Kidney Precision Medicine Meeting

Event Details

Meeting Summary

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• Download the Meeting Attendees (PDF, 372.54 KB) .

Purpose

Despite many academic and industry efforts to treat acute and chronic kidney disease, therapies remain limited. This conference aims to bring together basic, clinical, and translational scientists, health care professionals, industry and government representatives, and patients – all of whom are interested in the treatment of acute and chronic kidney disease:

1. To recognize the heterogeneity of acute and chronic kidney disease and the importance in differentiating such heterogeneity so that precise treatments can be developed and provided to individual patients.
2. To determine the quantity and usability of currently available kidney tissues obtained from patients with acute and chronic kidney disease (including transplant donors, partial nephrectomy for renal cell carcinoma).
3. To discuss the need, challenges, and barriers in obtaining research biopsies from patients with acute and chronic kidney disease, as well as the negative consequence of not obtaining kidney tissues in the current and future treatment of those patients.
4. To establish the scientific and clinical quality control/assurance metrics and training needed for setting up a network to obtain kidney research biopsies.
5. To discuss the phasing and priority needed to move the field forward.

Information regarding Hotel reservations at the Doubletree by Hilton Bethesda can be found under the Directions/Travel tab. The last day to reserve a room at the group rate is Friday, April 29.

Agenda

May 23, 2016

8:00 a.m.

Goals and expectations
Robert Star

Session 1: Success Stories—How has the study of human tissue significantly advanced other fields? Lessons learned

Moderator: Stephen Hewitt
(15 min. talk + 15 min. discussion for each speaker)

8:20 a.m.

Gliomas in children: Why did the field need tissue and how was it obtained? What value was added? What steps were taken to gain patient acceptance?
Kathy Warren

8:50 a.m.

Lessons from liver biopsies in viral hepatitis and NASH
David Kleiner

9:20 a.m.

Monitoring health and disease with big data and omics profiling
Mike Snyder

9:50 a.m.

Break

Session 2: AKI and CKDs—What are the major unsolved clinical questions?

Moderator: Matt Breyer
(10 min. talk + 10 min. discussion for each speaker)

10:10 a.m.

Major unsolved clinical questions in AKI
Joe Bonventre

• What is human AKI?
• Lack of specific therapies; difficulties with animal models
• Many targets in animals, but translation has been unsuccessful

10:30 a.m.

Major unsolved clinical questions in CKDs
Jonathan Himmelfarb

• CKDs rather than CKD; no single common pathway, lessons from FIND
• Why do we need earlier samples? Can a defining pattern of injury up front drive later treatment?
• Biopsy for stage?

Session 3: Tissue Interrogation—What have others done with tissue? What new technologies are available to address kidney cell type and disease heterogeneity?

Moderator: Ravi Iyengar
(10 min. talk + 10 min. discussion for each speaker)

10:50 a.m.

Redefining kidney disease phenotypes
Chip Brosius

• Multiscale description of healthy and diseased phenotypes (histology and beyond)
• Need for “normal,” pre-dysfunction, and early dysfunction
• Explain what is new and why it is feasible now

11:10 a.m.

Molecular analysis and mapping of biopsied tissue
Jeremy Norris
(20 min. talk + 10 min. discussion)

• Tissue preparation for in situ analysis
• Molecular analysis (proteomic, lipidomics, etc.) and imaging techniques
• Molecular mapping (linking structure to function in healthy and diseased tissues)

11:40 a.m.

Interrogating single cells to understand tissue heterogeneity
Rahul Satija

• Overview of single cell analysis techniques (including RNAseq vs. whole tissue)
• Issues with cell dissociation
• Identify signature profiles for cell types/rare cell types/cell subpopulations
• Identify cellular differences in different physiological and disease states
• Map cells within a tissue to understand cell biology in normal and acute injury/disease states (bottom-up approach)

12:00 p.m.

Lunch and posters

1:00 p.m.

Integrative data analysis and modeling of complex human disease
Olga Troyanskaya

• Analysis of large omic data collections to create tissue-specific functional networks
• Use of bioinformatics and computational modeling to identify crucial disease pathways and phenotypes (active pathways—genomics, epigenetics, and other; heterogeneity phenotype)
• Combining information to predict function, functional units, mechanisms of disease and phenotyping

1:20 p.m.

Six perspectives on how to analyze kidney tissue
(7 min. talks followed by a panel discussion)

1. Andy McMahon
2. Stephen Hewitt
3. Betty Diamond
4. Maria Gomez
5. Katalin Susztak
6. Avi Rosenberg

Session 4: Tissue Collection

Moderator: Katalin Susztak
(10 min. talk + 10 min. discussion for each speaker)

2:10 p.m.

Lessons learned about training, tissue collection, and quality control from an existing kidney cohort
Matthias Kretzler

2:30 p.m.

Break

Session 5: Bioethics—What are the ethical issues of the research renal biopsy?

Moderator: Paul Kimmel
(10 min. talk + 10 min. discussion for each speaker)

2:50 p.m.

Research biopsies in patients with AKI: Changing paradigms
Steve Korbet

• Practices and pitfalls in doing kidney biopsies in patients with acute illness
• How do we initiate a change in practice? What are the patient acceptance issues?

3:10 p.m.

Research biopsies in patients with CKDs: Changing paradigms
Sus Waikar

• How do we get started (DN, unclear etiology, patient wants exact diagnosis)?
• How do we obtain earlier samples (other sources)?
• Can tissue be used for staging and prognosis?

3:30 p.m.

Ethical and patient-centered issues in performing a renal biopsy
Robert “Skip” Nelson

• Usefulness of information to the individual and society; setting of unclear benefit
• Ethical perspectives on collaborating with critically ill patients
• Cost/benefit considerations
• Paradigmatic changes—clinicians, patients, and researchers
• Patient-centered issues

3:50 p.m.

Patient perspectives
Paul Conway
Richard Knight
Sandra Palumbo

4:10 p.m.

Break

Session 6: Day 1 Breakout Groups

Meeting will split into three different groups to discuss specific issues related to Tissue Interrogation (Ballroom C), Tissue Collection (Harmony Room), and Bioethics (Balance Room). Each session may include short talks, tasking smaller working groups, and facilitated discussions.

4:30 p.m.

Tissue Interrogation (Ballroom C)
How can we best obtain integrated knowledge about physiology and pathophysiology from biopsy samples? How will we integrate data from complementary technologies? Are analytic pathways different for AKI and CKDs (because the processes/cells might be different)? Are pathways sufficiently robust, scalable, and validatable? How deep should we go before diminishing returns? How do we deal with heterogeneity within kidney tissue and cells? How will we tie the data to sample site/assay noise/patient subgroups? How can we analyze and visualize results (and map back onto tissue?) Where do we start? What are the benchmarks (hierarchy)? What are the downstream studies (animals, etc.)?

• Technology Chairs: Andy McManon, Steve Potter, Katalin Susztak, Ravi Iyengar
• AKI Chairs: Manjeri Venkatachalam, Charlie Alpers
• CKD Chairs: Avi Rosenberg, Ray Harris
• NIDDK Reps: Krystyna Rys-Sikora and Deborah Hoshizaki

GOAL: How to best use tissue to understand the function of the kidney in healthy (normal) and disease states.

Tissue Collection (Harmony Room)
How will we collect tissue and from whom? How much tissue is needed for extensive molecular analysis? What new tools might improve collection? How will we ensure tissue quality control? What new tools might improve tissue quality and sampling variability? Which patients should be studied? Will biopsy be acceptable to the patients? Will control patients be necessary, or is normal tissue or data available? Are there specific issues for AKI? Are there specific issues for CKDs?

• Technology Chairs: Stephen Hewitt, Matthias Kretzler
• AKI Chairs: Lloyd Cantley, Joe Bonventre
• CKD Chairs: John Sedor, David Salant, Amy Mottl, Mike Mauer
• NIDDK Reps: Mike Flessner and Danny Gossett

Bioethics (Balance Room)
What are the risks? What are the benefits? How do we adequately communicate with patients? What will be required to change the existing culture? How will patients be selected and recruited? Are there specific issues for AKI? Are there specific issues for CKDs?

• AKI Chairs: Chirag Parikh, Steven Korbet
• AKI Patient: Sandra Palumbo
• CKD Chairs: William Knowler, Kathy Tuttle
• CKD Patients: Richard Knight, Paul Conway
• NIDDK Reps: Paul Kimmel, Andy Narva, and Kevin Abbott

4:30- 5:15 p.m.

Bullet Presentations
(order TBD, 3 slides max; 5 mins each)

Tissue Interrogation Breakout Session SHORT TALKS

1. SCA-disassociation and analysis to identify cell types (kidney biopsies from LN)
   Nir Hacohen
2. Epigenetics, genetics and proteomic analyses of DKD biopsies
   Katalin Susztak
3. Proteomics and lipidomics on whole renal tissue samples
   Jeremy Norris
4. Multiplex expression approaches
   Andy McMahon
5. Object oriented pathology and linking molecular pathology and physiology
   Stephen Hewitt
6. xMD techniques on extracellular matrix
   Avi Rosenberg
7. Deep Sequencing of microdissected tubules: omics and mapping pathways
   Mark Knepper
8. BEAt-DKD approaches for tissue interrogation
   Maria Gomez
9. SCA-spatial mapping
   Steve Potter

5:15-6:00 p.m.

Discuss strategies for moving forward and address the Tissue Interrogation questions above.

6:00 p.m.

Adjournment

May 24, 2016

8:00 a.m.

Welcome
Robert Star

8:10 a.m.

Keynote: Lessons from big data
Webinar: Nancy Cox
Moderator: Rebekah Rasooly
(20 min. talk + 20 min. discussion)

Session 7: Breakout Group Reports

Moderator: Chris Ketchum
(20 min. presentation + 30 min. discussion for each group)

8:50 a.m.

Tissue Interrogation

9:40 a.m.

Tissue Collection

10:30 a.m.

Break

10:50 a.m.

Bioethics

Session 8: Moving Forward—What have others done?

Moderator: Joe Bonventre
(20 min. talk + 20 min. discussion for each speaker)

11:40 a.m.

Lessons from AMP (Accelerating Medicines Partnerships), a public/private partnership on rheumatoid arthritis and lupus
Bob Carter

12:20 p.m.

Lunch and posters

1:20 p.m.

Lessons from NCI tissue collections
Stephen Hewitt

2:00 p.m.

Industry perspective—panel discussion
Moderator: Paul Kimmel

• Cynthia Arbeeny [Sanofi]
• Carine Boustany [Boehringer Ingelheim]
• Matt Breyer [Lilly]
• Maria Chiara Magnone [AstraZeneca]
• Dan Levy [Pfizer]
• Peter Linde [AbbVie]
• Ulf Meier-Kriesche [Bristol-Myers Squibb]

3:00 p.m.

Break

Session 9: Day 2 Breakout Groups

Meeting will split into three different groups to discuss specific issues related to AKI (Ballroom C), CKDs (Harmony room), and Data (Balance Room). Each session may include short talks, tasking smaller working groups, and facilitated discussions.

3:20 p.m.

AKI Session (Ballroom C)
Chair: Lloyd Cantley.
Other discussion leaders: Joseph V. Bonventre, Stephen Korbet, Manjeri Venkatachalam, Charlie Alpers, Robert “Skip” Nelson, Sandra Palumbo, Nicholas Sadovnikoff.
NIDDK Reps: Paul Kimmel and Kevin Abbott

Overall Goals

1. Assuming we are able to get adequate tissue from a substantial number of subjects with AKI, what would you like to do with it with what goal in mind?
2. Kidney biopsy: Will it lead to new pathways and drug targets in AKI?
3. What are the driver cells of interest? What are the driver pathways?

Other questions for discussion (will be given to discussion leaders)

1. Discuss the variety of AKI phenotypes and potential mechanisms: What is the state of our knowledge, and what is missing?
2. Will control patients/biopsies be necessary or is normal tissue and/or data available?

Defining the Cohort

1. Will research biopsy of patients with AKI be acceptable to patients?
2. What patient populations (questions, populations, endpoints, feasibility, safety)?
   1. Cisplatin, other nephrotoxins, delayed graft function, post cardiac surgery, contrast nephropathy, ICU without sepsis, ICU sepsis, pre-renal, ATN, other?
   2. Should populations be studied all at once, or in phases? If phases, who in Phase 1, 2, and 3?

Other questions for discussion (will be given to discussion leaders)

1. Will biopsy of patients with AKI require a shift in culture among nephrologists?
2. What are patients’ perceptions of these proposals?
3. Are there methods/techniques that can minimize the risk of collecting tissue?
4. How do we as a community increase the value of the biopsy in identifying new therapeutic targets? How do we communicate the importance of the biopsy to local IRBs?
5. What data should be collected in addition to tissue—longitudinal phenotypic data, environmental/work exposures, biosamples (urine, blood, stool, other)?
6. How many patients are needed? How many centers are needed?
7. What must be considered for Institutional Review Board (IRB) approval?

CKD Session (Harmony Room)
(The entire group will discuss Overall Goals, Defining the Cohort, and Phasing the Study sequentially for ~50 min each)
Discussion Leaders: Sus Waikar, William Knowler, Avi Rosenberg, Kathy Tuttle, Amy Mottl, Paul Conway, Maria Gomez, Ray Harris, John Sedor, Matthias Kretzler, David Salant, Jeffrey Kopp, and Brad Rovin.
NIDDK Reps: Mike Flessner and Tracy Rankin

Overall Goals
Chair: Ray Harris.
Other discussion leaders: Avi Rosenberg, Charles Alpers, David Salant, Jeffrey Kopp

1. Assuming we are able to get adequate tissue from a substantial number of subjects with CKDs, what would you like to do with it and with what goal in mind?
2. Using biopsy tissue as the diagnostic platform, what cellular processes or pathways would be most informative to establish CKD phenotypes?
3. What molecular pathways in CKDs would be most amenable to a therapeutic target? Repair pathways? Transport and signaling pathways? Uremic solute pathways?

Other questions for discussion (will be given to discussion leaders)

1. What have the CRIC and CKiD observational studies taught us regarding CKD sub-phenotypes, beyond diabetic and non-diabetic?
2. Have biomarker studies been informative in this regard?
3. Will “molecular phenotyping” be able to override albuminuria as a marker of CKD progression?
4. Discuss the array of CKD phenotypes and potential mechanisms: What is the state of our knowledge, and what is missing?
5. What have we learned from failed or negative trials?
6. Can novel insights be gained from the study of unusual populations (e.g., Mesoamerican nephropathy)?
7. Identify observations/data from other consortia like the African American Study of Kidney Disease (AASK) or the Nephrotic Syndrome Study Network (NEPTUNE) that point to the need for tissue biopsy. Have these studies pointed to new targets in CKDs?
8. Will control patients/biopsies be necessary or is normal tissue and/or data available? What are the best sources of “normal” tissue?

Defining the Cohort
Chair: Cathy Tuttle.
Other discussion leaders: Amy Mottl, John Sedor, William Knowler, Richard Knight, Paul Conway

1. Should nephrologists perform research biopsies or biopsies for indications, such as diabetes or long-term hypertension? When would it be best to biopsy during the course of “traditional” CKD for sub-type diagnosis?
2. Will research biopsy of patients in early stages of CKDs be acceptable to patients? How about repeat biopsies for research purposes?

Other questions for discussion (will be given to discussion leaders)

1. Will biopsy of patients with early stages of CKDs require a culture shift amongst nephrologists? What have we learned from the Pima Indian Biopsy Study?
2. What are the patients’ perceptions of these proposals?
3. Are there methods/techniques that can minimize the risk of collecting tissue?
4. How do we as a community increase the value of the biopsy toward identifying new therapeutic targets? How do we communicate the importance of the biopsy to the local IRBs?
5. Which patients should be studied? What indications warrant biopsy?
6. Do early events predict later events or disease progression?
7. What data should be collected in addition to tissue—longitudinal phenotypic data, environmental/work exposures, biosamples (urine, blood, stool, other)?
8. Will we be able to use the electronic health records (EHR) to identify possible patients and to collect their data?
9. How many patients are needed? How many centers are needed?

Phasing the Study
Chair: Sus Waikar.
Other discussion leaders: Mike Mauer, Brad Rovin, and Maria Gomez

• Introduction: KPMI Logic Model
• Task 1: Develop/test techniques/protocols
• Task 2: Pilot studies
• Task 3: Phase 2 patient study?
• Task 4: Phase 3 clinical study?

Other questions for discussion (will be given to discussion leaders)

1. Task 1: Develop and test techniques and protocols to collect tissue, phenotypic data, and other biosamples. Carry out preliminary studies in humans to validate these techniques and protocols
2. Task 2: Pilot studies
   1. Defining the population: early versus later progressors; high versus low ACR; diabetics versus non-diabetics
   2. Impact of patient selection on design of study
   3. Should a trial be restricted to proteinuric disease or have a stratum with a target proportion with proteinuria and normo-albuminuria? If so, how would proteinuria be defined?
   4. Is the recruitment strategy feasible?
   5. Is it possible to link EHRs to identify possible participants?
3. Task 3: Phase 2 patient study
   1. Broader population: non-diabetic CKD, hypertension, HIVAN
   2. Pilot treatment study to segregate patient sub-population
   3. Biomarkers for risk stratification
4. Task 4: Phase 3 study
   1. Cohort study. How large? CRIC-CKiD sized? Length of follow-up?
   2. Discuss pathways of cooperation among industry, academia, government, and patient advocacy groups for tissue-centric studies

Data Session (Balance Room)
Chair: Andy McMahon.
Other discussion leaders: Steve Potter, Sanjay Jain, and Chirag Parikh.
NIDDK Reps: Rebekah Rasooly and Deborah Hoshizaki

1. What types of data need to be collected or generated (clinical phenotype, cell and molecular omics, 2D histology, 3D images, super-resolution microscopy)?
2. What types of curation and annotation are needed to make data accessible to the research community?
3. What samples should be stored? How will they be stored?
4. How will samples be linked to longitudinal phenotypic and physiologic data? What data needs to be collected upfront to ensure later linkage to USRDS?
5. What are the advantages of a website versus a federated portal? Are there good examples to emulate? What are they?
6. How will we ensure confidentiality of data? How will we preserve the participant identity so that it can be linked to other efforts (without double counting)?
7. What should be the sharing policy?
8. When will data and samples be shared with the broader research community? Should data be shared upon validation (and prior to publication)?
9. Are there specific issues for AKI? CKDs?

6:00 p.m.

Adjournment

May 25, 2016

8:00 a.m.

Welcome
Robert Star

Session 10: Breakout Group Reports

Moderator: John Sedor
(30 min. talk + 30 min. discussion for each group)

8:10 a.m.

AKI breakout report

9:10 a.m.

CKD breakout report

10:10 a.m.

Break

10:30 a.m.

Data breakout report

11:30 a.m.

Meeting summary—Where do we go from here?
Robert Star

12:00 p.m.

Adjournment