Kidney Precision Medicine Project

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.

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 Exclusion Criteria:

Potential participants will be excluded if the risk of kidney biopsy is considered too high by either the clinicians caring for the potential participant or the investigators at the RS.

Anatomic or Imaging Exclusion Criteria Kidney depth more than 13 cm (percutaneous biopsies only)

• Kidney size less than 8 cm (percutaneous biopsies only)
• Solitary or single functioning kidney
• Evidence of urinary tract obstruction or hydronephrosis
• Multiple bilateral kidney cysts that will interfere with the safe performance of the biopsy
• Kidney infection, peri-renal infection, or cutaneous infection that overlies the kidney (percutaneous biopsies only)
• Any other imaging abnormality, which in the judgement of the operator, prevents biopsy being performed safely.

Bleeding Risk Exclusion Criteria

• International Normalized Ratios (INR) greater than 1.4
• Platelet count less than 100,000/uL
• Hemoglobin less than 8.5 g/dL
• Chronic anticoagulation
• Inability to withdraw aspirin, clopidogrel, cilostazol, or similar anti-platelet agents for at least 7 days prior to biopsy (unless bleeding time is normal before open surgical biopsy); clinical judgement will be used in the case of nonsteroidal anti-inflammatory drugs (NSAID) exposure occurring less than 7 days before percutaneous biopsy.
• Blood pressure of more than 160 mmHg systolic or 100 mmHg diastolic.

○ Peri-procedure blood pressure fluctuations between 140-160 mmHg systolic and 90-100 mmHg diastolic require management, ideally to target, based on clinician/investigator judgment.

• Ventilator-dependent patient (does not apply to open biopsies)
• Hypotension or pressor support requirement (does not apply to open biopsies)
• Any other condition where in the judgement of the operator, biopsy cannot be performed safely.