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Biomedical subjects

H David Humes

Publications and source records attributed to H David Humes.

At least 19 recordsLinked to original sources
PubMed2006

Kidney epithelial cells.

Kidney tubules are an essential component of an organism's blood clearance mechanism, recovering essential metabolites from glomerular filtration by active transport. Tubules are subject to injury, usually as the result of ischemia-reperfusion events that damage the polarized tubular cell layer that coats the tubule basement membrane, causing dysfunction and necrosis that is often associated with acute renal failure. However, tubules are capable of self-repair, forming new proximal tubular cells to replace failing or necrotic cells. The origin of the progenitor cells that give rise to new tubular cells is unknown. At one extreme, it is possible that all or a fraction of tubular cells can undergo a form of dedifferentiation and subsequent mitosis to form new tubular cells, or alternatively, it is possible that tubular regeneration follows the stem cell/transit-amplifying cell paradigm described for more rapidly regenerating organ systems. Regardless of the mechanism employed to generate new tubular cells, human tubular cells are readily grown in primary cultures and can recapitulate many of the metabolic, endocrine, and immunological properties attributable to endogenous renal proximal tubules when engrafted into bioartificial devices.

Adult Stem Cells↗
PubMed2006

Bioartificial kidney in the treatment of acute renal failure associated with sepsis.

Acute renal failure (ARF) associated with sepsis has a high rate of mortality. It is not merely a surrogate marker for severity of disease but also an independent predictor of mortality and a separate pathogenic entity, even when nearly physiological doses of fluid and small-molecule clearance are maintained with currently available renal replacement therapies (RRT). The techniques to remove cytokines, including high-volume haemofiltration, haemodialysis using high-cut-off haemofilters, and absorptive techniques, lead to some improvement in outcome but are still insufficient to reverse the complicated biological dysregulation resulting from ARF associated with sepsis. The novel and exciting technique of cell therapy, which is based on the principle of using functional cells to replace a greater range of renal functions, may add significant benefit to current RRT in dealing with this disease process. Because renal tubule cells appear to play critical roles in immunoregulation, renal tubule cell therapy during ARF associated with sepsis should alter the detrimental multiple-organ consequences of sepsis. The development of a bioartificial kidney consisting of a conventional haemofiltration cartridge in series with a renal tubule assist device containing renal proximal tubule cells represents a new therapeutic approach to this clinical disorder. The results to date of large animal studies and recent Phase I/II and Phase II clinical trials show that such a device replaces multiple kidney functions and modifies the sepsis condition to improve survival in ARF.

Acute Kidney Injury↗
PubMed2005

The future of renal support: high-flux dialysis to bioartificial kidneys.

Renal failure continues to cause a major burden of morbidity and mortality in both its acute and chronic forms, regardless of advances in current renal replacement therapies. A bioartificial kidney that includes a conventional dialysis filter and a renal tubule assist device containing approximately 10(8) renal proximal tubule cells was recently successfully engineered. This therapeutic modality may decrease the survival gap between current renal replacement therapies and healthy kidney functions and may lessen the heavy burden of morbidity and mortality associated with renal failure, both acute and chronic, in the near future.

Acute Kidney Injury↗
PubMed2005

Stem cell approaches for the treatment of renal failure.

The inadequacy of current treatment modalities and insufficiency of donor organs for cadaveric transplantation have driven a search for improved methods of dealing with renal failure. The rising concept of cell-based therapeutics has provided a framework around which new approaches are being generated, and its combination with advances in stem cell research stands to bring both fields to clinical fruition. This budding partnership is presently in its very early stages, but an examination of the cell-based therapies currently under development clearly shows the magnitude of the role that stem cells will ultimately play. The issue over reports of unexpected plasticity in adult stem cell differentiation remains a focus of debate, and evidence for bone marrow-derived stem cell contributions to renal repair has been challenged. The search for adult renal stem cells, which could have a considerable impact on much of the work discussed here, appears to be narrowing. The use of embryonic tissue in research continues to provide valuable insights but will be the subject of intense societal scrutiny and debate before it reaches the stage of clinical application. Embryonic stem (ES) cells, with their ability to generate all, or nearly all, of the cell types in the adult body and a possible source of cells genetically identical to the donor, hold great promise but face ethical and political hurdles for human use. Immunoisolation of heterologous cells by encapsulation creates opportunities for their safe use as a component of implanted or ex vivo devices.

Animals↗
PubMed2005

Rare incorporation of bone marrow-derived cells into kidney after folic acid-induced injury.

Results obtained in recent experiments suggest that bone marrow-derived cells (BMDCs) engraft into tissues and differentiate into various somatic cell types. However, it is unclear whether injury is required for the phenomenon to occur at appreciable frequencies. In this study we tested whether BMDCs engraft into kidneys and differentiate into renal cells in the absence or presence of toxic injury. Renal damage was induced by delivery of folic acid (FA) to bone marrow (BM)-recipient mice 1 or 9 months after bone marrow transplant, and kidneys were examined for donor-derived cells 2,4, or 8 weeks after injury. Donor-derived cells were abundant in the renal interstitium of injured kidneys and were detected in glomeruli of vehicle- and FA-treated mice. Most of these cells expressed the common leukocyte antigen CD45 and display morphological characteristics of white blood cells. No donor-derived renal tubule cells (RTCs) were detected in kidney sections of BM-recipient mice. However, in cell culture, a cluster of seven donor-derived cells of 4 x 10(6) RTCs examined (approximately 0.0002%) displayed morphological characteristics of RTCs. CD45+ cells of donor origin were also detected in glomeruli and glomerular outgrowths. Nested polymerase chain reaction analysis for the male-specific Sry gene in cultured RTCs and glomerular outgrowths confirmed the presence of donor-derived cells. These results suggest that BMDCs may incorporate into glomeruli as specialized glomerular mesangial cells; however, BMDCs rarely contribute to the repair of renal tubules in uninjured or FA-treated mouse kidneys.

Acute Kidney Injury↗
PubMed2005

Stem cells: the next therapeutic frontier.

Cell therapy is one of the most exciting fields in translational medicine. It stands at the intersection of a variety of rapidly developing scientific disciplines: stem cell biology, immunology, tissue engineering, molecular biology, biomaterials, transplantation biology, regenerative medicine, and clinical research. Cell-based therapy may develop into a new therapeutic platform to treat a vast array of clinical disorders. Blood transfusions and bone marrow transplantation are prime examples of the successful application of cell-based therapeutics; but recent advances in cellular and molecular biology have expanded the potential applications of this approach. Although recombinant genetic engineering to produce a variety of therapeutics such as human erythropoietin and insulin has proven successful, these treatments are unable to completely correct or reverse disease states, because most common disease processes are not due to the deficiency of a single protein but develop due to alterations in the complex interactions of a variety of cell components. In these complex situations, cell-based therapy may be a more successful strategy by providing a dynamic, interactive, and individualized therapeutic approach that responds to the pathophysiological condition of the patient. In this regard, cells may provide innovative methods for drug delivery of biologics, immunotherapy, and tissue regenerative or replacement engineering (1,2). The translation of this discipline to medical practice has tremendous potential, but in many applications technological issues need to be overcome. Since many cell-based indications are already being evaluated in the clinic, the field appears to be on the threshold of a number of successes. This review will focus on our group's use of human stem/progenitor cells in the treatment of acute and chronic renal failure as extensions to the current successful renal substitution processes of hemodialysis and hemofiltration.

Animals↗
PubMed2004

Is acetylcysteine effective in preventing contrast-related nephropathy? A meta-analysis.

PURPOSE: Clinical trials evaluating acetylcysteine for the prevention of contrast-related nephropathy have reported mixed results. Although previous meta-analyses have concluded that acetylcysteine is beneficial, the recent availability of additional trials calls for reassessment of current evidence. METHODS: We performed a computerized search to identify relevant published and unpublished randomized clinical trials that evaluated acetylcysteine for the prevention of contrast-related nephropathy. Abstracted data from each trial included assessments of clinical outcomes, trial quality, and additional characteristics. The primary outcome of interest was the incidence of nephropathy after contrast administration. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Subgroup analyses were also performed. RESULTS: Twenty trials involving 2195 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-related nephropathy was 0.73 (95% confidence interval: 0.52 to 1.0; P = 0.08), a nonsignificant trend towards benefit in patients treated with acetylcysteine. This effect varied, however, across the 20 trials (test of heterogeneity, P = 0.04). Although higher-quality trials demonstrated a stronger benefit for acetylcysteine in general, few reported important elements of study design, such as concealment of allocation, placebo-controls, or double-blinding. Heterogeneity was unexplained by subgroup analyses. CONCLUSION: Acetylcysteine may reduce the incidence of contrast-related nephropathy, but this finding is reported inconsistently across currently available trials. High-quality, large clinical trials are needed before acetylcysteine use in this indication can be recommended universally.

Acetylcysteine↗
PubMed2004

BKV and SV40 infection of human kidney tubular epithelial cells in vitro.

The interaction of BKV with its natural target cells, human kidney epithelial cells, has not been studied. In vitro infections of human primary kidney epithelial cells were performed to investigate a BKV infection in its natural host cell. BKV undergoes a lytic replication cycle in this system: high levels of T antigen expression were first detected at 36 h postinfection, while viral DNA replication, capsid protein expression, and progeny virus were observed at 48 h postinfection. It was observed that the related polyomavirus SV40 is incapable of infecting human kidney epithelium except in the presence of the GM1 ganglioside, recently reported to be an SV40 receptor.

Animals↗
PubMed2004

Advances in cell therapy for renal failure.

Cell therapy is one of the most exciting fields in translational medicine. It stands at the intersection of a variety of rapidly developing scientific disciplines: stem cell biology, immunology, tissue engineering, molecular biology, biomaterials, transplantation biology, regenerative medicine and clinical research. Cell-based therapy may develop into a new therapeutic platform to treat a vast array of clinical disorders. Blood transfusions and bone marrow transplantation are prime examples of the successful application of cell-based therapeutics; but recent advances in cellular and molecular biology have expanded the potential applications of this approach. Although recombinant genetic engineering to produce a variety of therapeutics, such as human erythropoietin and insulin has proven successful, these treatments are unable to completely correct or reverse disease states, because most common disease processes are not due to the deficiency of a single protein but develop due to alterations in the complex interactions of a variety of cell components. In these complex situations, cell-based therapy may be a more successful strategy by providing a dynamic, interactive and individualized therapeutic approach that responds to the pathophysiological condition of the patient. In this regard, cells may provide innovative methods for drug delivery of biologics, immunotherapy, and tissue regenerative or replacement engineering [Nature 392 (1998) 518-524, Nat Biotechnol 20 (2002) 339-343]. The translation of this discipline to medicinal practice has tremendous potential, but in many applications technological issues need to be overcome. Since many cell-based indications are already being evaluated in the clinic, the field appears to be on the threshold of a number of successes. This review will focus on our group's use of human stem/progenitor cells in the treatment of acute and chronic renal failure as extensions to current successful renal substitution processes of hemodialysis and hemofiltration.

Acute Kidney Injury↗
PubMed2004

Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure.

BACKGROUND: Acute renal failure (ARF) in intensive care unit patients continues to have mortality rates exceeding 70%, despite hemodialysis or continuous renal replacement therapy (CRRT). The delivery of cellular metabolic function to CRRT may provide more complete renal replacement therapy, thereby changing the natural history of this disease process. An FDA-approved Phase I/II clinical trial on 10 patients has been completed, and demonstrated that this experimental treatment can be delivered safely for up to 24 hours. METHODS: The bioartificial kidney is a synthetic hemofilter connected in series with a bioreactor cartridge containing approximately 10(9) human proximal tubule cells, as a renal tubule assist device (RAD), within an extracorporeal perfusion circuit utilizing standard hemofiltration pump systems. All 10 patients had ARF and multiorgan failure (MOF), with predicted hospital mortality rates averaging above 85%. RESULTS: Data indicate that the RAD maintains viability, durability, and functionality in this ex vivo clinical setting. The device also demonstrated differentiated metabolic and endocrinologic activity, with glutathione degradation and endocrinologic conversion of 25-OH-D(3) to 1,25-(OH)(2)-D(3). All but one treated patient with more than a 3-day follow-up in the intensive care unit showed improvement as assessed by acute physiologic scores 1 to 7 days following therapy. Six of the 10 treated patients survived past 30 days. One patient expired within 12 hours after RAD treatment due to his family's request to withdraw ventilatory life support. Three other patients died due to complications from acute or chronic comorbidities unrelated to ARF or RAD therapy. Plasma cytokine levels suggest that RAD therapy produced dynamic and individualized responses in patients. For the subset of patients who had excessive proinflammatory levels, RAD treatment resulted in significant declines in granulocyte colony stimulating factor (G-CSF), interleukin (IL)-6, IL-10, and IL-6/IL-10 ratios. CONCLUSION: The addition of human renal tubule cell therapy to CRRT has been accomplished and demonstrates metabolic activity with systemic effects in patients with ARF and MOF. These initial clinical results are encouraging, so that a randomized, controlled Phase II clinical trial is underway to further assess the clinical safety and efficacy of this new therapeutic approach.

Acute Kidney Injury↗
PubMed2004

Renal cell therapy in the treatment of patients with acute and chronic renal failure.

Hemodialysis and hemofiltration have been important technologies in saving the lives of patients with acute (ARF) and chronic renal failure by clearing small solutes from plasma and thereby preventing death from acidemia, hyperkalemia, volume overload, and uremia. These therapeutic approaches, however, are still suboptimal, as patients with ARF have mortality rates exceeding 50%, and patients with end-stage renal disease (ESRD) have, on average, a life expectancy of 4-5 years. The preeminent cause of death in patients with ARF is the development of sepsis or the systemic inflammatory response syndrome with resulting systemic vasodilation, hypotension, ischemic injury to solid organs, multi-organ failure, and death. This vasodilation is due to persistent and excessive pro-inflammation. Similarly, the reduced survival times of patients with ESRD on chronic dialysis have been associated with a persistent and chronic systemic pro-inflammatory state. We have hypothesized that the loss of renal tubule cell mass acutely in acute tubule necrosis and chronically in ESRD results in an immunologically dysregulated state leading to excessive pro-inflammation. The replacement of renal tubule cell function may thus change the current dismal prognosis of patients with these disorders. In this regard, this report presents the first patient ever treated with a bioartificial kidney consisting of a synthetic hemofilter in series with a renal tubule assist device (RAD) containing approximately 10(9) human renal tubule cells. This treatment in a critically ill patient with multi-organ failure and ARF in the intensive care unit was associated temporally with improved cardiovascular parameters and enhanced native kidney function. Multiple systemic plasma cytokine levels and gene expression profiles of peripheral white blood cells were also temporally changed with cell therapy. Clinical trials in patients suffering from either ARF or ESRD are currently ongoing to evaluate the influence of the RAD on the inflammatory response in these groups of patients.

Acute Kidney Injury↗
PubMed2003

Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals.

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.

Animals↗
PubMed2003

Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock.

OBJECTIVE: Gram-negative septic shock has a clinical mortality rate approaching 50%. The cause of death is secondary to a systemic inflammatory response syndrome with resulting cardiovascular collapse, ischemic damage to vital organs, and multiple-organ systems failure. Renal tubule cell injury occurs early in septic shock but is not clinically appreciated. Since renal tubule cells appear to play a critical role in the immunoregulation of stress states, renal cell therapy during septic shock may alter the detrimental multiple-organ consequences of systemic Gram-negative infection. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 109 renal proximal tubule cells may be a new therapeutic approach to this clinical disorder. DESIGN: Laboratory study. SETTING: University medical school. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the bioartificial kidney and the RAD in septic shock, pigs were administered 30 x 10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in a continuous venovenous hemofiltration extracorporeal circuit with either a sham RAD without cells or a RAD with cells. MEASUREMENTS AND MAIN RESULTS: In this animal model, septic shock resulted within hours in acute tubule necrosis in the kidneys of all animals. Renal cell therapy resulted in significantly higher cardiac outputs and renal blood flow rates in treated animals compared with sham controls. RAD treatment also was associated with significantly lower plasma circulating concentrations of interleukin-6 and interferon-gamma compared with sham-treated animals. IL-6 release rates from peripheral blood mononuclear cells isolated from RAD-treated animals were significantly higher after endotoxin stimulation than those isolated from control animals. These physiologic and molecular alterations were associated with nearly a doubling of the average survival time in the RAD-treated group compared with the sham control group. CONCLUSION: These results demonstrate that renal cell therapy ameliorates cardiac and vascular dysfunction, alters systemic cytokine abnormalities, and improves survival time in a large animal model of Gram-negative septic shock. A cell therapeutic approach with a tissue-engineered bioartificial kidney may be a new treatment modality for this current unmet medical need.

Acute Kidney Injury↗
PubMed2003

Renal cell therapy is associated with dynamic and individualized responses in patients with acute renal failure.

BACKGROUND: Renal cell therapy in conjunction with continuous hemofiltration techniques may provide important cellular metabolic activities to patients with acute renal failure (ARF) and may thereby change the natural history of this disorder. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) human renal proximal tubule cells provides an opportunity to evaluate this form of therapy in patients with ARF in the intensive care unit. METHODS: Nine patients with ARF and multi-organ systems failure (MOSF) have been treated so far with a tissue-engineered kidney in an FDA-approved Phase I/II clinical study currently underway. Acute physiologic parameters and serum cytokine levels were assessed before, during and after treatment with a bioartificial kidney. RESULTS: Use of the RAD in this clinical setting demonstrates maintenance of cell viability and functionality. Cardiovascular stability appears to be maintained during RAD treatment. Human tubule cells in the RAD demonstrated differentiated metabolic and endocrinologic activity. Acute physiologic and plasma cytokine data demonstrate that renal cell therapy is associated with rapid and variable responses in patients with ARF and MOSF. CONCLUSION: The initial clinical experience with the bioartificial kidney and the RAD suggests that renal tubule cell therapy may provide a dynamic and individualized treatment program as assessed by acute physiologic and biochemical indices.

Acute Kidney Injury↗
PubMed2002

The bioartificial kidney in the treatment of acute renal failure.

The application of cell therapy to the successful substitution process of hemofiltration may improve the poor prognosis of patients with acute renal failure (ARF) in the intensive care unit. An extracorporeal bioartificial kidney consisting of a conventional hemofilter followed in series with a renal tubule assist device (RAD) has been developed. The RAD is a hemofiltration cartridge containing 109 human renal tubule cells grown as monolayers along the inner surface of the hollow fibers. The fibers provide a porous scaffold that is immunoprotective. The ultrafiltrate from the hemofilter is delivered to the luminal compartment of the RAD, and the postfiltered blood is delivered to the extracapillary space of the RAD. The RAD has been shown to possess multiple differentiated transport, metabolic, and endocrinologic activities of renal epithelium. These activities have been demonstrated to occur when the RAD is placed in the extracorporeal circuit of the bioartificial kidney in uremic animals. This approach may improve the current therapies used to treat patients with ARF because of the RAD's ability to restore lost metabolic renal function and cytokine balance in these desperately ill patients. In this regard, the RAD was able to ameliorate endotoxin and bacteremic shock in uremic animals by altering cytokine levels, improve mean arterial blood pressure, and maintain better cardiac output. With these supportive preclinical data, an FDA-approved phase I/II clinical trial has been initiated and early results are encouraging.

Acute Kidney Injury↗
PubMed2002

Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells.

Current renal substitution therapy with hemodialysis or hemofiltration has been an important life-sustaining technology, but it still has suboptimal clinical outcomes in patients with end-stage renal disease or acute renal failure. This therapy replaces the small solute clearance function of the glomerulus but does not replace the metabolic and endocrinologic functions of the tubular cells. This article shows that the combination of a synthetic hemofiltration cartridge and a renal tubule cell assist device (RAD) containing human cells in an extracorporeal circuit replaces filtration, metabolic, and endocrinologic functions in acutely uremic dogs. The RAD maintained excellent performance and durability characteristics for 24 hours of continuous use in the uremic animals. The RAD increased ammonia excretion, glutathione metabolism, and 1,25-dihydroxyvitamin D3 production. Cardiovascular stability in the animals was documented in these studies during this extracorporeal treatment. With these results, clinical evaluation of this device in the treatment of severely ill patients with acute renal failure in an intensive care unit has been initiated.

Acute Kidney Injury↗