over 30-fold without compromising dioxygen binding, (iii) slow the rate of autooxidation, (iv) slow the rate of hemin loss, (v) impede subunit dissociation, and (vi) diminish irreversible subunit denaturation. Recombinant Hb production is potentially unlimited and readily subjected to current good manufacturing practices, but may be restricted by cost. Acellular Hb-based O 2 carriers have superior shelf-life compared to red blood cells, are universally compatible, and provide an alternative for patients for whom no other alternative blood products are available or acceptable. Critical Issues: Remaining objectives include increasing Hb stability, mitigating iron-catalyzed and iron-centered oxidative reactivity, lowering the rate of hemin loss, and lowering the costs of expression and purification. Although many mutations and chemical modifications have been proposed to address these issues, the precise ensemble of mutations has not yet been identified. Future Directions: Future studies are aimed at selecting various combinations of mutations that can reduce NO scavenging, autooxidation, oxidative degradation, and denaturation without compromising O 2 delivery, and then investigating their suitability and safety in vivo. Antioxid. Redox Signal. 18, 2314-2328.

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Section: Engineering Principles For Rhboc Productsmentioning

confidence: 99%

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Varnado

Mollan

Birukou

et al. 2013

Antioxidants & Redox Signaling

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“…The early studies showed considerable side effects, most notably renal impairment due to vasoconstriction [75][76][77]. As a consequence, SHF has been abandoned as blood substitute.…”

Section: Stroma-free Haemoglobin (Sfh)mentioning

confidence: 99%

Haemoglobin, oxygen carriers and perioperative organ perfusion

Kocián¹,

Spahn²

2008

Best Practice & Research Clinical Anaesthesiology

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“…Nevertheless, several investigators described a continuous decrease in flow when perfusing kidneys with a SFH solution, with histology revealing hemoglobin deposits in the glomeruli [84] and tubules [9]. Other investigators confirmed these adverse effects on kidney function using ultrapure SFH, which was not observed with polymerized hemoglobins [44, 59,83, 981. Confirmation of the low-grade toxicity to the kidney using different purified and polymerized or cross-linked hemoglobin derivatives was obtained in several studies.…”

Section: Oxidative Metabolism During Warm Preservationmentioning

confidence: 99%

Kidney preservation in the next millenium

Stubenitsky¹,

Booster²,

Nederstigt³

et al. 1999

Transplant Int

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For the past decades, severe hypothermia has represented the foundation of organ preservation in clinical transplantation. Beneficial as hypothermia has proven to be in preserving grafts from heartbeating donors, hypothermia does not seem to provide the window necessary for the prospective evaluation of organ function. With the increasing use of non-heart-beating donors, it is logical to propose that if organs are to be evaluated prospectively, it will be necessary to preserve them at warmer temperatures. Since both glomerular and tubular functions are inhibited at temperatures below 18 "C, such a goal will necessitate organ preservation at a temperature above 20 "C. The principle of preservation at warmer temperatures is not new, but with future developments and approaches, successful realization appears within reach. In this overview, a brief history of previous attempts at warm preservation, in the context of the current status of kidney preservation, is presented. Future developments and approaches, with the potential for prospective testing of the function and enhanced resistance to ischemic damage, will be discussed.Key words Kidney preservation . Viability testing . Ischemia . Non-heartbeating donor . Heart-beating donor Organ preservation and the organ shortageThe evolution of transplantation has made kidney allografting the preferred treatment for patients with endstage renal failure. Transplantation provides improved quality of life and is more cost-effective than dialysis [33]. Currently, l-year graft survival rates for cadaveric donor transplants are above 80% and l-year patient survival rates 95 % [loo].Offsetting this success is the increasing discrepancy between the availability of, and demand for, transplantable kidneys. Within the Eurotransplant region, procurement rates remained stable during 1996 and 1997, whereas the number of potential recipients on the waiting list increased by 4 % [2S], resulting in approximately 3,000 procedures compared to 11,000 patients awaiting transplantation [70].A major factor contributing to the organ shortage is the detrimental effect of ischemia. Upon harvesting, the loss of the vascular circulation causes ischemia, with the concomitant depletion of oxygen and nutrients to the kidney. The ischemia, with the resulting loss of metabolic activity, initiates a cascade of cellular damage. This injury cascade leads to the breakdown of high-energy compounds necessary for cellular metabolism, a generalized loss of cellular integrity, and activation of degenerative enzymes. The result is the loss of all structural and functional components of the cell. While it has been proposed that the kidney can tolerate as much as 2 h of warm ischemia before the damage becomes so severe that it is irreversible and reperfusion with blood will not restore a life-sustaining function, transplanting an allograft with warm ischemic exposure of this magnitude is never considered clinically. Once a 84 kidney is removed, preservation techniques must preserve the organ sufficiently to...

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A clinical safety trial of stroma‐free hemoglobin

Cited by 349 publications

References 3 publications

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Haemoglobin, oxygen carriers and perioperative organ perfusion

Kidney preservation in the next millenium

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