William F. Weitzel

Replacement of renal function in uremic animals with a tissue-engineered kidney.

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.

ELASTICITY IMAGING FOR EARLY DETECTION OF RENAL PATHOLOGY

Early detection of renal pathology may be possible with elasticity imaging. This hypothesis was experimentally tested by quantitatively imaging internal mechanical strain due to surface deformations in an in vitro animal model of nephritis. Preliminary data support the hypothesis that kidney elasticity changes with renal damage and concomitant scarring before problems are detectable by traditional diagnostic techniques such as laboratory measurements of renal function.

Bioartificial Kidney Alters Cytokine Response and Hemodynamics in Endotoxin-Challenged Uremic Animals

The mortality from sepsis complicated by renal failure remains extremely high despite the application of modern renal replacement therapy. This study investigated whether treatment with a bioartificial kidney consisting of a hemofilter in a continuous venovenous hemofiltration circuit (CVVH) with a cartridge containing renal proximal tubule cells, also called the Renal Tubule Assist Device (RAD), would alter the course of sepsis in an animal model. The RAD has been previously characterized in vitro and ex vivo and provides transport, metabolic and endocrine activity. Mongrel dogs (n = 10) underwent surgical nephrectomy and 48 h later were treated with CVVH and either a RAD containing cells (n = 5) or an identically prepared sham cartridge (n = 5). After 4 h of therapy, intravenous endotoxin 2 mg/kg was infused over 1 h to simulate gram-negative septic shock. Data on blood pressure, cardiac output and systemic markers of inflammation were collected. Mean peak levels of an anti- inflammatory cytokine, IL-10, were significantly higher in cell-treated animals (15.25 vs. 6.29 ng/ml; p = 0.037), and mean arterial pressures were higher in cell-treated versus sham-treated animals (p < 0.04). We have demonstrated that treatment of an animal model of endotoxin shock and renal failure with a bioartificial kidney has measurable effects on circulating mediators of inflammation and on hemodynamic stability of the challenged animal.

Sonographic elasticity imaging of acute and chronic deep venous thrombosis in humans.

Objective. The purpose of this study was to assess the ability of sonographic elasticity imaging to distinguish acute from chronic deep venous thrombosis (DVT). Methods. Fifty‐four patients, 26 with acute DVT and 28 with chronic DVT, were studied, and we analyzed the data in 46 patients, 23 with acute (mean age, 5.7 days) and 23 with chronic (>8 months) DVT. Scanning was performed with a 5‐MHz linear array transducer during continuous freehand external deformation of each thrombus using the ultrasound scan head. The strains in the thrombi were normalized to the average strain between the skin surface and the back wall of the vein. Relative thrombus echogenicity was measured by comparing the echogenicity of the thrombus with that of the adjacent arterial lumen. Statistical analyses were performed with the Mann‐Whitney U test and receiver operating characteristic analysis. Results. The median normalized strain magnitude for the acute cases was 2.75, with an interquartile range of 2.4 to 3.71, whereas the median normalized strain magnitude for the chronic cases was 0.94, with interquartile range of 0.48 to 1.36. The difference was highly significant (P < 10−7). The area under the receiver operating characteristic curve (Az) was 0.97 ± 0.02 (SE). The echogenicity difference between the populations was highly significant (P < 10−5), with Az of 0.92 ± 0.04. The difference between the Az values was not significant (P > .05). Conclusions. In this population, sonographic elasticity imaging performs at least as well as thrombus echogenicity. Thrombus aging using elasticity imaging would be particularly helpful in evaluating symptoms in patients with post‐thrombotic syndrome.

A Markov model of the natural history of prostate cancer.

The objective of this study was to lay a foundation for future cost-benefit analyses evaluating the public health impact of treatment and screening protocols for prostate cancer. Specifically we wanted to define the relative impact on cancer-specific mortality rates of the individual epidemiological components: pathological incidences by age groups, cancer progression rates, and the effect of competing causes of death, assuming expectant management (i.e. no definitive treatment). A biological model of prostate cancer incidence and progression was converted into a standard Markov tree where competing causes of death could occur. Weighted averages of progression rates were obtained from clinical studies. Separate cohorts of 30 year old black and white men were followed for 50 years. The model yielded cancer-specific mortality rates, overall mortality rates, and pathologic prevalences for both white and black males, consistent with the literature. Sensitivity analyses showed that of all the parameters studied, the pathological incidence of cancer in men under 50 years of age had the greatest impact on the cancer-specific mortality rates. Also important was the annual probability of progression of A1 lesions. However the other parameters including pathological incidence in older males, and progression from locally-extensive to metastatic lesions had much smaller effects. In summary, this model correlates the clinical literature with the epidemiology of prostate cancer and can be used for further decision analyses. We recommend that future research be done to more precisely quantify the pathological incidence of prostate cancer in men under 50-60 years of age. More certainty is also needed before generalizing the results of relatively small A1 series to millions of men, since A1 progression rates critically affect the eventual cancer-specific mortality. Enough uncertainty remains at this point however, that we cannot advocate widespread screening for prostate cancer until its merit be demonstrated either by the definitive long term study, or by examination of costs and quality-of-life-adjusted benefits.

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 109 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.

System and method for determining blood flow rate in a vessel

A system and method are provided for determining the performance of a vessel, such as a hemodialysis access, which communicates blood between two locations of a patient. A conduit, such as an external dialysis circuit or an intravascular catheter, is provided in fluid communication with the vessel, and has a diversion point for diverting blood from the vessel into the conduit. The system further includes means for determining a flow rate of the diverted blood through the conduit. A first sensor in communication with the vessel generates at least one signal that is a function of a blood flow rate in the vessel downstream from the diversion point, wherein the downstream flow rate depends on the determined conduit flow rate and the performance of the vessel can be determined based on the signal. In addition, a processor can be provided in communication with the first sensor for determining a flow rate in the vessel upstream from the diversion point from the signal and the conduit flow rate. In a preferred embodiment, the first sensor is an ultrasonic sensor, and the at least one signal represents a time-averaged mean Doppler velocity of blood flow. Still further, additional sensors may be employed to provide a measure of the upstream flow rate as well as the conduit flow rate.

Endocrine abnormalities in chronic renal failure.

Much needs to be achieved in improving survival and quality of life for chronic renal failure patients. Progress in attaining this goal may accrue from attention to underlying pathophysiologic processes early and throughout a persons life. The endocrine perturbations described in this article--alterations in the homeostasis of phosphorus, calcium, vitamin D and parathyroid hormone; erythropoietin deficiency; and sexual dysfunction in uremia--provide good examples for the need to identify early and manage prospectively over time manifestations of chronic renal failure. The complexity of the skeletal and extraskeletal sequelae of dysregulated mineral metabolism and the complications of chronic anemia have been discussed, while stressing possible implications of these endocrine abnormalities for both morbidity and mortality. There is a great need for more randomized clinical trials to evaluate new and old treatment approaches, with the goal of developing better evidence-based practice guidelines.

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 109 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.

Successful Use of Indwelling Cuffed Femoral Vein Catheters in Ambulatory Hemodialysis Patients

Three hemodialysis patients with multiple upper extremity vascular access complications and central vein stenosis were treated for as long as 3 months using an indwelling femoral vein catheter having a buried felt cuff in its subcutaneous tunnel. Four catheters were placed in these three patients. In one case, initial failure due to poor flow and clotting occurred using a straight catheter with its tunnel crossing the inguinal ligament and exiting caudally on the anterior thigh. Otherwise, each patient had successful placement of a 180-degree, curved catheter that exited the femoral vein in the usual fashion but had a subcutaneous tunnel and skin exit pointing cephalad in the inferior portion of the right lower quadrant. The three successful devices functioned immediately after placement, having acceptable outflow pressures and recirculation values. One of three catheters was removed 3 weeks after placement when persisting infection was thought to reside on the device. No other bleeding, thromboembolic, or infectious complications occurred in these patients. In conclusion, short-term indwelling femoral vein access may be feasible in ambulatory hemodialysis patients with previous access difficulties that complicate temporary dialysis treatment.