Cell-Based Therapies


Objectives

This chapter will:

  • 1.

    Present the scientific rationale for renal stem cell and progenitor cell therapy.

  • 2.

    Describe an extracorporeal approach to renal cell replacement therapy.

  • 3.

    Present the scientific basis of continuous cell processing in an extracorporeal device.

  • 4.

    Summarize preclinical and clinical data on these cell-based approaches.

Acute and chronic solid organ failures are costly disease processes with high mortality rates. Inflammation plays a central role in acute and chronic organ failure, including heart, lung, and kidney. In this regard, new therapies for these disorders have focused on inhibiting the mediators of inflammation, including cytokines and free radicals, with little or no success in clinical studies. Recent novel treatment strategies have been directed to cell-based rather than mediator-based approaches, designed to immunomodulate the deleterious effects of inflammation on organ function. One approach, cell therapy, replaces cells that were damaged in the acute or chronic disease process with stem/progenitor technology, to rebalance excessive inflammatory states. As an example of this approach, the use of an immunomodulatory role of renal epithelial progenitor cells to treat acute renal failure and multiorgan failure arising from acute kidney injury, is reviewed. A second therapeutic pathway, cell processing, removes and modulates in situ the primary cellular leukocyte components of inflammation, which promote worsening organ tissue injury. The use of an immunomodulating leukocyte selective cytopheretic inhibitory device (SCD) also is reviewed as an example of this cell processing approach. Both of these unconventional strategies have shown early clinical efficacy in pilot clinical trials and may transform the therapeutic approach to organ failure disorders.

Loss of immunoregulation results in a propensity to develop systemic inflammatory response syndrome (SIRS), sepsis, multiple organ failure (MOF), and a high risk of death because of systemic immunologic or inflammatory imbalance. In acute kidney injury (AKI), activation and release of inflammatory proteins from circulating activated leukocytes, and imbalance between pro- and antiinflammatory proteins are provoked and aggravated by kidney cell injury. These conditions play a central role in the proinflammatory state in AKI with SIRS and/or MOF. SIRS is a catastrophic consequence of a variety of clinical insults and is usually present with AKI.

Growing evidence suggests that AKI is not merely a surrogate marker for severity of disease but also an independent predictor of death and a separate pathogenic entity, even when nearly physiologic levels of small-molecule clearance are administered. This possibility gives rise to the hypothesis that the native kidney has clinically important functions that are not replaced by dialysis or hemofiltration. These functions may include synthesis of cytokines, antigen presentation, reclamation of glutathione, synthesis of glutathione reductase, oxidative deamination and gluconeogenesis, 1,25-dihydroxyvitamin D 3 hydroxylation, trace mineral and element reclamation, and other, as-yet-undiscovered entities.

Renal Tubule Assist Device

Human renal cells have been isolated from cadaveric kidneys and cultured for the purpose of integrating them within a filtration device to provide more complete renal replacement. These tubule cells, obtained from adult tissue and having stem cell–like characteristics, are grown in confluent monolayers along the inner surface of the hollow fibers in a conventional hemofiltration cartridge. The resulting construct containing these living cells is called a bioartificial renal tubule assist device (RAD). The RAD is clearly feasible when conceived of as a combination of living cells supported on polymeric substrata acting as scaffolds for the cells. The renal tubule progenitor cells were cultured on the biomatrix-coated, hollow-fiber membrane of a standard high-flux hemofiltration cartridge. The membrane is both water and solute permeable, allowing for differentiated vectorial transport and metabolic and endocrine activity. Immunoprotection of cultured progenitor cells is achieved concurrently with long-term functional performance so long as conditions support tubule cell viability.

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