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, Type 1 Diabetes (T1D)
Conditions
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.
Interventions
PROCEDUREKidney Biopsy
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.
OTHERMRI
Images will be acquired using 3.0T whole body scanner. The participant will undergo a series of sequences (e.g., BOLD, diffusion-weighted, ASL MRI, native T1, and fat fraction sequences). The participant will receive 20 mg of IV furosemide as a bolus. BOLD MRI sequences will be repeated 15 minutes after furosemide administration. ASL sequences are acquired using investigational protocols that are not FDA-approved. Siemens machines will use Body ASL PCASL Perfusion WIP 1023, Phillips will use Body ASL 2D PCASL Perfusion software, and GE machines will use Body ASL PCASL Perfusion software.
OTHERRetina Scan
Fundus photography, fluorescein angiography, optical coherence tomography, optical coherence tomography angiography, and ophthalmologic exam and history will take place during one retina study visit. The retina visit will take place up to 6 weeks prior to the KPMP kidney biopsy OR up to 8 weeks post-biopsy.
Sponsors
Icahn School of Medicine at Mount Sinai
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Washington
University of Michigan
Brigham and Women's Hospital
Broad Institute of MIT and Harvard
The Cleveland Clinic
Columbia University
Indiana University
Johns Hopkins University
Joslin Diabetes Center
Pacific Northwest National Laboratory
Princeton University
Ohio State University
University of Pittsburgh
The University of Texas Health Science Center at San Antonio
University of Texas
Washington University School of Medicine
Yale University
Mayo Clinic
University of North Carolina, Chapel Hill
University of Illinois at Chicago
Vanderbilt University
Providence Health & Services
Harvard University
University of Arizona
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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: o Hemoglobin A1C greater than or equal to 6.5%, confirmed with a repeat test within the past year o 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 people with acute medical illnesses and changing kidney function: * Estimated glomerular filtration rate 30-59 mL/min/1.73m2 or * Estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73m2 with urine albumin excretion greater than or equal to 30 mg/g creatinine (or mg/day) or * Estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73m2 with urine protein excretion greater than or equal to 150 mg/g creatinine (or mg/day) * Most recent eGFR must be within the past year and be ≥30 mL/min/1.73m\^2. Hypertension-associated Chronic Kidney Disease (H-CKD) * 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 people 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 less than or equal to 2000 mg/g creatinine (or mg/day), or proteinuria less than or equal to 3000 mg/g creatinine (or mg/day), or ≤1+ proteinuria on urinalysis, or * Estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73m2 with urine albumin excretion 30-2000 mg/g creatinine (or mg/day) or * Estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73m2 with urine protein excretion 150-3000 mg/g creatinine (or mg/day) * Most recent eGFR must be within the past year and be ≥30 mL/min/1.73m2 Acute Kidney Injury Inclusion Criteria 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 are 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. * If the AKI RS PI believes that the baseline serum creatinine under or over-estimates baseline, a unanimous vote of AKI site PIs can confirm eligibility based on a review of deidentified serum creatinine values provided by the site PI. AND ONE of the following criteria must be met: * Drop in urine output (\<500 ml/24 hours) * Any rise in serum creatinine ≥0.3 mg/dl over the baseline serum creatinine * A rise in serum creatinine \>0.1 mg/dl in a patient with high risk of AKI and at least one of the following: * 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. \[25\] ▪ 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) Type 1 Diabetes Inclusion Criteria Clinical diagnosis of T1D without evidence of other diabetes types (monogenic, secondary to pancreas disease, etc.), reviewed and approved by KPMP site endocrinologist, and supported by at least one of the following: One or more positive antibodies associated with T1D • Low C-peptide, defined as at least one of the following: * Prior/historical test undetectable (below lower limit of assay) * C peptide \<0.6 ng/ml if estimated glomerular filtration rate (eGFR) ≥60 mL/min per 1.73m2 and use of multiple daily insulin injections or insulin pump use for \>1 year * C peptide \<2.0 ng/ml if eGFR \<60 mL/min per 1.73m2 and use of multiple daily insulin injections or insulin pump use for \>1 year • Diabetes mellitus diagnosis for 5 years and complex insulin defined by multiple daily insulin injections ( 3 or more) or basal insulin injection plus inhaled insulin for meals or insulin pump therapy \> 1 year continuously AND one of the following (CKD, at risk of CKD, or DM-R): * CKD: 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 people with acute medical illnesses and changing kidney function: o eGFR 30-59 mL/min per 1.73m2 or o eGFR greater than or equal to 30 mL/min per 1.73m2 with urine albumin excretion greater than or equal to 30 mg/g creatinine (or mg/day) * eGFR greater than or equal to 30 mL/min per 1.73m2 with urine protein excretion greater than or equal to 150 mg/g creatinine (or mg/day) * Note: Most recent eGFR must be within the past year and be ≥30 mL/min per 1.73m2 . * Note: Most recent urine albumin/creatinine or urine protein/creatinine must be within the past year. * At risk of CKD: defined by any one or more of the following: * Age \<40 years and eGFR 60-75 mL/min per 1.73m2 (persistent eGFR \<75 mL/min per 1.73m2 * at least 3 months apart and including the most recent measurement prior to screening, but not persistently \<60 mL/min per 1.73m2 ) o eGFR slope \<-5 mL/min/1.73m2 per year, calculated using all available outpatient serum creatinine values over ≥3 years prior to screening, excluding those obtained during acute illness, and including ≥1 creatinine measurement ≥3 years prior to screening o HbA1c ≥8% on 2 occasions and T1D duration ≥5 years o Hypertension as defined by KPMP protocol (for hypertension and CKD cohort) o UACR ≥10 mg/g (twice, at least 3 months apart) * BMI ≥30 kg/m2 with dyslipidemia (defined as triglycerides (TG) ≥150 mg/dL, high-density lipoprotein (HDL) \<40/50 mg/dL for men/women, or TG/HDL ratio \>3) or lipid lowering treatment * sTNFR1 \>870 pg/mL * DM-R: defined by all of the following: * T1D for over 25 years * Estimated glomerular filtration rate greater than or equal to 60 mL/min per 1.73m2 * Urine albumin excretion less than 30 mg/g creatinine (or mg/day) DM-R Inclusion Criteria A special population of people with long-standing type 1 diabetes (\>25 years) who remain free of clinically-evident DKD (i.e. DKD "resilient" or "DM-R" individuals) will also be included. Study of the DKD resilient population using KPMP protocols offers a unique opportunity to identify protective factors against complications of diabetes mellitus. Diabetic Kidney Disease Resilient individuals are defined as individuals with diabetes for more than 25 years that are free from clinical nephropathy * Type 1 diabetes for over 25 years * Estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73m2 * Urine albumin excretion less than 30 mg/d (or mg/g creatinine) General
Exclusion criteria
* Under 18 years of age * Severe allergy to iodinated contrast * Pregnancy * 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) Safety
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biopsy-related outcomes | Immediately after the procedure for up to 6 months | 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. |
| Kidney disease progression outcomes | Through study completion (up to 10 years, depending on enrollment date of participant) | 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) |
Countries
United States
Contacts
CONTACTAshveena Dighe, MS, MPH
CONTACTKristina Blank, MPH
PRINCIPAL_INVESTIGATORJonathan Himmelfarb, MD
Icahn School of Medicine at Mount Sinai
Outcome results
None listed