Biomedical subjects
Publications and source records attributed to H D Humes.
Although the cause may be inadequate blood flow or a toxic insult to the renal tubules--or a combination thereof--iatrogenesis often underlies acute renal failure. Awareness of the procedures and treatments most likely to precipitate renal failure can help physicians to prevent the condition, or at least to detect it at the earliest opportunity.
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Current renal substitution therapy with hemodialysis or hemofiltration has been the only successful long-term ex vivo organ substitution therapy to date. Although this approach is life sustaining, it is still unacceptably suboptimal with poor clinical outcomes of patients with either chronic end-stage renal disease or acute renal failure. This current therapy utilizes synthetic membranes to substitute for the small solute clearance function of the renal glomerulus but does not replace the transport, metabolic, and endocrinologic functions of the tubular cells. The addition of tubule cell replacement therapy in a tissue-engineered bioartificial kidney comprising both biologic and synthetic components will likely optimize renal replacement to improve clinical outcomes. This report demonstrates that the combination of a synthetic hemofiltration device and a renal tubule cell therapy device containing porcine renal tubule cells in an extracorporeal perfusion circuit successfully replaces filtration, transport, metabolic, and endocrinologic functions of the kidney in acutely uremic dogs.
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Current therapy for acute tubular necrosis (ATN) continues to have an exceedingly high mortality rate, exceeding 50% even with dialytic or hemofiltrative support. Current renal replacement therapy in ATN only substitutes for filtration function of the kidney but not its cellular metabolic functions. Replacing these metabolic functions may optimize current therapy for this devastating disease process. In this regard, a renal tubule assist device (RAD) has been developed to be placed in an extracorporeal continuous hemoperfusion circuit in series with a hemofilter. The RAD consists of porcine renal proximal tubule cells grown as confluent monolayers of a multifiber bioreactor with a membrane surface area from 0.4 to 1.6 m2. The cells along the inner surface of the hollow fibers are immunoprotected from the patient's blood by the hollow fiber membrane. In preliminary experiments in uremic dogs, this device has been shown to tolerate a uremic environment while providing reabsorptive, metabolic, and endocrinologic activity. Pilot human trials of the RAD are anticipated within the next year to improve current renal replacement therapy in ATN.
The developing technologies of cell therapy and tissue engineering may, in the next two decades, provide alternatives to current methods of renal replacement therapy. First, suitable organs for xenotransplantation from animals to humans may be developed, or second, as described in this report, application of tissue engineering may result in development of a range of devices to aid care of patients with renal failure. The simplest and easiest achievable devices could replace a specific aspect of renal function, such as an implantable device to produce erythropoietin. Both a bioartificial hemofilter and a renal tubule device may be developed. Ultimately this work may result in an implantable bioartificial kidney.
The rapid understanding of the cellular and molecular basis of organ function and disease will be translated during the next several decades into new therapeutic approaches to a wide range of clinical disorders, including acute renal failure (ARF). The development of the biotechnology for recombinant genetic engineering has led to the prospect of using purified protein products for therapy. In this regard, the repair of ischemic and toxic ARF is critically dependent on a redundant, interactive cytokine network of growth factors to return kidney function to near normal baseline function. Recombinant growth factors are being tested both experimentally and clinically to accelerate the repair of kidney tissue in this disorder. A newer strategy in biotechnology is the development of cell therapy derivatives. Cell therapy is based on the ability to expand specific cells in tissue culture to perform differentiated tasks and to introduce these cells into the patient either in extracorporeal circuits or as implants as drug delivery vehicles of a single protein or to provide physiological functions. Cell therapy devices are being developed to replace components of renal function that are lost during ARF and chronic renal failure and are not replaced with current hemodialysis or hemofiltration. These new approaches may result in therapeutic modalities that diminish the degree of renal failure and the time needed to recover renal function in acute tubular necrosis. This article examines the future prospects of these developing therapies in the treatment of ARF.
The adult mammalian kidney tubule epithelium exists in a relatively dormant, slowly replicative state but has a large potential for regenerative morphogenesis following severe ischemic or toxic injury. Under selective serum-free growth conditions, which included epidermal growth factor and retinoic acid, a subpopulation of renal proximal tubule cells isolated from adult rabbit kidney were grown in cell culture. These cells possessed two important characteristics: 1) an ability to differentiate morphogenically into tubule structures when grown in three-dimensional collagen gels and 2) a high capacity for self-renewal, since cell lineage analysis with a recombinant retrovirus demonstrated that in vitro tubulogenesis arose from clonal expansion of a single cell. Thus individual cells in the adult kidney have retained the ability for kidney tubulogenesis in vitro.
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Cell therapy and tissue engineering may well likely dominate medical therapeutics in the next century. Growing a functional glomerular filter and tubule reabsorber from a combination of cells, biomaterials, and synthetic polymers to replace renal excretory and regulatory functions is a specific example of these evolving technologies. The kidney was the first organ whose function was substituted by an artificial device. The kidney was also the first organ to be successfully transplanted. The ability to replace renal function with these revolutionary technologies in the past was due to the fact that renal excretory function is based on natural physical forces which govern solute and fluid movement from the body compartment to the external environment. The need for coordinated mechanical or electrical activities got renal substitution was not required. Accordingly, the kidney may well be the first organ to be available as a tissue-engineered implantable device as a fully functional replacement part for the human body. The prospects of a "universal donor" bioartificial kidney for the treatment of end-stage renal disease are clearly achievable as we approach the next millennium.
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Experimental data suggests the recovery of renal function after ischemic or nephrotoxic acute renal failure is due to a replicative repair process dependent upon predominantly paracrine release of growth factors. These growth factors promote renal proximal tubule cell proliferation and a differentiation phase dependent on the interaction between tubule cells and basement membrane. These insights identify the molecular basis of renal repair and ischemic and nephrotoxic acute renal failure, and may lead to potential therapeutic modalities that accelerate renal repair and lessen the morbidity and mortality associated with these renal disease processes. In this regard, there is a prominent vasoconstrictor response of the renal vasculature during the postischemic period of developing acute renal failure. The intravenous administration of pharmacologic doses of atrial natriuretic factor (ANF) in the postischemic period have proven efficacious by altering renal vascular resistance, so that renal blood flow and glomerular filtration rate improve. ANF also appears to protect renal tubular epithelial integrity and holds significant promise as a therapeutic agent in acute renal failure. Of equal or greater promise are the therapeutic interventions targeting the proliferative reparative zone during the postischemic period. The exogenous administration of epidermal growth factor or insulin-like growth factor-1 in the postischemic period have effectively decreased the degree of renal insufficiency as measured by the peak serum creatinine and has hastened renal recovery as measured by the duration of time required to return the baseline serum creatinine values. A similarly efficacious role for hepatocyte growth factor has also been recently demonstrated.
UNLABELLED: The purpose of this study was to investigate the use of [1-11C]acetate as a metabolic tracer for renal imaging in human subjects. METHODS: Eighteen patients underwent dynamic PET imaging of the kidneys after intravenous bolus injection of 10-20 mCi [1-11C]acetate. Time-activity curves of renal parenchyma tracer activity were fitted to a two-compartment model using direct arterial blood sampling for the arterial input function. RESULTS: Renal uptake of [1-11C]acetate is prompt and high target-to-background ratios are achieved even in the presence of markedly reduced renal function. Carbon-11-acetate is cleared from the renal parenchyma without any urinary excretion and the rate of clearance is comparable to myocardial clearance rates. Among normal subjects, K1, ranged from 0.653 to 1.37 ml/min-g, and was reduced to as low as 0.363 ml/min-g in severe renal disease (serum creatinine greater than 5 mg/dl), while k2 ranged from 0.114 to 0.166 min-1 among normal subjects and was reduced to as low as 0.053 min-1 in severe renal disease. Kinetic parameters K1 and k2 were both reduced in the presence of intrinsic renal disease or significant renal artery stenosis. Renal cell carcinoma demonstrated similar uptake of [1-11C]acetate, but substantially reduced the rate of clearance compared to normal and diseased non-neoplastic renal tissue, allowing for ready differentiation of renal cell carcinoma from non-neoplastic renal tissue on images acquired beyond 10 min of tracer administration. CONCLUSION: Carbon-11-acetate is a promising physiologic tracer for the study of renal disease.
The increasing understanding of the molecular and cellular basis of acute renal failure and the development of cell culture methodology to grow differentiated cells in engineered structures provide substantial promise for new therapeutic derivatives to treat patients with acute renal failure (Table 3). The use of disintegrins to ameliorate intratubular obstruction, the administration of ANF to improve glomerular filtration, or the injection of growth factors to speed re-epithelialization may prove effective in altering the natural history of this severe clinical disorder. Furthermore, the development of cell therapy with a renal tubule replacement device may add critical renal functional components not currently substituted with dialysis or hemofiltration. The potential therapeutic advances which may occur as we enter the next century to treat this devastating clinical disease process have substantial promise.
Experimental data suggest that the recovery of renal function after ischemic or nephrotoxic acute renal failure is due to a replicative repair process dependent on predominantly paracrine release of growth factors. These growth factors promote renal proximal tubule cell proliferation and a differentiation phase dependent on the interaction between tubule cells and basement membrane. These insights identify the molecular basis of renal repair in ischemic and nephrotoxic acute renal failure and may lead to potential therapeutic modalities that accelerate renal repair and lessen the morbidity and mortality associated with these renal disease processes.
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Transforming growth factor-beta (TGF-beta) is a critical cell regulatory protein which influences cell growth, cell differentiation and cell chemotaxis. TGF-beta 1 has been previously shown to promote a migratory and adherent transformation of monolayers of renal proximal tubule cells in primary culture to form solid clusters of cells. To better understand the cellular basis of this TGF-beta 1 effect, these studies evaluated the influence of TGF-beta 1 on the synthesis of proteoglycans and on cytoskeleton rearrangement in rabbit renal proximal tubule cells in primary culture, and their role in this transformation effect of TGF-beta 1. Biosynthetic labeling of proteoglycans with 35S sulfate and enzyme digestion studies demonstrated that TGF-beta 1 promoted the synthesis of heparan sulfate proteoglycans in these cells. The importance of proteoglycan synthesis induced by TGF-beta 1 in this migration and aggregation process was demonstrated with the use of two chemically-dissimilar proteoglycan synthesis inhibitors: xyloside and galactosamine. Both compounds inhibited TGF-beta 1 stimulation of proteoglycan synthesis and diminished TGF-beta 1 promoted transformation of proximal tubule cells as assessed by quantitative morphometry. Further experiments evaluated the influence of TGF-beta 1 on actin microfilaments with the use of rhodamine conjugated phalloidin staining and immunofluorescent microscopy, and demonstrated that TGF-beta 1 provoked a dramatic rearrangement of actin microfilaments into stress fibers. The use of actin microfilament disrupting agents, cytochalasin B and D, attenuated the stress fiber formation promoted by TGF-beta 1 and inhibited the TGF-beta 1-induced morphologic transformation of these cells. Further studies evaluated these effects on the rate of DNA synthesis in these cells, as assessed with 3H-thymidine incorporation. Proteoglycan synthesis inhibitors significantly diminished the maximal proliferative response of these epithelial cells to epidermal growth factor (EGF). In contrast, actin microfilament disaggregation with cytochalasin B or D did not change the rate of DNA synthesis in response to EGF but did attenuate the antiproliferative effect of TGF-beta 1 on EGF-induced DNA synthesis cells. These studies demonstrate that the TGF-beta 1 promoted synthesis cells. These studies demonstrate that the TGF-beta 1 promoted an increase in the production of proteoglycans and a higher ordered structure of the cytoskeleton. Both effects were instrumental in the adhesive migratory response of proximal tubule cells to TGF-beta 1 as well as the DNA synthesis rate response to both EGF and TGF-beta 1.