Clinical trial NCT04334707: Kidney Precision Medicine Project
Official title: Kidney Precision Medicine Project
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Acute Kidney Failure
Acute Kidney Insufficiency
Acute Renal Failure
Acute Renal Injury
Acute Renal Insufficiency
Kidney Failure, Acute
Kidney Insufficiency, Acute
Renal Failure, Acute
Renal Insufficiency, Acute
Chronic Kidney Diseases
Chronic Kidney Insufficiency
Chronic Renal Diseases
Chronic Renal Insufficiency
Kidney Insufficiency, Chronic
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Michigan
name: Icahn School of Medicine at Mount Sinai
name: Brigham and Women's Hospital
name: Broad Institute of MIT and Harvard
name: The Cleveland Clinic
name: Columbia University
name: European Molecular Biology Laboratory
name: Indiana University
name: Johns Hopkins University
name: Joslin Diabetes Center
name: Pacific Northwest National Laboratory
name: Princeton University
name: Stanford University
name: Ohio State University
name: University of California, San Diego
name: University of California, San Francisco
name: University of Pittsburgh
name: The University of Texas Health Science Center at San Antonio
name: University of Texas
name: Washington University School of Medicine
name: Yale University
First posted: 2020-04-06
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The KPMP will focus on participant populations that account for large proportions of the public health burden of acute and chronic kidney diseases as evidenced by research and federal data.

For CKD, high priority populations include CKD in the setting of diabetes (diabetic kidney disease, DKD) and hypertension-associated CKD (H-CKD). A special population of people with long-standing type 1 diabetes (more than 25 years) who remain free of clinically-evident DKD will also be included.

For AKI, the focus will be on acute intrinsic non-glomerular disease, primarily on acute tubular necrosis (ATN). KPMP will also include a special population of patients at risk for AKI or with early AKI captured by an open (surgical) kidney biopsy performed at the time of clinically indicated laparotomy. The rationale for including this special AKI population is that AKI often occurs early in the clinical course of conditions like sepsis, major surgery and trauma.

Brief summary: Acute kidney injury (AKI) and chronic kidney disease (CKD) impose a significant global health burden. Yet, no effective therapies currently exist for AKI, and only a few are available for CKD.

Despite significant effort from industry and academia, development of pharmacologic therapies for AKI and CKD has been hampered by:

Non-predictive animal models The inability to identify and prioritize human targets The limited availability of human kidney biopsy tissue A poor understanding of AKI and CKD heterogeneity Historically, AKI and CKD have been described as single, uniform diseases. However, growing consensus suggests that different disease pathways lead to different subgroups of AKI and CKD (AKIs and CKDs).

Access to human kidney biopsy tissue is a critical first step to define disease heterogeneity and determine the precise molecular pathways that will facilitate identification of specific drug targets and ultimately enable individualized care for people with AKI and CKD.

A number of research centers across the United States are collaborating to bring state-of-the-art technologies together to:

* Ethically obtain and evaluate kidney biopsies from participants with AKI or CKD
* Define disease subgroups
* Create a kidney tissue atlas
* Identify critical cells, pathways, and targets for novel therapies

The KPMP is made up of three distinct, but highly interactive, activity groups:

* Recruitment Sites: The recruitment sites (RS) are responsible for recruiting participants with AKI or CKD into the longitudinal study and performing the kidney biopsy.
* Tissue Interrogation Sites: The tissue interrogation sites (TIS) are responsible for developing and using innovative technologies to analyze the biopsy tissue.
* Central Hub: The central hub is responsible for aggregating, analyzing, and visualizing the generated data and providing scientific, infrastructure, and administrative support for the KPMP consortium.

Detailed description: The Kidney Precision Medicine Project (KPMP) is a prospective cohort study, whose goal is to use deep molecular phenotypes of kidney biopsies, along with longitudinally collected clinical phenotypic data, in order to develop new disease ontologies, classification systems, and treatments for acute kidney injury (AKI) and chronic kidney disease (CKD). Since its inception, the KPMP has sought out and included substantive patient-representative feedback regarding disease experience, lack of innovation in new kidney disease therapies and patient tolerance for risk levels in balance with potential benefits both to the individual and society.

The KPMP Has publicly and operationally committed itself to always put participants and their best interests first and this foundational principle informs and undergirds every facet of the study. Both AKI and CKD are conditions that impose a significant global health burden. Yet, no effective therapies currently exist for AKI, and only a few are available for CKD. The network will utilize state-of-the-art methods to perform molecular interrogation of the tissue and to link the molecular data to kidney structure and clinical information in the form of a kidney tissue atlas.

Molecular and imaging data derived from kidney tissue will be integrated with clinico-pathologic and genetic information, as well as other data derived from analyses of fluid biospecimens, including peripheral blood, urine, and stool. Using advanced analytics to integrate the data, KPMP will aim to define kidney disease subgroups in molecular terms by identifying critical cells, pathways and targets for novel therapies.

Patients with AKI or CKD will be recruited from clinical care encounters (e.g., clinic visits for CKD patients, hospitalization or emergency room visits for AKI patients) and from electronic resources (e.g., existing registries, electronic health records). All study procedures are designed to optimize participant safety and will be ethically conducted, ensuring subjects fully understand the scope of the study and any possible risks.

For each participant, kidney tissue will be obtained for molecular phenotyping and clinical diagnosis. The diagnostic interpretation will be returned to the participant's primary caregiver to inform clinical care, but no treatment interventions will be prescribed by the KPMP. In addition to kidney biopsy, the study will involve collection of baseline (time of biopsy) and longitudinal biospecimens (including urine, plasma, serum, DNA and stool) and demographic, clinical, and laboratory data. Participants will be followed through scheduled in-person and remote (telephone) study visits, as well as through periodic review of electronic health records.

Eligibility criteria: Chronic Kidney Disease Subjects Inclusion Criteria Diabetic kidney disease (DKD)

* Diagnosis of diabetes mellitus (type 1 or 2) established by at least one of the following criteria:

  * Hemoglobin A1C greater than or equal to 6.5%, confirmed with a repeat test within the past year
  * Fasting blood sugar greater than or equal to 126 mg/dL, confirmed with a repeat test within the past year
  * Use of glucose-lowering therapy (insulin or oral or other subcutaneous agents)
  * International Classification of Diseases (ICD) 9/10 diagnostic code for diabetes
* Evidence of persistent kidney damage, manifest as any of the following present on at least two clinic assessments prior to enrollment and at least 3 months apart and excluding subjects with acute medical illnesses and changing kidney function:

  * Estimated glomerular filtration rate 30-59 mL/min/1.73m2
  * Estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73m2 with urine albumin excretion greater than or equal to 30 mg/g creatinine (or mg/day)
  * Estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73m2 with urine protein excretion greater than or equal to 150 mg/g creatinine (or mg/day)

Hypertension-associated Chronic Kidney Disease (H-CKD) Inclusion Criteria

* Diagnosis of hypertension (HTN) established by at least one of the following criteria:

  * BP greater than 140/90 mmHg measured on three occasions over at least 1 month
  * Taking antihypertensive medication for blood pressure (BP) control
  * International Classification of Diseases (ICD) 9/10 diagnostic code for hypertension
* Evidence of persistent kidney damage, manifested as any of the following present on at least two assessments at least 3 months apart and excluding subjects with acute medical illnesses and changing kidney function:

  * Estimated glomerular filtration rate 30-59 mL/min/1.73m2 on two assessments at least 3 months apart with albuminuria or proteinuria less than 2000 mg/g creatinine (or mg/day)
  * Estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73m2 with urine albumin excretion 30-2000 mg/g creatinine (or mg/day)
  * Estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73m2 with urine protein excretion 150-2000 mg/g creatinine (or mg/day)

Acute Kidney Injury Subjects Inclusion Criteria

All three of the following criteria must be met:

* Baseline estimated glomerular filtration rate greater than 45 mL/min/1.73m2. Baseline defined by the median of the last three outpatient serum creatinine measurements from day 7 to 365 prior to enrollment.

  * If only two measurements obtained within this window, the two results will be averaged.
  * If only one measurement was obtained within this window, this result will be used
  * If baseline is missing the potential participant can be enrolled with an estimated baseline, but only if there is no past medical history of chronic kidney disease.
* Elevated serum creatinine (greater than or equal to 1.5 times baseline as defined above).
* And at least ONE of the following:

  * A repeat serum creatinine within 48 hours of initial serum creatinine, showing a further increase of 0.3 mg/dL
  * Positive kidney injury urine biomarker, as defined by any of the following:

    * NGAL level greater than or equal to 150 ng/mL by ELISA or clinical analyzer
    * KIM1 level greater than or equal to 2.8 ng/mL by ELISA
    * TIMP2 x IGFBP7 greater than or equal to 2.0 by NephroCheck®
  * Urine microscopy suggestive of acute tubular necrosis defined as a urine microscopy score of greater than or equal to 2.

    * greater than or equal to 1 Renal Tubular Epithelial cells (RTE) per high powered field (HPF) AND greater than or equal to 1 granular cast/ low powered field (LPF); or
    * greater than or equal to 5 Renal Tubular Epithelial cells (RTE) per high powered field (HPF); or
    * greater than or equal to 5 granular cast/ low powered field (LPF)

General Exclusion Criteria:

* Under 18 years of age
* Body Mass Index (BMI) greater than 40 kg/m2
* Allergy to iodinated contrast (any reaction)
* Pregnancy
* Malignancy - Receiving active chemotherapy or radiation to treat malignancy (except for nephrectomy tissue for reference and feasibility studies)
* Transplant recipient (includes solid transplant and bone marrow)
* Additional vulnerable individuals (incarcerated, institutionalized, or otherwise unable to participate in the study)
* Inability to provide informed consent
* Clinical diagnosis of kidney disease from an autoimmune disease, dysproteinemia, viral disease or glomerular disease other than DKD or H-CKD
* Unwilling to receive blood transfusion (if needed)

Primary outcomes:
measure: Biopsy-related outcomes
timeFrame: Immediately after the procedure for up to 6 months
measure: Kidney disease progression outcomes
timeFrame: Through study completion (up to 10 years, depending on enrollment date of participant)
measure: Kidney disease progression outcomes
timeFrame: Through study completion (up to 10 years, depending on enrollment date of participant)
measure: Kidney disease progression outcomes
timeFrame: Through study completion (up to 10 years, depending on enrollment date of participant)
Secondary outcomes:
Other outcomes:
measure: Number of Participants with Additional Outcome Measures
timeFrame: Through study completion (up to 10 years, depending on enrollment date of participant)
measure: Number of Participants with Outcomes Specific to AKI
timeFrame: Through study completion (up to 10 years, depending on enrollment date of participant)
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: New York
country: United States
facility: Columbia University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas at Southwestern
state: Texas
Study officials:
affiliation: University of Washington
name: Jonathan Himmelfarb, MD
role: PRINCIPAL_INVESTIGATOR
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