Novel Serum and Urinary Biomarkers of Diabetic Kidney DiseasePrincipal Investigator: Steven Coca, DO, MS
Funding for this project comes from the 1R01DK096549 (NIH-NIDDK) grant.
Type 2 diabetes is a major public health problem worldwide. Progressive chronic kidney disease (CKD) in type 2 diabetes is associated with significant morbidity and mortality. There are few approaches available for the early detection of CKD in diabetes. The primary goal of this project is to develop novel urine biomarkers to better predict progressive CKD in diabetics. We propose that there are better markers to predict CKD in diabetics than albuminuria alone. These include biomarkers that reflect tubulointerstitial injury, inflammation and fibrosis, and oxidative stress. We have identified several promising serum and urinary biomarkers that reflect these different pathways of injury in diabetic kidney disease.
The ACCORD trial demonstrated that intensive glycemic control vs. standard glycemic control over a period of 3.5 years reduced the incidence of albuminuria but did not reduce incident CKD nor end-stage renal disease (2.1% vs. 2.2%) between the two glycemia-treatment arms. These findings require explanation and only underscore the necessity to predict incident and progressive CKD in type 2 diabetes. By analyzing the blood and urine samples collected and stored in the ACCORD study for biomarkers of kidney injury, we have two major goals in this proposal:
1) To identify biomarkers for primary prevention of incident diabetic kidney disease and for secondary prevention of progressive kidney disease; and
2) To better understand the renal outcomes of the ACCORD in relation to the applied interventions.
The ultimate goal is to identify better surrogates or therapeutic targets for kidney disease in diabetics.
Yale University – Chirag R Parikh, MD, PhD
Tulane University – Vivian Fonseca, MD
University of Arkansas – Sudhir Shah, MD
Case Western University – Faramarz Ismail-Beigi, MD
Mike Simonson, MD
University of Cincinnati – Prasad Devarajan, MD
University of Washington – Santica Marcovina, PhD
Wake Forest University – Bob Byinton, MD; Tim Craven, PhD
•Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR: Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med. 2012 May 28. PMID: 22636820
Chronic Kidney Disease Biomarker Consortium-2
Principal Investigator: Steven Coca, DO, MS, Chirag R Parikh, MD, PhD (Yale School of Medicine).
Co-Investigator: Girish Nadkarni, MD, MPH, CPH
Funding for this project comes from the UO1 DK106962 grant.
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the CKD Biomarkers Consortium (BioCon) to promote the discovery and validation of biomarkers to advance the field of chronic kidney disease (CKD) research. Phase II of BioCon began in July 2015. The NIDDK CKD Biomarkers Consortium brings together investigators whose expertise includes clinical nephrology, epidemiology, molecular biology, genomics, proteomics, metabolomics, systems biology, laboratory medicine, biostatistics, and laboratory test verification and qualification. BioCon is a collaborative effort involving numerous investigators from multiple institutions working together to pursue the development and validation of novel biomarkers for CKD by assaying biological specimens and utilizing data from the nation’s largest epidemiological studies of kidney disease.
Our role in this consortium will be to attempt to derive and validate prognostic, predictive and efficacy biomarkers in patients with type 2 diabetes for outcomes of kidney function progression, cardiovascular events, and death. We will utilize banked samples and longitudinal data from three large clinical trials of diabetic kidney disease: ACCORD; VA NEPHRON-D and Sun-MACRO trial.
The ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Network
Principal Investigator: Chirag R Parikh, MD, PhD, FACP
Co-Investigator: Steven Coca, DO, MS
Funding for this project comes from the 1U01DK082185 (NIH-NIDDK) grant.
The ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Network is an epidemiological study of long term outcomes following episodes of AKI. The AKI Network includes Clinical Research Centers at Kaiser Permanente of Northern California, Vanderbilt University – Validation of Acute Lung Injury Biomarkers for Diagnosis (VALID) Study, and Translational Research Investigating Biomarker End-Points (TRIBE) consortium (Yale University, University of Cincinnati, University of London, Ontario, McGill University, Montreal) and a Data Coordinating Center at Penn State University. The overall goals of ASSESS-AKI are to make significant contributions to the field of AKI in the five following areas:
• Establishing a diverse prospective parallel, matched cohort of adults and children with and without AKI.
• Characterizing the short-term and long-term natural history of AKI based on current serum creatinine-based criteria.
• Evaluating the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI.
• Developing a prognostic risk score that integrates patient characteristics and biomarkers to help inform providers and patients about the risks of adverse events after an episode of AKI.
• Identifying the subset of high-risk patients with AKI who could be targeted for future interventional clinical trials to improve outcomes after an episode of AKI.
University of Cincinnati – Prasad Devarajan, MD.
London Health Science Center – Amit Garg.
Montreal Children’s Hospital – Michael Zappitelli.
Go AS, Parikh CR, Ikizler TA, Coca S, Siew ED, Chinchilli VM, Hsu CY, Garg AX, Zappitelli M, Liu KD, Reeves WB, Ghahramani N, Devarajan P, Faulkner GB, Tan TC, Kimmel PL, Eggers P, Stokes JB, Assessment Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury Study Investigators: The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods. BMC Nephrol. 2010 Aug 27; 2010 Aug 27. PMID: 20799966.
Impact of Exercise on Kidney Function and Injury among Elders in the LIFE Trial
Principal Investigator: Steven Coca, DO, MS, Michael Shlipak, MD, MSc (UCSF)
Chronic Kidney Disease (CKD) is increasingly recognized as a major comorbid condition in older adults. The burden of CKD is predominantly due to its adverse physiological effects that promote cardiovascular disease, heart failure, physical and cognitive functional declines, bone disease, and death. Extensive observational research has shown that physical inactivity is a consistent risk factor for progressive kidney disease in older adults. However, no large, randomized controlled trial (RCT) has ever been attempted with the objective of preventing or treating age-related kidney disease, and no adequately powered, clinical trial in any setting has evaluated whether an exercise intervention can delay the progression of kidney disease. The Lifestyle Interventions and Independence for Elders (LIFE) trial demonstrated that a structured physical activity intervention can reduce the incidence of disability compared with a health education control intervention. Now that it has been completed, the LIFE trial offers an ideal and efficient opportunity to test whether a physical activity intervention can improve kidney health in elders in an RCT setting. Our study proposes to transform LIFE into the first large trial to evaluate the impact of exercise on kidney health, utilizing stored blood and urine specimens that have been serially collected from baseline to 24 months.
Risk Clustering and Stratification in Genetically High-Risk Individuals Using Electronic Medical Records and Biomarkers
Principal Investigator: Girish N Nadkarni, MD, MPH, CPH
Co-Investigator: Steven Coca, DO, MS
Funding for this project comes from the 1K23DK107908-01A1 (NIH/NIDDK) grant.
Ethnic minorities are at higher risk of both development and progression of chronic kidney disease. This has been linked in part to risk variants in the APOL1 gene that are present in up to 14% in populations of African descent (including African Americans [AAs] and Hispanic Latinos [HLas]) but are absent in non-Hispanic Whites. Although APOL1 high-risk genotype is, in general, associated with faster eGFR decline, only about 50% progress to ESRD and patients within this group have differing rates of renal functional decline. Thus, risk stratification within this group is poor, limiting early intervention. With a large proportion of vulnerable ethnic minorities at increased risk, innovative methods for predicting renal function decline within this genetically high-risk group are urgently needed. Therefore, our specific aims are:
(1) Establish associations of clinical predictors, lifestyle factors and laboratory parameters with longitudinal eGFR decline in AA/HLas with APOL1 high-risk genotype;
(2) To develop a novel plasma biomarker panel assessing inflammation, injury, vascular insult and fibrosis, for risk prognostication of longitudinal eGFR decline in self-reported AA/HLas with APOL1 high-risk genotype; and
(3) To conduct comprehensive, external validation of the highest performing plasma biomarkers and traditional predictors and derive risk clusters using validated predictors for longitudinal eGFR decline in self-reported AA/HLa’s with APOL1 high-risk genotype.
Aims 1 and 2 will be conducted using the largest cohort of participants with APOL1 risk variants ever assembled (n=809).
Aim 3 will be conducted using four external cohorts, the Vanderbilt BioVU cohort, the Genetic testing to Understand and Address Renal Disease Disparities (GUARDD) study, the Atherosclerosis Risk in Communities (ARIC) study and the Chronic Renal Insufficiency Cohort (CRIC).
These approaches integrating genetic, biomarker and electronic medical record clinical information, will form the basis for future work investigating targeted enrolment of high-risk patients in pragmatic, randomized controlled trials.
Center for Translational Transplant Research at Mount Sinai: Peter S Heeger, MD
Department of Genetics and Genomic Sciences at Mount Sinai: Judy Cho, MD
Novel Biomarkers of Acute Kidney Injury (AKI) after Cardiac Surgery
Principal Investigator: Chirag Parikh,
Co-Investigator: Steven Coca, DO, MS
Funding for this project comes from the R01 HL085757 (NIH/NIDDK) grant.
The Translational Research Investigating Biomarker Endpoints (TRIBE) consortium aims to improve the outcomes and safety of cardiac surgery. This multicenter prospective observational study is sponsored by the NHLBI to investigate novel biomarkers in the detection of early AKI after major cardiac surgery. The main objective of the study is to determine whether the novel biomarkers can be used as diagnostic tests to improve pre-operative and post-operative risk-stratification of AKI. TRIBE-AKI is in its 10th year and has measured dozens of biomarkers and continues explore the associations between peri-operative markers and long-term outcomes.
Linking 9/11 Effects on Kidney Disease
Principal Investigator: Mary Ann McLaughlin, MD
Co-Investigator: Christina Wyatt, MD, MS, Steven Coca, DO, MS
Funding for this project comes from the U01 OH011326-01-A1 (NIH) grant.
This study focuses on the prevalence and identification of kidney disease among World Trade Center Health Program patients and assessment of kidney disease in a multi-factorial manner. The CTRU lab will be responsible for measuring several plasma and urine biomarkers via Mesoscale multiplex for this project.
Impact of early antiretroviral therapy on kidney disease outcomes
Principal Investigator: Christina Wyatt, MD
Co-Investigator: Steven Coca
This project will evaluate the incidence of kidney disease in adults who initiate antiretroviral therapy with high CD4 cell counts, balancing the benefits of virologic suppression for HIV-related kidney disease and the risks of antiretroviral nephrotoxicity with prolonged use.