Kidney Precision Medicine Project

Study Overview
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Brief Summary
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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
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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.

Official Title
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Kidney Precision Medicine Project

Conditions
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Chronic Renal Insufficiency, 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, Kidney Insufficiency, Chronic

Intervention / Treatment
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* Procedure: Kidney Biopsy


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Acute Kidney Injury Cohort<br>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. | Procedure: Kidney Biopsy<br>* A kidney biopsy is a procedure that involves taking a small piece of kidney tissue for examination with a microscope. A licensed health care provider will perform a kidney biopsy.<br>* Other names: Laparotomy;|
| Chronic Kidney Diseases Cohort<br>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. | Procedure: Kidney Biopsy<br>* A kidney biopsy is a procedure that involves taking a small piece of kidney tissue for examination with a microscope. A licensed health care provider will perform a kidney biopsy.<br>* Other names: Laparotomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biopsy-related outcomes | Biopsy-related complications will be collected by KPMP study staff using standardized case report forms. Clinical utility of the biopsy results will be assessed using standardized surveys of clinical providers, and participant-reported outcomes will be assessed using standardized questionnaires. Biopsy-related outcomes data will be collected around the time of the biopsy and within the six months following procurement of the kidney biopsy. | Immediately after the procedure for up to 6 months | 
| Kidney disease progression outcomes | Longitudinal change in estimated glomerular filtration rate (eGFR): Primary composite longitudinal outcome, defined by any of the following: ESRD, defined as initiation of maintenance dialysis or kidney transplantation Sustained decline in eGFR by 40% or more from baseline Individual components of the primary composite outcome Slope of eGFR change (from baseline to the latest value) | Through study completion (up to 10 years, depending on enrollment date of participant) | 
| Kidney disease progression outcomes | Longitudinal change in urine albumin excretion defined by the following: -Slope of change in urine albumin-creatinine ratio | Through study completion (up to 10 years, depending on enrollment date of participant) | 
| Kidney disease progression outcomes | Longitudinal change in urine albumin excretion defined by the following: -Change of Kidney Disease Improving Global Outcomes (KDIGO) albuminuria stage | Through study completion (up to 10 years, depending on enrollment date of participant) |