Inflammatory cytokines in acute kidney injury (Reeves, Ramesh). Acute kidney injury (AKI) occurs in about 5% of patients admitted to hospitals. Many of these individuals die or suffer permanent kidney damage. Investigators here have made the discovery that certain molecules (cytokines) produced by the immune system play an important role in causing AKI. Efforts are underway to learn how these molecules damage the kidney and to develop treatments which interfere with the actions of these molecules.

Ischemic injury in transplanted kidneys (Kwon). Dr. Kwon is interested in clarifying the pathophysiology of acute kidney injury/acute renal failure for better management of the condition. She uses freshly transplanted kidneys from deceased donors as a model of ischemic injury and measures structural and functional endpoints and biomarkers to elucidate the underlying pathophysiology.

Geographic disparities in kidney disease management (Ghahramani). Little is known concerning the impact of geography on the incidence and/or treatment of kidney disease. Using survey methods, meta-analysis and database analysis, Dr. Ghahramani performs observational studies in the following general areas: Geographic aspects of renal disease;  Rural/urban disparities in kidney transplantation; The impact of perceptions of physicians and patients on quality of healthcare.

Natural history of acute kidney injury (Ghahramani, Reeves). Although the high short-term morbidity and mortality associated with AKI are well established, relatively little is known regarding the long-term outcomes of AKI survivors. Together with collaborators in the Department of Public Health Sciences, we serve as the data Coordinating Center for a multicenter NIH-sponsored study of the Natural History of Acute Kidney Injury.

Innate immune responses in acute kidney injury (Reeves, Ramesh). Increasing evidence indicates that inflammation is an important component of AKI. However, it is not clear how the inflammatory response is triggered or how it results in kidney injury. We are examining the role of certain components of the innate immune system in kidney injury. The innate immune response is the initial defense against certain types of infections. However, it also appears to be important in other types of tissue injury. Using genetically modified mice, we have discovered that certain molecules of the innate immune system, such as toll-like receptors and defensins, are critically important mediators of injury. Current studies are examining the mechanisms whereby the immune response is activated and how it leads to injury.

The treatment of anemia in kidney disease (Verma). Anemia is a common complication of kidney disease. In addition to causing generalized fatigue among patients, anemia may accelerate heart disease and require blood transfusions, which carries a small risk of transmitting certain diseases. For the past two decades, dialysis patients have benefited from treatment with erythropoietin to correct their anemia. Researchers in the Division of Nephrology are involved in studies to test new derivatives of erythropoietin in conjunction with iron in order to develop optimal treatment regimens for patients with anemia. We are also one of the first centers to test a new drug which may be able to stimulate erythropoietin production, thereby avoiding the need to give injections of erythropoietin.

Organic anion transport in acute kidney injury (Kwon). Kidney function is a complex combination of glomerular filtration, tubular reabsorption and tubular secretion. Most research in acute renal failure has focused on the effects on filtration and tubular reabsorption. Dr. Kwon has made the discovery that tubular secretion may be an important target of kidney injury and may account for some of the failure to excrete toxic substances. Her work focuses on a specific transport protein, OAT1, which secretes a wide variety of organic compounds into the urine. Her work indicates that OAT1 is mislocalized and inactivated after kidney injury. She is using a combination of animal and human studies to investigate this process further. It is hoped that stimulation of OAT1 might speed the recovery from kidney injury.

Biomarkers for kidney injury (Kwon, Reeves, Ramesh). Current tests of kidney function are not sensitive for early stages of kidney injury. There is a need to develop fast and sensitive tools to detect kidney injury in its earliest stages, before severe damage occurs. We are using animals and humans with kidney injury to look for protein markers in the urine which may be used to detect early injury. Our current work uses a novel fluorescent assay for inflammatory cytokines and sophisticated mass spectroscopy to identify additional markers. We are also collaborating with engineers at the Penn State University to develop sensitive nanoscale detection platforms for these molecules. Our hope is that these detection platforms could be used on a routine basis in high risk patients to detect early AKI and initiate treatment before further injury occurs.

Netrin-1 as a mediator and marker of acute kidney injury (Ramesh). Dr. Ramesh has discovered that Netrin-1, a protein initially discovered as a neuronal guidance cue, plays an important role in AKI. Netrin-1 expression is dramatically increased in the kidney in several forms of experimental kidney injury in mice. Infusion of exogenous Netrin-1 helps to reduce kidney injury. Netrin-1 levels in the urine may be an early marker for a wide range of kidney disorders. Dr. Ramesh is currently exploring the mechanisms which account for the beneficial effects of Netrin-1 in AKI and is determining the diagnostic and prognostic value of urinary Netrin-1 levels in humans with kidney disease.

Tissue plasminogen activator in renal fibrosis (Hu). Kidney fibrosis is a common final pathway for various types of kidney disease. Dr. Hu has discovered that a plasma protease, tissue plasminogen activator (TPA), may play an important role in the progression of kidney fibrosis through receptor-mediated effects on interstitial fibroblasts and myofibroblasts. His current research is focused on elucidating the actions of TPA on fibroblast proliferation and turnover as well as the intracellular signaling pathways which regulate these processes.

Macrophages in diabetic nephropathy (Awad). Accumulating evidence indicates that diabetic nephropathy is a disorder of the immune system. Dr. Awad is studying the critical role of macrophages in the development and progression of diabetic nephropathy through direct effects on podocytes or through alterations of the podocyte niche (microenvironment). In diabetic nephropathy, alterations in the podocyte niche are likely responsible for abnormal podocyte function leading to progressive albuminuria and progressive renal failure. Podocyte function is intimately linked to its complex cytoskeletal structure. As a result of injury, cytoskeletal rearrangement ensues leading to foot process effacement. Demonstrating that macrophages or its effect on podocyte environment play a central role in DN will have important clinical relevance. A number of pharmacological agents targeted to macrophages secretory products could be considered in future trials