The Translational Research in Biomarker Endpoints and Applications in Kidney Disease (TRIBE-AKD)

tribe aki
dr parikh

Chirag R. Parikh, M.D., PhD,
Director, Division of Nephrology
Ronald Peterson Professor of Medicine,
1830 E. Monument Street
4th Floor, Suite 416
Baltimore, MD 21287

Hopkins Nephrology
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My research group is dedicated to the application of laboratory and preclinical-based discoveries to clinical studies in kidney disease and related disorders. An overarching component of our mission is to advance the mechanistic understanding of novel biomarkers and to enhance their clinical utility in complex diseases. Our multidisciplinary team is comprised of talented physicians and scientists committed to patient-oriented research and developing solutions in clinical medicine and disease management in the community. Our group aims to leverage our collective creativity, commitment, experiences, and skills to improve the care of patients and communities.

I founded the Translational Research in Biomarker Endpoints and Applications in Kidney Disease (TRIBE-AKD) consortium in 2005. This consortium has conducted multicenter studies for efficient discovery and validation of novel biomarkers of kidney diseases. Current clinical definitions of kidney disease are largely based on serum creatinine, an imperfect measure that obscures much of the heterogeneity in kidney diseases thereby impeding clinical management and drug development. Work from the TRIBE-AKD group has dissected this heterogeneity in kidney diseases through biomarkers of renal tubular injury, repair, and inflammation.

The TRIBE-AKD group has developed assays for several kidney injury biomarkers and amassed novel translational research methodologies for biomarker development and assessing biomarker performance. We have assembled multicenter longitudinal prospective cohorts for translational research studies across several clinical settings of acute kidney injury and chronic kidney disease supported by a large biosample repository with associated bioinformatic methods. Leveraging both our biosample repository and bioinformatics, we are positioned to support all phases of translational research and biomarker development. Our studies have advanced clinical management in several settings such as; expand deceased donor kidney transplantation by reducing discard of kidneys with acute kidney injury, refine the clinical definitions of perioperative AKI and hepatorenal syndrome and identify patients with rapid decline in kidney function in diabetic kidney disease. Our studies have also advanced the regulatory approvals of kidney injury biomarkers.

We have created a collaborative environment supported by a strong research network and infrastructure. We actively seek the perspective of patients, communities, and other fields of research. The group also seeks to recruit and train students and young scientists to translate pathophysiological mechanisms into clinical practice that can directly improve patient outcomes.


Meet the Johns Hopkins Team




Former Team Members












Collaborators

Translational Research Investigating Biomarker Endpoints (TRIBE) Study

Deceased Donor Study

Kidney Precision Medicine Project (KPMP)

Overview of Projects


The group has a variety of projects, both ongoing and complete in data collection. Below you will find information regarding each of them. If you are interested in learning more or would like to work with these studies, you can explore their individual pages using the navigation bar on the left side of this page, or you can contact us.

Translational Research in Biomarker Endpoints Consortium (TRIBE-AKI)
This consortium aims to investigate novel biomarkers in the detection of early AKI after major cardiac surgery.

Deceased-Donor Biomarker Study
The shortage of kidneys for transplantation is a major dilemma. Efforts have been taken to expand the organ supply by using kidneys from deceased donors. However, deceased donor kidneys often come with risk factors for allograft dysfunction, such as older age and acute kidney injury. This project has identified novel biomarkers in kidney transplantation associated with allograft outcomes. This study will assess real-time point-of-care biomarker measurements via rapid-testing lateral-flow devices to validate associations with graft outcomes in kidney transplant recipients.

Kidney Precision Medicine Center of Excellence (KPMCOE)
The KPMCOE repository of EPIC data consists of all patients with serum creatinine values ever checked at Johns Hopkins Hospital (1.7 million patients, 16 million serum creatinine values, 54 million outpatient contacts) from 2003 onwards. In processing and curating repository data, this study aims to modernize kidney disease research, improve shared decision making, and facilitate the execution of future kidney research studies.

Kidney Precision Medicine Project (KPMP)
In the hopes of discovering therapeutic targets for acute kidney injury, which currently has no specific therapy, the NIH/NIDDK has created the Kidney Precision Medicine Project consortium.

Caring for OUTPatiEnts after Acute Kidney Injury (COPE-AKI)
This trial aims to develop the best practices in caring for patients after hospitalization with moderate to severe acute kidney injury (AKI) by comparing the standard of care against a study team intervention. Individuals assigned to the study intervention will receive multidisciplinary care recommendations from a team of providers, including a study nephrologist, nurse navigator, and pharmacist.

Novel Approaches in the Investigation of Kidney Disease (NAIKiD)
This study aims to establish a biorepository of clinical data, kidney biopsy tissue, blood samples, and urine samples from adult patients scheduled for clinically indicated biopsies. Through this project, novel blood and urine biomarkers will be identified to develop better diagnostic tools that recognize the determinants of kidney disease.

The ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Network
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.

Personalized Recommendations for Acute Kidney Injury (AKI) Care Using a Kidney Action Team (KAT): A Randomized Trial
Hospitalized patients who develop acute kidney injury (AKI) are at greater risk for clinical decline and death. This clinical trial investigates the impact of individualized AKI-specific recommendations by trained nephrologists and pharmacists delivered immediately upon the detection of AKI in hospitalized patients.

Novel Serum and Urinary Biomarkers of Diabetic Kidney Disease
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. The primary goal of this project is to develop novel urine biomarkers to better predict progressive CKD in diabetics.

Chronic Kidney Disease in Children
Progression of chronic kidney disease (CKD) in children leads to end stage renal disease (ESRD), which is associated with mortality rates 30-150 times higher than in the general pediatric population. In this project, novel biomarkers of kidney injury, inflammation, repair, and fibrosis will be combined with traditional measures to facilitate risk prediction of CKD progression.

Kidney Biomarkers and the Differential Diagnosis and Prognosis of AKI in Patients with Cirrhosis
Renal dysfunction is a common complication in hospitalized patients with cirrhosis. The diagnosis of Type 1 Hepatorenal syndrome (HRS) is one of exclusion and cannot be made until other causes of renal failure, particularly acute tubular necrosis (ATN), are ruled out. In this prospective multicenter cohort study, we are determining the efficacy of biomarkers in correctly identifying ATN in hospitalized patients with cirrhosis and renal dysfunction, thereby facilitation the diagnosis of Type 1 HRS.


PRESERVE Trial (Sub-Study 578) Biomarker Collection and Analysis Among Participants
The PRESERVE trial (Prevention of Serious Adverse Events Following Angiography) is a multicenter VA Healthcare System study that is led by Steven Weisbord, MD, MSc and Paul Palevsky, MD, of the Pittsburgh VA Healthcare System. This study seeks to collect and analyze serum and urine biomarkers in high-risk patients undergoing coronary and non-coronary angiography to enhance our understanding of their role in the setting of CIAKI.

Translational Research Investigating Biomarker Endpoints (TRIBE)


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 National Heart, Lung, and Blood Institute 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 acute kidney injury (AKI). Nine North American sites are participating in this projects. Over 3,000 patients, both adult and children, undergoing cardiac surgery were enrolled. Blood and urine specimens were collected preoperatively and daily during the first 5 days of hospitalization. Some key results from this study are given below:

  1. Kidney injury biomarkers peaked earlier than serum creatinine and were associated with AKI.

    Parikh CR, Devarajan P, Zappitelli M, Sint K, Thiessen-Philbrook H, Li S, Kim RW, Koyner JL, Coca SG, Edelstein CL, Shlipak MG, Garg AX, Krawczeski CD. Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J Am Soc Nephrol 2011; 22(9): 1748-1757.

  2. Mortality Rates approx. 3 years after cardiac surgery increased monotonically by tertile of urinary biomarkers in the patients with and without AKI during index hospitalization. The mortality rate in the highest tertile of urinary biomarkers of kidney injury in those without clinical AKI approximated the mortality rate in the lowest tertile of biomarkers in those with clinical AKI (except for L-FABP).

    Coca,S.G.; Garg,A.X.; Thiessen-Philbrook,H.; Koyner,J.L.; Patel,U.D.; Krumholz,H.M.; Shlipak,M.G.; Parikh,C.R. Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery. J Am Soc Nephrol 2014; 25(5):1063-71.

  3. Clinical AKI at the time of cardiac surgery is indicative of concurrent cardiovascular stress rather than an independent renal pathway for long-term adverse cardiovascular events.

    Coca,S.G.; Garg,A.X.; Thiessen-Philbrook,H.; Koyner,J.L.; Patel,U.D.; Krumholz,H.M.; Shlipak,M.G.; Parikh,C.R. Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery. J Am Soc Nephrol 2014; 25(5):1063-71.

Funding information for this project

The TRIBE-AKI Consortium is supported by the NIH/NHLBI (R01HL085757, “Novel Biomarkers in Cardiac Surgery to Detect Acute Kidney Injury”)



PubMed

Biomarker Consortium in Acute Kidney Injury (TRIBE-AKI)

Deceased-Donor Study


The shortage of kidneys for transplantation is a major dilemma, which has driven efforts to expand the organ supply by using kidneys from deceased donors; however these have higher risk factors for allograft dysfunction. Greater use of kidneys with uncertain quality and the lack of precise tools to measure kidney quality during procurement have led to high organ discard rates and increasing numbers of transplant recipients with allograft dysfunction. Without precise methods to assess kidney quality, it is likely that some useful kidneys are discarded and some low-quality kidneys are transplanted with potentially harmful results. This project has identified novel biomarkers in kidney transplantation associated with allograft outcomes. This study will assess real-time point-of-care biomarker measurements via rapid-testing lateral-flow devices to validate associations with graft outcomes in kidney transplant recipients.

This biomarker study is one of the largest, applied, translational research studies in kidney transplantation. In collaboration with several organ procurement organizations, urine was collected from 1,679 deceased donors at the time of procurement along with samples of transport solution for every pumped kidney. We have measured known injury biomarkers including IL-18, NGAL, KIM-1, LFABP, and cystatin C, with further plans to measure biomarkers of chronic kidney disease, such as uromodulin, albumin, and TGF-ß. We are evaluating rates of delayed graft function and allograft failure in recipients of these kidneys by linkage to the United Network for Organ Sharing database. We are also collecting detailed recipient data about estimated glomerular filtration rate, immunosuppression, acute rejection, and other complications for two years after transplant via chart review at several participating transplant centers. Our ultimate goals are to help maximize the allocation of viable kidneys, develop therapies for ischemia-reperfusion injury, and improve recipient outcomes through the study of noninvasive deceased-donor biomarkers at the time of procurement.

We are using lateral flow devices (LFD) in a real-time point-of-care setting as an innovative approach to assess kidney graft quality for the early determination of kidney allograft prognosis. We have previously identified three urine biomarkers (YKL-40, UMOD, and OPN) that are associated with kidney repair in kidneys. Compared with existing methods, noninvasive donor biomarkers have the potential advantage of rapidly assessing AKI repair mechanisms and immune activation. Fast, cost-effective, and objective biomarker measurement at the time of organ procurement will enable these data to have an impact on transplant centers’ organ quality assessment and acceptance decisions. Donor biomarkers may also be useful in monitoring early management and designing innovative therapies. The workflow for collecting urine samples for real-time point-of-care biomarker measurement is given below:



Some key results from this study are given below:





Funding Information for this Project

The Deceased Donor Study is supported by the NIH/NIDDK (R01DK093770, “Novel Kidney Injury Tools in Deceased Organ Donation to Predict Graft Outcome”)


PubMed

Deceased Donor Study

Kidney Precision Medicine Center of Excellence (KPMCOE)


The KPMCOE was founded with the vision to transform the care of patients with kidney disease. To modernize clinical practice, the KPMCOE analyzes electronic health records, identifying barriers to care and implementing real-time digital tools to improve risk assessment or integrate quality improvement initiatives. Alongside clinical optimization, the KPMOCE aims to advance kidney disease research by improving the diagnosis and classification of patients with kidney disease and enrich enrollment in prospective trials or studies.

The KPMCOE repository of EPIC data on Hopkins Precision Medicine Analytic Platform (PMAP) consists of all patients with serum creatinine values ever checked at Johns Hopkins Hospital (1.7 million patients, 16 million serum creatinine values, 4 million inpatient records, 54 million outpatient contacts) from 2003 onwards. The database is subject to weekly updates, processing, and cleaning to create curated data tables for analysis.

The primary aims of KPMCOE include:
  • Diagnosis and Prevention: Can improved clinical phenotyping aid in the early diagnosis and management of acute kidney injury? Can real-time interrogation of the electronic health record prevent iatrogenic kidney injury?
  • Measure Outcomes: Can prevention of acute kidney injury reduce subsequent chronic kidney disease? Does a multipronged approach, including the implementation of risk tools in electronic medical records, lead to better outcomes in patients with kidney disease?
  • Discovery: Can we efficiently identify opportunities for enrollment in clinical trials and biorepository registries that will lead to new discoveries for treatment and prevention?


More information can be found here.

Kidney Precision Medicine Project (KPMP)


In the hopes of discovering therapeutic targets for acute kidney injury, which currently has no specific therapy, the NIH/NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) has created the Kidney Precision Medicine Program (KPMP) consortium. The KPMP project is composed of recruitment sites, tissue interrogation sites, and central hubs. Together, the project intends to create a kidney tissue atlas, define disease subgroups, inform critical cells and pathways, and identify targets for novel therapies through kidney biopsies from participants with AKI or CKD. More information on the Kidney Precision Medicine Project can be found on the NIDDK and KPMP website.



Funding Information for this Project

Funding for this project comes from the NIH-NIDDK (UG3DK114866, "AKI Matched Phenotype Linked Evaluation with Tissue")


PubMed

Kidney Precision Medicine Project

Caring for OUTPatiEnts after Acute Kidney Injury (COPE-AKI)


Acute Kidney Injury (AKI) affects ~60% of all ICU patients and is associated with non-ICU hospital complications including kidney failure, clinical decline, and death. Most research investigates the diagnosis, prevention, and treatment of hospitalized patients with AKI. Few interventional studies, however, address AKI patient outcomes following hospital discharge, a concerning gap given that 20% of patients with AKI are readmitted within 30 days post-hospitalization and are at greater risk for adverse clinical outcomes. Managing AKI post-hospitalization is further exacerbated by delayed follow-ups, lack of continuity of care, and suboptimal medication management.

This trial aims to develop best practices in caring for patients after hospitalization with moderate to severe acute kidney injury (AKI) by comparing the standard of care against the study team intervention. Individuals assigned to the study intervention will receive multimodal care recommendations from a team of providers, including a nephrologist, nurse navigator, and pharmacist. The primary study outcome will evaluate the number of hospital-free days through 90 days of follow-up. Secondary measures within this 90-day window include rates of recurrent AKI, rates of major adverse kidney events, and patient-reported quality of life outcomes.

Funding information for this project

The COPE-AKI Trial is funded by NIDDK (1U01DK129984).

Novel Approaches in the Investigation of Kidney Disease (NAIKiD)


NAIKiD aims to establish a biorepository of clinical data, kidney biopsy tissue, blood samples, and urine samples from adult patients scheduled for either inpatient or outpatient clinically indicated biopsies. Approximately 1000 participants will be enrolled over a period of 10 years. The primary objectives of the study are to 1) identify novel blood and urine biomarkers of kidney injury, repair and disease, and 2) develop diagnostic tools and treatment options for kidney disease.

Funding information for this project

Funding for this project comes from Edward S. Kraus, M.D. Endowment for Young Investigators.

ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI)


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 the Clinical Research Centers at Kaiser Permanente of Northern California, the Vanderbilt University - Validation of Acute Lung Injury Biomarkers for Diagnosis (VALID) Study, the 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.
The ASSESS-AKI Study will address the following Specific Aims through the initiation and follow-up of a long-term prospective cohort of patients with and without evidence of having AKI:

Primary Aims
  • Aim 1 — To determine whether patients who survive an episode of AKI have a greater risk of developing chronic kidney disease or faster progression of pre-existing chronic kidney disease than hospitalized patients without AKI after accounting for pre-existing level of kidney function and potential confounders.
  • Aim 2 — To determine whether patients who suffer an episode of AKI have a higher risk of death, cardiovascular events, and other adverse events after hospital discharge than matched patients who did not suffer AKI during hospitalization, after accounting for pre-existing level of kidney function and potential confounders.

Secondary Aims
  • Aim 3 — To evaluate the incremental value of serial measurements of several different blood and urine biomarkers for predicting short- and long-term clinical outcomes after an episode of AKI currently defined using a serum creatinine-based criteria.
  • Aim 4 — To assess whether severity and type of the AKI episode and the presence of pre-existing chronic kidney disease influence long-term risks of loss of kidney function, death, and cardiovascular events in patients with AKI.
  • Aim 5 — To determine if patients who completely recover kidney function within three months of an episode of AKI have a lower risk of adverse events than those patients with AKI whose recovery is incomplete.
  • Aim 6 — To develop a risk score incorporating demographic features, clinical factors, and/or biomarkers that accurately predicts outcomes after an episode of AKI.

More information on the project can be found here

Funding Information for this Project

The ASSESS AKI study is sponsored by the NIDDK (U01DK082185, “Progression of Acute Kidney Injury to Chronic Kidney Disease”)



PubMed

ASSESS-AKI

Personalized Recommendations for Acute Kidney Injury (AKI) Care Using a Kidney Action Team (KAT): A Randomized Trial


Acute Kidney Injury (AKI) is a common hospital complication, occurring in roughly 5-20% of inpatients and contributing to a greater risk for dialysis initiation, clinical decline, and death. Yet, AKI is frequently asymptomatic and overlooked in hospital settings, while internationally defined “best practices” for treatment – namely drug dosing, avoiding nephrotoxic exposures, and further laboratory work-up – show inconsistent follow-through.

Rather than simply increase provider awareness of AKI, this clinical trial investigates whether the impact of real-time personalized recommendations for the workup and treatment of patients with AKI will improve the rates of “AKI best practices” and decrease occurrences of inpatient dialysis, mortality, and AKI progression. Given the diversity of both AKI patients and AKI etiologies, these real-time recommendations are provided by an interdisciplinary “Kidney Action Team” (KAT) consisting of a trained nephrologist and pharmacist. Patients will be randomized to either receive standard of care treatment or to an active intervention arm in which the KAT’s individualized recommendations are delivered to their primary care team.

Funding information for this project

This study is funded by a grant from the Association of Healthcare Research and Quality.

Diabetic Kidney Disease


Chronic kidney disease (CKD) and end stage renal diseases (ESRD) represent an enormous burden in the United States and worldwide. Diabetic kidney disease (DKD) is the single largest cause of CKD and ESRD. DKD is progressive and few therapies are able to alter its course. Currently, clinical risk assessment of DKD depends upon measures of estimated GFR (eGFR) and glomerular injury (albuminuria). However, these two markers fall short of providing sufficient risk stratification for progression to advanced DKD, ESRD and cardiovascular (CV) events. Development of prognostic biomarkers to identify patients with a high risk of progression will aide future clinical trials by serving to enrich the enrollment with patients with a higher event rate, thereby allowing for a reduced sample size to detect an intervention with a given relative risk reduction. Moreover, there is an urgent need to identify the subgroups of patients that are most likely to drive benefit from various forms of intensive therapy (predictive biomarkers) and to identify better surrogate endpoints. By leveraging the data and stored blood and urine samples from three large clinical trials in patients with type 2 diabetes (VA- NEPHRON-D, ACCORD, and Sun-MACRO), we will measure blood and urine biomarkers from diverse pathways including inflammatory, glomerular, tubule injury, and tubulointerstitial fibrosis markers.

There are three principal aims of this project:
  • Aim 1 - To derive and validate biomarker panels for prognosis of renal endpoints (GFR progression and dialysis)
  • Aim 2 - To derive and validate biomarker panels for prognosis of cardiovascular events and death
  • Aim 3 - To test for effect modification by biomarkers to determine if there were sub-groups that demonstrated benefit with various interventions employed in the trials (specifically, dual renin angiotensin aldosterone blockade, intensive glycemic control, or lower systolic blood pressure targets)

Funding Information for this Project

Funding for this project comes from the NIH/NIDDK (U01DK106962, “Leveraging Clinical Trials of Diabetic Kidney Disease to Advance Biomarkers”) and utilizes blood and urine samples from two large clinical trials: VA- NEPHRON-D and ACCORD


PubMed

Diabetic Kidney Disease

Chronic Kidney Disease in Children


We have several ongoing epidemiologic and translational research studies that examine risk factors, early diagnosis and prognosis of kidney disease in children. Several of these are multicenter studies done in collaboration with Yale University, University of Cincinnati and academic centers in Canada. The following protocols had children enrolled and are being followed longitudinally. Data and samples from these studies are available for ancillary studies:

  • In TRIBE-AKI, over 300 children undergoing congenital cardiac surgery were enrolled during hospitalization and the cohort has been followed for seven years through phone calls, medical chart review and data linkages.
  • The Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI) cohort has annual in-person follow-up of over 100 children for five years.
  • We are also measuring urine and serum biomarkers of kidney injury, inflammation, repair, and fibrosis from the samples of the children enrolled in the CKD in Children (CKiD) cohort

Greenberg JH, Whitlock R, Zhang WR, Thiessen-Philbrook HR, Zappitelli M, Devarajan P, Eikelboom J, Kavsak PA, Devereaux PJ, Shortt C, Garg AX, Parikh CR; TRIBE-AKI Consortium. Interleukin-6 and interleukin-10 as acute kidney injury biomarkers in pediatric cardiac surgery. Pediatr Nephrol 2015; 30(9):1519-27.



Funding Information for this Project

The TRIBE-AKI Consortium is supported by the NIH/NHLBI (R01HL085757, “Novel Biomarkers in Cardiac Surgery to Detect Acute Kidney Injury”) and the ASSESS AKI study is sponsored by the NIDDK (U01DK082185, “Progression of Acute Kidney Injury to Chronic Kidney Disease”)


PubMed

Chronic Kidney Disease in Children

AKI in Cirrhosis


Renal dysfunction is a common complication in hospitalized patients with cirrhosis. The diagnosis of Type 1 Hepatorenal syndrome (HRS) is one of exclusion and cannot be made until other causes of renal failure, particularly acute tubular necrosis (ATN), are ruled out. The treatment for ATN is solely supportive via hemodialysis. Differentiating between Type 1 HRS and ATN may be difficult and often takes several days, as traditionally-used distinguishing common urinary parameters may be altered in advanced liver disease. Additionally, it is challenging to differentiate patients who are at risk for AKI progression early in the course of their disease. Crucial delays in diagnosis impair the ability to begin early treatment which can lead to increased morbidity and mortality. Research in both experimental animals and humans has identified urine biomarkers that are capable of detecting renal tubular injury, a prerequisite for ATN with high degrees of sensitivity and specificity which also associate with AKI progression. In this prospective multicenter cohort study, we enrolled ~200 patients from four major academic medical centers with cirrhosis and renal dysfunction. Our mission is twofold – (1) to determine the ability of urinary IL-18, NGAL, KIM-1, and L-FABP to correctly differentiate between Type 1 HRS and ATN and (2) to evaluate the association of these biomarkers with AKI progression and mortality to identify high risk patients.


Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, Coca SG, Parikh CR; TRIBE-AKI Consortium. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013; 57(2):753-62.



Funding Information for this Project

This study was supported by the NIH/NIDDK (1R21-DK078714, “Identifying Acute Tubular Necrosis in Cirrhosis Patients with Renal Dysfunction”)


PubMed

Acute Kidney Injury in Cirrhosis

PRESERVE Sub-Study 578


Contrast-induced acute kidney injury (CIAKI) is a common form of iatrogenic renal disease that is associated with serious, adverse, short- and long-term outcomes. While certain risk factors for CIAKI (e.g., chronic kidney disease, heart failure) are well known, our current capacity to accurately predict which patients are going to develop CIAKI based on these factors is limited. This results in the need to implement resource-intensive preventive care on a widespread basis, rather than in the sub-group of patients at greatest risk. Furthermore, the clinical diagnosis of CIAKI, which is based on small increments in serum creatinine (SCr), is delayed by up to 2-5 days following contrast administration because elevations in SCr reflect the functional effects of renal injury rather than tubular cell damage itself. Identifying serum and/or urine biomarkers that effectively stratify patients' risk fr CIAKI and diagnose its incipient stages could help concentrate the use of preventive care in those patients most likely to derive benefit and facilitate the provision of supportive care early after renal injury in order to mitigate further tubular damage and attenuate the risk for serious, adverse, longer-term outcomes.

The PRESERVE trial (Prevention of Serious Adverse Events Following Angiography) has been funded by the Department of Veterans Affairs to conduct a multicenter, randomized, clinical trial of high-risk patients with chronic kidney disease undergoing angiography to compare the effectiveness of intravenous (IV) isotonic sodium bicarbonate with IV isotonic sodium chloride and oral N- acetylcysteine with oral placebo for the prevention of serious adverse outcomes (i.e., death, need for dialysis, persistent decline in kidney function at 90 days) associated with CIAKI. Dr. Parikh served on the Executive Committee for the trial which oversaw study operations, the performance of participating medical centers, and data quality. He leveraged the substantial resources committed to this large trial to establish a biorepository of blood and urine samples collected from study participants. This biorepository, which will be available as a common-use resource for future investigation of putative and yet-to-be identified biomarkers of CIAKI, will be used for the current proposal to address the following specific aims:

  • Aim 1 - To assess whether serum and/or urine biomarkers measured prior to angiography are able to stratify the risk of developing: a) CIAKI and; b) serious, adverse, longer-term outcomes (90-day death, need for dialysis, persistent renal injury)
  • Aim 2 - To assess whether serum and/or urine biomarkers measured 4 hours following angiography: a) permit the early diagnosis of CIAKI and; b) are able to stratify the risk of developing serious, adverse, longer-term outcomes (90-day death, need for dialysis, persistent renal injury)
  • Aim 3 - To examine the effect of the clinical trial interventions (i.e., IV isotonic sodium bicarbonate and oral N-acetylcysteine) on serum and urine biomarkers 4 hours following angiography and their capacity to predict the development of: a) CIAKI and; b) serious, adverse, longer-term outcomes

Liu C, Mor MK, Palevsky PM, Kaufman JS, Thiessen Philbrook H, Weisbord SD, Parikh CR. Postangiography Increases in Serum Creatinine and Biomarkers of Injury and Repair. Clin J Am Soc Nephrol. 2020 Sep 7;15(9):1240-1250.



Funding Information for this Project

The PRESERVE Trial was supported by the U.S. Department of Veterans Affairs Office of Research and Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Health and Medical Research Council of Australia

ClinicalTrials.gov Identifier: NCT01467466

PubMed

PRESERVE Trial

Biorepository


The TRIBE Biorepository System (TBS) facilitates global sharing of specimens among investigators to facilitate research leading to treatments and cures for complex clinical syndromes by improving researchers' access to human biospecimens. The scope of the biorepository includes providing guidance and support for all aspects of translational research studies that involve human biospecimens. This incorporates practices for the collection, handling, and processing of specimens, models and templates for informed consent, ethical and legal guidelines for handling human subject material for research and treatment, and links to related publications and protocols and other useful information. The TBS objectives can be summarized as follows:
  • Acquire biospecimens for the TRIBE Biorepository System by supporting recruitment in translational research protocols
  • Store DNA, plasma, serum, perfusates, urine, and other human biospecimens for future analysis at optimal temperatures
  • Establish and maintain secured databases for data storage and sample inventory
  • Share stored biological specimens to interested investigators for research
  • Development and maintenance of a quality assurance program with continuous auditing and real time reporting

Biomarker Research Laboratory


The TRIBE Biomarker Laboratory (TBL) promotes discovery and analysis of novel biomarkers in human bio specimens for translational research studies. The laboratory utilizes a variety of instrumentation for sample analysis including a compound light microscope, IDEXX SediVue DX automated urine microscope, BioTek Synergy HT muli-mode microplate reader for ELISA analysis, and Meso Scale Discovery (MSD) MESO QuickPlex SQ 120 instrument for electrochemiluminescence detection of biomarkers in singleplex and multiplex assay formats. Additionally, the laboratory operates an automated Rx Daytona clinical chemistry analyzer from Randox Laboratories capable of measuring electrolytes, creatinine, albumin, cystatin C, and a variety of other analytes listed below. The laboratory employs Sorvall legend X1R bench top centrifuges, refrigerators, and freezers (-20°C and -80°C) for processing and temporary storage of samples and reagents. Long term sample storage is also offered through our biorepository.
Automated clinical chemistry analyzer assays
MESO QuickPlex SQ 120 instrument assays
  • 4-plex (IL-18, KIM-1, MCP-1, YKL-40)
  • 2-plex (Ang-1, Ang-2)
  • 2-plex (Eotaxin, Eotaxin-2)
  • 2-plex (IL-5, IL-9)
  • 2-plex (TNFR-1, TNFR-2)
  • 7-plex Kidney Injury Panel-5 (Albumin, B2M, Cystatin C, EGF, NGAL/LCN2, Osteopontin, Uromodulin)
  • 10-plex Proinflammatory Panel (IL-10, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, IL-12p70)
  • 7-plex Angiogenesis Panel (bFGF, Flt-1,PIGF, Tie-2, VEGF, VGEF-C,VGEF-D)
  • 3-plex (Galectin-3,NT-proBNP,ST-2)
  • Singleplex (NT-proBNP, Follistatin, Tie-1, NGAL)
  • Full list of analytes

Methodology Work for Biomarker Development

Novel biomarkers have great potential in preventing, detecting, and guiding treatment of diseases. We have collaborated to develop methodologies that meet the analytic demands for evaluating novel biomarkers.

Publications

Prognostic Enrichment of Biomarkers for Clinical Trials

We have developed tools to evaluate biomarkers for prognostic enrichment of clinical trials. Enriching clinical trials with prognostic biomarkers can help trials to better evaluate an intervention in a patient population with a higher rate of the unwanted event than the broader patient population. This higher event rate translates to a lower sample size for the clinical trial. Our methodology has been implemented for trials with dichotomous/binary outcomes (BioPET) and for trials with survival/time-to-event outcomes (BioPETsurv). More details regarding BioPET can be found in the Clinical Trials paper: Evaluating biomarkers for prognostic enrichment of clinical trials. Additional information about BioPETsurv can be found in the PLoS One paper: BioPETsurv: Methodology and open source software to evaluate biomarkers for prognostic enrichment of time-to-event clinical trials.

Somalogic Information

We have worked with SomaLogic, a protein biomarker discovery and clinical diagnostics company. We have compared several blood and urine proteins by immunoassay method and aptamer method (SomaLogic), the results of which can be found here (see updated supplementary figures). Further details regarding the assays and measurements can be found here.

Careers


  • We are seeking candidates with experiences in fields such as epidemiology and biostatistics. Persons interested in working in a dynamic translational research environment are encouraged to contact us to discuss career opportunities.

    • Postdoctoral Fellowship positions are available at Johns Hopkins University in translational research, biomarker development, clinical epidemiology, and biostatistics. Postdoctoral fellows are supported by NIH T32 Training Grants restricted to U.S. citizens and permanent residents. Please send curriculum vitae, statement of research training interest and email addresses of three references to: alindem1@jhmi.edu

    • Junior Faculty positions are available at the Division of Nephrology at the Johns Hopkins University School of Medicine. Please send curriculum vitae, statement of research training interest and email addresses of three references to: alindem1@jhmi.edu

    • Postgraduate research positions are available for 1-2 years in the Division of Nephrology. The position involves direct patient interaction, collection and processing of human blood and urine specimens, medical chart abstraction using electronic health records, study database entry, literature review, and reporting at team meetings. Requirements for the position include BA/BS in the life sciences or completion of the pre-medical track. Interested applicants should send a cover letter, resume and unofficial transcript to: alindem1@jhmi.edu