Insights into Ototoxicity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136274/1/nyas00278.pd

The Role of a Bioengineered Artificial Kidney in Renal Failure

Renal failure continues to carry substantial burden of morbidity and mortality in both acute and chronic forms, despite advances in transplantation and dialysis. There is evidence to suggest that the kidney has metabolic, endocrine, and immune effects transcending its filtration functions, even beyond secretion of renin and erythropoietin. Our laboratory has developed experience in the tissue culture of renal parenchymal cells, and has now been able to demonstrate the metabolic activity of these cells in an extracorporeal circuit recapitulating glomerulotubular anatomy. We have observed active transport of sodium, glucose, and glutathione. We describe the design and initial preclinical testing of the bioartificial kidney, as well as future directions of our research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71995/1/j.1749-6632.2001.tb03841.x.pd

Distribution of gentamicin among subcellular fractions from rat renal cortex

A substantial amount of data is available to suggest that lysosomal sequestration of amino-glycoside antibiotics plays a role in the pathogenesis of aminoglycoside induced renal tubule cell injury; however, relatively little information is available on the subcellular distribution of Aminoglycosides in the kidney during treatment protocols of the type that ultimately go on to produce extensive lethal renal tubule cell injury and acute renal failure in experimental animals. This study assessed the distribution of gentamicin and subcellular membranes on a discontinuous sucrose density gradient after in vivo exposure of rats to four daily 100 mg/kg doses of gentamicin as compared to in vitro exposure of normal rat renal cortex to gentamicin during tissue homogenization at drug levels comparable to those seen after in vivo treatment. After both in vivo and in vitro exposure, major localization of gentamicin, the lysosomal marker enzyme (NAG), and the endoplasmic reticulum marker enzyme NADPH-cytochrome c reductase, occurred in a very light membrane fraction. Within this membrane fraction, gentamicin was more closely associated with the NAG than with the NADPH-cytochrome c reductase. The results could not be explained by complete lysosomal disruption during subcellular fractionation after in vivo gentamicin. These data provide additional insights into both the possibilities for subcellular interactions of aminoglycosides in the kidney, and into the methodology required to optimally assess such interactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25665/1/0000217.pd

Development of a wearable bioartificial kidney using the Bioartificial Renal Epithelial Cell System (BRECS)

Cell therapy for the treatment of renal failure in the acute setting has proved successful, with therapeutic impact, yet development of a sustainable, portable bioartificial kidney for treatment of chronic renal failure has yet to be realized. Challenges in maintaining an anticoagulated blood circuit, the typical platform for solute clearance and support of the biological components, have posed a major hurdle in advancement of this technology. This group has developed a Bioartificial Renal Epithelial Cell System (BRECS) capable of differentiated renal cell function while sustained by body fluids other than blood. To evaluate this device for potential use in endâ stage renal disease, a large animal model was established that exploits peritoneal dialysis fluid for support of the biological device and delivery of cell therapy while providing uraemic control. Anephric sheep received a continuous flow peritoneal dialysis (CFPD) circuit that included a BRECS. Sheep were treated with BRECS containing 1 à  108 renal epithelial cells or acellular sham devices for up to 7 days. The BRECS cell viability and activity were maintained with extracorporeal peritoneal fluid circulation. A systemic immunological effect of BRECS therapy was observed as cellâ treated sheep retained neutrophil oxidative activity better than shamâ treated animals. This model demonstrates that use of the BRECS within a CFPD circuit embodies a feasible approach to a sustainable and effective wearable bioartificial kidney. Copyright © 2016 John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140038/1/term2206.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140038/2/term2206_am.pd

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

BACKGROUND: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system. AIM: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF. METHODS AND RESULTS: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation. CONCLUSION: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

Alterations in Renal Structure and Function in a Rat Model of Cyclosporine Nephrotoxicity1

ABSTRACT ABBREVIATiONS: GFR, glomerular filtration rate; RBF, renal blood flow: MAP, mean arterial pressure. 74

A Biomimetic Membrane Device That Modulates the Excessive Inflammatory Response to Sepsis

OBJECTIVE: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis. DESIGN: Laboratory investigation. SETTING: University of Michigan Medical School. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the SCD in septic shock, pigs were administered 30×10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD. MEASUREMENTS AND MAIN RESULTS: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation. CONCLUSIONS: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway

Long term health related quality of life following colorectal cancer surgery: patient reported outcomes in a remote follow-up population

Background: Remote follow-up (RFU) after colorectal cancer (CRC) surgery allows delivery of surveillance tests without the need for regular outpatient clinical appointments. However, little is known about health related quality of life (HRQoL) in RFU patients.Methods: EQ-5D, QLQ-C30 and QLQ-C29 questionnaires were distributed to CRC patients enrolled in a RFU programme. The primary outcome of HRQoL scores was analysed by year of RFU, demographics, operation-type, stoma and adherence to RFU protocols. Results:428 respondents (59.3%), mean age of 71years(SD 10.1) and a median RFU time of 2.6years (IQR: 1.6-4.8 years) were included. 26.6% of patients reported ‘perfect health’. The median EQ-5D index score was 0.785 (IQR: 0.671-1) and QLQ-C30 Global HRQoL score was 75 (IQR: 58.3-83.3). Females had significantly lower EQ-5D median score of 0.767 (IQR: 0.666-0.879, p=0.0088). Lower QLQ-C30 HRQoL scores were seen in stoma patients, median 66.6 (IQR: 58.3-83.3, p=0.0029). Erectile dysfunction (p=0.0006) and poor body image (p=0.001) were also reported more frequently in stoma patients. Patients undergoing right-sided resection reported a lower median EQ-5D score of 0.765 (IQR: 0.666-0.879, p=0.028) and higher pain severity (p=0.0367) compared with left-sided resections. There were 128 (29.4%) patients that breached RFU protocol and were seen in adhoc colorectal clinics. However, there was no statistical difference in HRQoL between patients who adhered to or breached RFU protocols.Conclusions: Overall HRQoL in patients in RFU is good, with no difference in those strictly followed up remotely. However, females, right-sided resections and patients with stomas may require additional clinical reviews.

Contemporary review of risk-stratified management in acute uncomplicated and complicated diverticulitis

BACKGROUND: Acute colonic diverticulitis is a common clinical condition. Severity of the disease is based on clinical, laboratory, and radiological investigations and dictates the need for medical or surgical intervention. Recent clinical trials have improved the understanding of the natural history of the disease resulting in new approaches to and better evidence for the management of acute diverticulitis. METHODS: We searched the Cochrane Library (years 2004-2015), MEDLINE (years 2004-2015), and EMBASE (years 2004-2015) databases. We used the search terms "diverticulitis, colonic" or "acute diverticulitis" or "divertic*" in combination with the terms "management," "antibiotics," "non-operative," or "surgery." Registers for clinical trials (such as the WHO registry and the https://clinicaltrials.gov/) were searched for ongoing, recruiting, or closed trials not yet published. RESULTS: Antibiotic treatment can be avoided in simple, non-complicated diverticulitis and outpatient management is safe. The management of complicated disease, ranging from a localized abscess to perforation with diffuse peritonitis, has changed towards either percutaneous or minimally invasive approaches in selected cases. The role of laparoscopic lavage without resection in perforated non-fecal diverticulitis is still debated; however, recent evidence from two randomised controlled trials has found a higher re-intervention in this group of patients. CONCLUSIONS: A shift in management has occurred towards conservative management in acute uncomplicated disease. Those with uncomplicated acute diverticulitis may be treated without antibiotics. For complicated diverticulitis with purulent peritonitis, the use of peritoneal lavage appears to be non-superior to resection