StemCell Therapy

I. Introduction

Total United States expenditure on end-stage renal disease (ESRD1) therapy topped $25 billion in 2002, an increase of 11.5% on the previous year (U.S. Renal Data System, 2004), representative of a trend extending back to the early 1970s and projected to continue into the foreseeable future (Lysaght, 2002). This reflects not only a steady increase in patient numbers (431,284 on December 31, 2002, up 4.6% from 2001) (U.S. Renal Data System, 2004) but also rising costs of treatment and extended therapy periods as survival rates improve. Morbidity and mortality rates associated with maintenance dialysis, however, remain high, with a dialysis patient in their early 20s having the same expected remaining lifespan as a 70-year-old in the general population (U.S. Renal Data System, 2004). Outcomes are considerably improved following transplantationa transplant patient in their early 20s can expect to survive as many years as a member of the general population in their early 40sbut organ supply lags far behind demand, with only around one-quarter of the extant ESRD population having benefited from a transplant (U.S. Renal Data System, 2004).

The statistics for patients suffering from acute renal failure (ARF) are even worse. Affecting up to 200,000 people in the United States annually, or approximately 5% of all long-term hospital patients, the current mortality rate of around 50% has remained unchanged since the advent of dialysis 30 to 40 years ago (Thadhani et al., 1996; Lieberthal and Nigam, 2000; Nigam and Lieberthal, 2000). ARF develops predominantly due to the injury and necrosis of renal proximal tubule cells (RPTCs) as a result of ischemic or toxic insult (Lieberthal and Nigam, 1998). The cause of death subsequent to ARF is generally the development of systemic inflammatory response syndrome, frequently secondary to bacterial infection or sepsis, resulting in cardiovascular collapse and ischemic damage to vital organs, culminating in multiple organ failure (Breen and Bihari, 1998).

There is growing recognition that the disease state arising from renal failure is the result of more than just the loss of blood volume regulation, small solute, and toxin clearance that are replaced by conventional dialysis therapy (Humes, 2000). The kidney's role in reclamation of metabolic substrates, synthesis of glutathione, and free-radical scavenging enzymes, gluconeogenesis, ammoniagenesis, catabolism of peptide hormones and growth factors, and the production and regulation of multiple cytokines critical to inflammation and immunological regulation are not addressed by current treatment modalities (Kida et al., 1978; Tannen and Sastrasinh, 1984; Deneke and Fanburg, 1989; Maak, 1992; Frank et al., 1993; Stadnyk, 1994).

Thus, there is considerable drive to develop improved therapies for renal failure with the capacity to replace a wider range of the kidney's functions, thereby reducing morbidity, mortality, and the overall economic impact associated with this condition. Such an ambition lies beyond the reach of conventional medicine, with its mainly monofactorial approach to the treatment of disease. Into this breach steps the nascent and expanding field of cell therapy, which offers the promise of harnessing the native abilities of the cell, endowed to it by a billion years of evolution (Humes, 2003).

Cell therapy, as a blanket term covering the disciplines of regenerative medicine, tissue, and bioengineering, is dependent on cell and tissue culture methodologies to expand specific cells to replace important differentiated functions lost or deranged in various disease states. Central to the successful development of cell-based therapeutics is the question of cell sourcing, and advances in stem cell research have a vital impact on this problem.

Stem cell is itself a blanket term that covers a number of separate entities, although, as discussed below, there is at present a great deal of speculation over the extent to which stem cell populations traditionally considered distinct may in fact be interchangeable. As an in-depth treatment of the biology of stem cells and their relationship to more general aspects of regenerative medicine lies outwith the scope of this paper; the reader is directed to several recent reviews (Alison et al., 2002; Rosenthal, 2003; Grove et al., 2004; Rippon and Bishop, 2004).

Briefly, stem cells are characterized by their capacity for self-renewal and ability to differentiate into specialized cell types. Levels of competence form the basis of their classification as totipotent (giving rise to all three embryonic germ layers as well as extraembryonic tissues), pluripotent (able to contribute to all three germ layers of the embryo), and multipotent (with the potential to differentiate into multiple cell types, but not derivatives of all three germ layers). Progenitor cells are more lineage-restricted than stem cells but retain the proliferative capacity lacking in terminally differentiated cells.

ES cells, pluripotent derivatives of the inner cell mass of the blastocyst, are the most primitive cell type likely to find application in cell therapy. Their potential to generate any given cell type of the embryo makes them in some ways the most attractive stem cell for cell therapy but also the one with the greatest challenges to surmount in the laboratory. The political and ethical questions that surround the use of human ES cells have added a further layer of complexity to research aimed at bringing their potential benefits into the clinical arena (Daley, 2003; de Wert and Mummery, 2003; Drazen, 2003; Phimister and Drazen, 2004). These factors have combined to intensify the focus on multipotent adult stem cells such as hematopoietic stem cells (HSCs) and neural stem cells as sources for cell-based therapeutics.

In this review, we consider several potential cell-based therapies for renal failure that are currently under development and which provide a route, direct or indirect, for the application of stem cell technology. The direct route is exemplified by simple administration of stem cells to the diseased or injured organ and relies on their inherent capabilities for differentiation, organization, and integration into existing tissues to restore function. Indirect routes include the bio- and tissue-engineering approaches, which are based on in vitro differentiation of stem cells and the organization of their derivatives within matrices or in association with biomaterials to augment or replace function following implantation or as part of an extracorporeal circuit.

Read more:
Stem Cell Approaches for the Treatment of Renal Failure

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