Over the last several years, significant developments have occurred in science and technology, especially in the area of kidney disease. Translating these advancements into clinically applicable interventions that improve patient outcomes is the next challenge in the realm of patient-oriented research. Our overall mission is to develop strategies that will improve clinically relevant outcomes in patients with kidney disease. We aim to accomplish our goals by examining the mechanisms by which kidney disease patients are predisposed to adverse outcomes and by testing novel interventions that would counteract or ameliorate these factors. Our patient population of interest spans from patients with early kidney disease to ones with end-stage renal disease, as well as ones with acute kidney injury. Our areas of research interest include, but are not limited to, nutritional and metabolic aspects of kidney disease, basic and clinical acute kidney injury models, discovery and validation of biomarkers, use of electronic health records ad bioinformatics, pharmacogenomics, and social determinants and behavioral interventions. We have ongoing collaborations in studies examining bioartificial kidney models, biomedical imaging, and alternative medicine, including mind and body practices.

 

Research Areas

We aim to delineate the mechanisms through which wasting syndrome develops in patients with kidney disease and examine nutritional and metabolic interventions that would counteract these catabolic signals by stimulating protein and energy anabolism. Over the last decade, we employed state-of-the-art techniques to investigate specific research questions related to this subject. In a series of investigations, we measured how dialysis changes protein and energy metabolism and showed that the hemodialysis procedure per se stimulates protein degradation in muscle and other tissues (Am. J. Physiol., 2002). We extended our initial observations to show that dialysis-stimulated proteolysis is due in part to inflammation (Kidney Int. 2002) and that the defects in protein breakdown can be blunted by giving parenteral nutrition (J. Clin. Invest., 2002) and/or exercise (Am. J. Physiol., 2004) during dialysis. We also showed that parenteral nutrition can increase albumin synthesis in dialysis patients (J. Am. Soc. Nephrol., 2004). We subsequently applied these strategies to show the effectiveness oral nutritional supplementation, alone or with resistance exercise (J. Am. Soc. Nephrol., 2006, Eur. J. of Clin Nutr. 2006, Neph Dial Transpl. 2007). These studies have led to the development of clinical guidelines regarding the most appropriate nutritional management of patients on maintenance dialysis (Kidney International 2014) and urged the regulators to change the principles for allowance of nutritional supplementation during hemodialysis.

In a series of concurrent studies, we investigated the role of systemic inflammation and insulin resistance and deprivation in muscle wasting in dialysis patients and showed their critical importance as modifiable targets (Kidney international, 2005, 2005, 2007; JASN 2012; CJASN 2016). We have also  demonstrated that obesity and systemic inflammation are major determinants of insulin resistance in ESRD patients. In order to assess insulin effects on protein homeostasis, we have recently established the dual-clamp technique where we are measuring the sensitivity and responsiveness to insulin in the carbohydrate and protein levels. We are also testing the effects of anti-inflammatory and insulin-sensitizing agents on these outcomes.

Our group has also focused on delineating the mechanisms through which metabolic derangements develop in chronic kidney disease and the interplay between progressive loss of kidney function, the associated metabolic abnormalities and increased cardiovascular risk profile in this patient population. In a series of publications, they were able to show the inter-relationships between oxidative stress, inflammation and endothelial dysfunction in patients with chronic kidney disease through a prospective longitudinal study (Kidney Int 2004, J. Am. Soc. Nephrol., 2007,Amer. J. of Clin Nutr. 2007). The comprehensive laboratory markers of oxidative stress, inflammation, and insulin resistance, coupled with systematic measurements of endothelial function and the degree of carotid arteriosclerosis were the unique aspects of these studies. Based on these data, we completed a prospective randomized pilot study examining the effects of antioxidant therapy on oxidative stress, inflammation, and endothelium dependent vascular function in patients with chronic kidney disease (TALAT study - Journal of Renal Nut 2011). We subsequently extended these findings to patients on maintenance hemodialysis and completed one of the largest RCTs in MHD patients examining the effects of antioxidant therapy on biomarkers of inflammation, lipid oxidation and ESA utilization (PATH study – JASN 2014). The combined results of these RCTs suggested that interventions other than non-specific anti-oxidant therapy might be necessary to attenuate the increased inflammatory and oxidative stress burden in Stage 3-5 CKD patients. Our concurrent studies also indicated that obesity, especially the extent of fat mass was one of the most important determinants of systemic inflammation and oxidative stress burden in CKD patients (JASN 2008, JRN 2009). Based on these data, we embarked another RCT examining the effects of diet and exercise, alone or in combination on metabolic profile of Stage 3-4 CKD patients. This particular study has been recently completed and the results will be available within the next several months.

Finally our research group, in collaboration with Kidney Research institute at University of Washington in Seattle, has been awarded a collaborative U01 grant to examine novel therapies to improve cardiovascular outcomes in hemodialysis patients. The initial studies for this initiative started in early 2015.

Our research group (Drs. Ikizler, Siew, Fissell, Billings, Matheny and Parr) is studying a number of different aspects of acute kidney injury (AKI).  We were one of the major participants in the multi-center AKI research initiative (Project to Improve Care in Acute Renal Disease - PICARD), which was the earliest and most comprehensive epidemiological study of AKI patients in the intensive care unit. This group published a series of landmark studies examining the epidemiology of AKI, its prognostic implications and strategies to manage acute kidney failure (initiation, dose and modality selection for dialysis).

We currently study biomarkers of acute kidney injury, development of prognostic tools for acute kidney injury, post-AKI practice patterns and pharmacokinetics of different antibiotics in patients receiving renal replacement therapy in the critical care setting.

Our group is also a participant of the NIDDK funded The ASessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study, which is a multicenter parallel-matched cohort study of the long-term consequences of AKI. The ASSESS-AKI study includes a diverse cohort of patients with and without AKI and a balanced distribution of patients with and without CKD followed prospectively for 8 years.  VUMC clinical site is the leading recruitment site with over 550 subjects enrolled to date (total cohort 1600). The primary aims of the study are to determine if survivors of AKI are at greater risk of: 1) Developing incident or progressive CKD, 2) Death, CV events (stroke, MI, CHF), or other adverse events compared to well-matched patients without AKI. Another primary aim of ASSESS-AKI is to investigate the incremental value of serial measurements of blood and urine biomarkers for predicting short- and long-term clinical outcomes after AKI.  ASSESS-AKI is designed to overcome methodologic limitations of earlier retrospective long-term AKI studies including better anchoring of baseline kidney function, AKI phenotyping, and tracking of kidney function using serum creatinine instead of administrative codes, the inclusion of appropriately matched non-AKI controls, the proper adjudication of clinical events, and a standardized protocol for sample processing and storage across sites. These strengths provide adequate substrate to properly examine the diagnostic and prognostic value of novel and traditional biomarkers among AKI survivors. Further, the balanced inclusion of non-AKI controls will facilitate the examination of renal and cardiovascular biomarkers in patients with and without CKD while providing opportunities for discovery and cross-validation within the consortium.

Dr. Khaled Abdel-Kader leads studies focused on quality of life (QoL) and quality of care in patients with CKD.  In previous work, we described the significant physical and mental burdens that patients with advanced CKD suffer, burdens that are comparable to patients with ESRD.  In addition, we implemented novel, individualized QoL measures to elicit patient-centered domains when assessing QoL.  More recent work has used frequent sampling techniques to provide novel, more comprehensive assessments of patient symptom burdens in the setting of CKD.

A second area of research led by Dr. Abdel-Kader is the use of medical informatics to describe and address gaps in care in CKD.  Our previous work examined the quality of CKD care in an academic primary care provider setting and discovered substantial gaps in care.  Subsequently, we developed and implemented a clinical decision support system as part of a randomized controlled trial targeting improved CKD care by primary care physicians. More recently, we have described disparities in CKD patient access to health IT tools and potential effects on outcomes. Dr. Abdel-kader continues his focus by working to develop and validate predictive models in CKD using EHR data from multiple medical centers and comparing modeling techniques including machine learning and traditional statistical approaches. Such models could be used to help risk stratify populations and guide screening, evaluation, and treatment initiatives with the aim of improving CKD care and QoL.

Under the leadership of Dr. Kelly Birdwell, our group examines the factors involved in the pathogenesis, course, and survival of patients with kidney failure and kidney transplantation, with studies ranging from genotypic variation and molecular consequences to biologic markers of disease. In particular, our work focuses on the cardiovascular and metabolic complications associated with kidney transplant and immunosuppression, investigating the interplay of phenotypic, genetic and biochemical abnormalities present post transplantation. Using a pharmacogenomics approach, we conduct research using BioVU, Vanderbilt’s DNA biobank, and the Synthetic Derivative, corresponding electronic medical record data. Our initial study of tacrolimus pharmacogenomics highlighted the association of CYP3A5 variation and dose-corrected blood concentrations (Pharmacogenet Genomics, 2012), providing the framework for clinical implementation of pre-emptive CYP3A5 testing  in kidney and heart transplant recipients at out institution, as well as evidence for tacrolimus dosing guideline (in review). We have current pharmacogenomics investigations of acute rejection, calcineurin inhibitor toxicity (Pac Symp Biocomput, 2014), squamous cell cancer, and new onset diabetes after transplant. We direct a longitudinal prospective observational study of kidney transplant recipients, collecting blood, urine, body composition measurements, and vascular ultrasound studies to understand the metabolic changes occurring in kidney transplant patients over time and how these relate to development of new onset diabetes and cardiovascular events.  This cohort also provides a unique resource for the prospective pharmacogenomics assessment of kidney transplant patients, with the goal of ongoing discovery as well as implementation of findings to bring personalized medicine to clinical practice.

 

Dr. Birdwell and Dr. Kensiger are also focusing on the evolution of cardiovascular risk factors following renal transplantation in a longitudinal cohort study.   In addition to the traditional cardiovascular risk factors, renal transplant patients have other non-traditional risk factors such has oxidative stress, inflammation, and adverse metabolic effects of immunosuppression.   It remains unclear how these complex interactions effect endothelial function and cardiac morphology and function.  The aim is to gain an improved understanding of cardiovascular disease progression following renal transplant by analyzing annual echocardiograms, carotid ultrasounds, and brachial artery ultrasounds in a cohort of transplant recipients.  These studies are performed in conjunction with the studies in CKD patients not on dialysis.

In collaboration with Dr. Gurjeet Birdee from the Division of General Internal Medicine and Public Health and Osher Center for Integrative Health, we aim to study the potential effectiveness and mechanisms of mind-body practices for patients with chronic kidney and metabolic disease. Mind-body practices focus on the interactions of the brain, mind, body, and behavior with the intent to affect physical functioning and promote health. Common forms of mind-body practices in the United States include yoga, meditation, t’ai chi, and biofeedback. Utilizing patients with end-stage renal disease on maintenance hemodialysis, we are investigating if mind-body practices, such as yoga, may provide a novel therapeutic intervention for patients with end-stage renal disease to improve quality of life, symptoms associated with disease, and reduce cardiovascular risk factors. In a survey among patients receiving maintenance hemodialysis, we identified that a majority of patients were interested in learning mind-body practices (Evid Based Complement Alternat Med 2013). In a randomized clinical pilot study, we demonstrated the feasibility of delivering yoga during hemodialysis during a 12-week intervention (manuscript under review, 2014). Presently, we are conducting a larger randomized clinical trial among patients receiving hemodialysis to determine the clinical effectiveness of intra-dialysis yoga as compared to an educational comparison group on outcomes of quality of life, exercise capacity, blood pressure, and mood. 

Under the leadership of Dr. Kerri Cavanaugh, our team examines the practices and factors that influence exchange of information between patients, their families, providers and health systems. We have contributed to the understanding of the role of health literacy and numeracy (Annals of Internal Medicine, 2008) among patients with chronic disease, including kidney diseases (JASN, 2010; Transplantation, 2014). This research includes the development and testing of a variety of patient-centered intervention strategies to enhance patient-provider communication (Diabetes Care 2009), improve patient understanding of their health status (AJKD, 2013), motivate their behaviors for optimal self-care and ultimately lead to better clinical outcomes, quality of life and satisfaction with care. These research programs include patients who may be a risk for kidney diseases, those with established chronic kidney disease, or with end-stage kidney disease receiving dialysis or a kidney transplant.  In addition, our team is experienced in qualitative methods such as focus groups and interviewing strategies to elicit important patient and provider perspectives to inform intervention improvements and also prioritize future research (J Ren Nutrition 2010; Transplantation, 2015). Our team’s expertise in survey development has contributed novel validated assessments of health numeracy (Patient Educ & Counsel, 2013), kidney awareness and kidney knowledge (CJASN, 2009; AJKD, 2011; Kidney International, 2011).  Future research examines kidney disease health communication practices internationally, among pediatric patients and specifically at the level of the health system.