Standardized Review and Approval Process for High-Cost Medication Use Promotes Value-Based Care in a Large Academic Medical System.

Background: As healthcare costs rise and reimbursements decrease, healthcare organization leadership and clinical providers must collaborate to provide high-value healthcare. Medications are a key driver of the increasing cost of healthcare, largely as a result of the proliferation of expensive specialty drugs, including biologic agents. Such medications contribute significantly to the inpatient diagnosis-related group payment system, often with minimal or unproved benefit over less-expensive therapies.

A quality improvement project to improve early sepsis care in the emergency department.

Background: Sepsis causes substantial morbidity and mortality in hospitalised patients. Although many studies describe the use of protocols in the management of patients with severe sepsis and septic shock, few have addressed emergency department (ED) screening and management for patients initially presenting with uncomplicated sepsis (ie, patients without organ failure or hypotension).

Objective: A quality improvement task force at a large, quaternary care referral hospital sought to develop a protocol focusing on early identification of patients with uncomplicated sepsis, in addition to severe sepsis and septic shock.

A multidisciplinary care pathway significantly increases the number of early morning discharges in a large academic medical center.

In an environment where there is increased demand for hospital beds, it is important that inpatient flow from admission to treatment to discharge is optimized. Among the many drivers that impact efficient patient throughput is an effective and timely discharge process. Early morning discharge helps align inpatient capacity with clinical demand, thereby avoiding gridlock that adversely affects scheduled surgical procedures, diagnostic procedures, and therapies.

SPARC accelerates disease progression in experimental crescentic glomerulonephritis.

Podocytopenia characterizes many forms of glomerular disease, preceding the development of glomerulosclerosis. While detachment of viable podocytes from the underlying glomerular basement membrane is an important mechanism of podocyte loss, the underlying factors involved remain unclear. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein with counteradhesive properties, is normally expressed at low levels by the podocyte but is markedly increased following podocyte injury.

Rosuvastatin protects against podocyte apoptosis in vitro.

Background: Clinical studies suggest that statins reduce proteinuria and slow the decline in kidney function in chronic kidney disease. Given a rich literature identifying podocyte apoptosis as an early step in the pathophysiological progression to proteinuria and glomerulosclerosis, we hypothesized that rosuvastatin protects podocytes from undergoing apoptosis. Regarding a potential mechanism, our lab has shown that the cell cycle protein, p21, has a prosurvial role in podocytes and there is literature showing statins upregulate p21 in other renal cells.

Inducible rodent models of acquired podocyte diseases.

Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases.

Activation of a local renin angiotensin system in podocytes by glucose.

ANG II is a critical mediator of diabetic nephropathy. Pharmacologic inhibition of ANG II slows disease progression beyond what could be predicted by the blood pressure lowering effects alone, suggesting the importance of nonhemodynamic pathways of ANG II in mediating disease. Podocyte injury and loss are cardinal features of diabetic nephropathy.

The renin-angiotensin system in glomerular podocytes: mediator of glomerulosclerosis and link to hypertensive nephropathy.

The renoprotective effects of pharmacologic inhibition of angiotensin II extend beyond the blood pressure-lowering effects alone, consistent with the observation that angiotensin II is produced locally within the kidney and mediates tissue injury through a series of nonhemodynamic effects. Podocytes are terminally differentiated epithelial cells that contribute to the filtration barrier of the kidney, but also safeguard against the development of glomerulosclerosis. Mounting evidence demonstrates that podocytes are not only a local source of angiotensin II production, but are also vulnerable to its deleterious effects, thus fueling the future development of glomerular scarring.

Podocyte injury and targeting therapy: an update.

Purpose Of Review: Podocyte injury is a central event in the development of glomerulosclerosis. This review highlights contributions from the past year to our understanding of mechanisms of podocyte injury and implications for potential treatment strategies of glomerular disease.

Recent Findings: Rearrangement of the actin cytoskeleton, the backbone linking the slit diaphragm, apical domain and sole plate, serves as a common denominator during foot process effacement.

Mechanical strain increases SPARC levels in podocytes: implications for glomerulosclerosis.

Glomerular capillary hypertension is a final common pathway to glomerulosclerosis. Because podocyte loss is an early event in the development of glomerulosclerosis, it is logical that the deleterious effects of glomerular capillary hypertension involve podocyte injury. Yet, the mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood.

Viable podocytes detach in experimental diabetic nephropathy: potential mechanism underlying glomerulosclerosis.

Background: A decrease in podocyte number contributes to the development of glomerulosclerosis in diabetic nephropathy. Although podocytes have been detected in the urine in certain glomerular diseases, their viability is poorly understood.

Methods: Diabetes was induced in rats with streptozotocin.

Mechanical stretch induces podocyte hypertrophy in vitro.

Background: Increased intraglomerular pressure is a final pathway toward glomerulosclerosis in systemic hypertension, diabetes, and focal segmental glomerulosclerosis (FSGS). Increased intraglomerular pressure causes stress-tension, or stretch, on resident glomerular cells. However, the effects of stretch on podocyte growth, and the mechanisms that underlie this, have not been elucidated.

Activation of a local tissue angiotensin system in podocytes by mechanical strain.

Background: Glomerular capillary hypertension, a common denominator in various forms of progressive glomerular disease, results in mechanical distention of the capillary tuft, and subsequent injury of the overlying podocyte layer. The mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Angiotensin II plays a central role in the pathogenesis of chronic renal injury, largely through its actions on the subtype 1 receptor.

The role of cell cycle proteins in Glomerular disease.

Although initially identified and characterized as regulators of the cell cycle and hence proliferation, an extended role for cell cycle proteins has been appreciated more recently in a number of physiologic and pathologic processes, including development, differentiation, hypertrophy, and apoptosis. Their precise contribution to the cellular response to injury appears to be dependent on both the cell type and the nature of the initiating injury. The glomerulus offers a remarkable situation in which to study the cell cycle proteins, as each of the 3 major resident cell types (the mesangial cell, podocyte, and glomerular endothelial cell) has a specific pattern of cell cycle protein expression when quiescent and responds uniquely after injury.

Podocytes that detach in experimental membranous nephropathy are viable.

Background: Podocyte loss contributes to the development of glomerulosclerosis. Although podocytes have been detected in the urine in certain glomerular diseases, the viability of detached cells is not known.

Methods: Urine was collected from rats with experimental membranous nephropathy [passive Heymann nephritis (PHN) model], centrifuged, and following resuspension in tissue culture media, cells were seeded onto collagen-coated tissue culture plates.

Podocyte proliferation and differentiation in glomerular disease: role of cell-cycle regulatory proteins.

Injury to the podocyte underlies many forms of glomerular disease. In contrast to mesangial and endothelial cells, podocytes do not typically proliferate. Moreover, the lack of proliferation is thought to underlie the development of glomerulosclerosis.

Cell cycle control in glomerular disease.

The sequential activation of the cyclin-dependent kinases by their partner cyclins underlies the progression of the cell cycle from quiescence through growth to cell division. More recently a role for these proteins and their inhibitors has been appreciated in several diverse renal and non-renal cell processes, including proliferation, development, differentiation, hypertrophy and apoptosis. The glomerulus represents a unique micro-environment in which to study the cellular outcome following injury, as each of the three resident cell types undergoes a specific and distinct response to a given stimulus.

DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes.

In response to Ab-complement-mediated injury, podocytes can undergo lysis, apoptosis, or, when exposed to sublytic (<5% lysis) amounts of C5b-9, become activated. Following the insertion of sublytic quantities of C5b-9, there is an increase in signaling pathways and growth factor synthesis and release of proteases, oxidants, and other molecules. Despite an increase in DNA synthesis, however, sublytic C5b-9 is associated with a delay in G(2)/M phase progression in podocytes.

Mitotic cell cycle proteins increase in podocytes despite lack of proliferation.

Background: Podocyte proliferation is an uncommon response to glomerular injury and its lack may underlie the development of glomerulosclerosis. However, whether podocytes have the capacity to enter and finish mitosis and cytokinesis is not known.

Methods: The expression of mitotic cell cycle proteins (phosphorylated Histone 3, Cdc2, cyclin B1 and B2) was examined by immunohistochemistry in kidneys of embryonal mice, transgenic HIV-mice, and rats with experimental membranous nephropathy (passive Heymann nephritis, PHN).

Insulin is a potent survival factor in mesangial cells: role of the PI3-kinase/Akt pathway.

Background: Elucidating the mechanisms of apoptosis is important for understanding the molecular mechanisms underlying glomerular disease. The phosphatidylinositol 3 kinase (PI3-kinase)/Akt pathway is essential for survival signaling in non-renal cells. However, little is known about the anti-apoptotic effect of insulin and the role of the PI3-kinase/Akt pathway in mesangial cells (MC) apoptosis.