Matthias Kretzler, MD
Warner-Lambert/Parke-Davis Professor of Medicine
Professor of Internal Medicine
Research Professor, Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Li Yang, MD
杨莉教授
Director and Professor
Institute of Nephrology
PKU First Hospital

JI Program: Renal

Project Status: Active/Ongoing

Acute Kidney Injury (AKI) is a common complication in those who are hospitalized, and uniformly portends a worse prognosis. Survivors of AKI may develop Chronic Kidney Disease (CKD), which is presumably due to failure to repair of the proximal tubular epithelial cells (PTEC). An AKI event increases the risk of subsequent CKD by 8-fold, and initial data suggests that the problem is even more pronounced among those who survived AKI in the setting of a SARS-CoV2 infection. Animal model data shows that several transcriptional changes occur in PTEC that fail to repair and progress to tubular atrophy, although it is not known which transcriptional changes are shared in episodes of human AKI. This is a critical gap as identification of shared cell-type specific transcriptional changes would be imperative to prioritize non-invasive biomarker development and potential drug targets. The overarching goal of this grant is to leverage the power of single cell RNA sequencing (scRNAseq) to identify shared, cell-specific transcriptional changes between animal models of ischemia-reperfusion injury (IRI) and AKI in human data. Trajectory analysis of the murine data from Dr. Yang’s laboratory at PKUFH will identify transcriptional changes that portend future tubular atrophy. As we hypothesize that transcriptional changes that portend tubular atrophy will be associated with worse outcomes, these transcriptional changes will be associated with outcomes using publicly available data from the Kidney Precision Medicine Project (KPMP) and local cohorts at the University of Michigan (UM) and Peking University First Hospital (PKUFH). These data will serve as valuable preliminary data for future grant applications to external funding agencies to identify cell-type specific, non-invasive biomarkers of failure to recover from an AKI event.

Charles Friedman, PhD
Chair, Department of Learning Health Sciences
Josiah Macy Jr. Professor of Medical Education
Division Chief, Learning and Knowledge Systems
Professor of Information, Public Health
University of Michigan Medical School
[email protected]

Luxia Zhang, MD
张路霞教授
Professor of Renal Division
Peking University Institute of Nephrology
Peking University First Hospital

Program: Renal

Status: Active/Ongoing

One advent of the widespread adoption of Electronic Health Records (EHR) in the US is the secondary use of the information to improve patient safety and quality of care. Learning Health Systems can leverage the power of big data, accelerating the process of translating newly generated knowledge to clinical practice. China is in the process of adopting EHR systems. We plan to utilize a limited data set derived from regional EHR data from Yinzhou to test the feasibility of building a Learning Health System to improve chronic kidney disease (CKD) care, specifically focusing on anemia. A new Anemia-in-CKD Research Database will help us develop several predictive models for outcomes of common anemia treatments, such as changes in hemoglobin from iron therapy or from using erythropoietin-stimulating agents (ESAs). In addition, we plan to represent, in fully computable form, the actionable recommendations published in the current KDIGO guideline recommendations in both English and Chinese. We will use the open-source Knowledge Grid technology from U-M to package, manage and execute the predictive models we develop and the computable KDIGO guideline recommendations we build. Finally, as proof of concept, we will use real-world patient data from Yinzhou to test the potential impact of the predictive models and computable guidelines as the potential logic of a future clinical decision support system for use in Yinzhou.

Rodica Busui, MD, PhD
Professor of Internal Medicine
University of Michigan Medical School
[email protected]

Luxia Zhang, MD
张路霞教授
Professor of Renal Division
Peking University Institute of Nephrology
Peking University First Hospital

JI Program: Renal

Status: Active/Ongoing

Summary

The global trend towards obesity, physical inactivity and energy-dense diets has led to a rapid rise in the prevalence of diabetes. It is estimated that 415 million people live with diabetes, with a projected increase to 642 million by 2040. Practical and cost-effective interventions at national levels are essential to attenuate the global burden of diabetes. Current evidence have shown that glucose control designed to achieve near-normal glycemia may reduce the risk of chronic complications in patients with type 1 diabetes (T1D) and some patients with type 2 diabetes (T2D). However, a critical knowledge gap remains in understanding what persons with diabetes do or do not develop complications, independently of glucose control, and whether there are populations and regions-specific differences in this risk. We hypothesize that populations from different ethnic origin/regions express diverse specific phenotypes of diabetes and its complications. Understanding the heterogeneity in the risk for diabetes complications could enrich the knowledge of the pathophysiologic pathways, help to identify the high-risk population, as well as develop target intervention strategies for primary and secondary prevention of diabetes. The specific objectives are to understand the heterogeneity in the phenotype of chronic diabetes complications among patients with diabetes in the two nations, including (a) describing differences in phenotypes and patterns of long-term complications between two countries; and (b) unveiling clinical and biological biomarkers and using deep learning systems and precision medicine approaches to identify increased risk and/or protection from complications among Chinese and US populations. By tracking the adverse outcomes, we hope to identify mechanism-based therapies for the treatment of diabetes complications so treatment can be individualized and targeted appropriately.

Subramaniam Pennathur, MBBS
Norman Radin Professor of Nephrology
Professor of Internal Medicine
Professor of Molecular and Integrative Physiology
University of Michigan Medical School
[email protected]

Nan Hu, MD, PhD
胡楠教授
Attending & Assistant Researcher
Renal Division, Peking University First Hospital
Institute of Nephrology, Peking University

JI Program: Renal

Status: Active/Ongoing

Summary

Diabetic kidney disease (DKD) is a significant public health problem. Progression to end-stage renal disease (ESRD) leads to dramatic increases in morbidity and mortality. The mechanisms underlying progression of DKD are poorly defined and current noninvasive markers incompletely correlate with disease progression. Our recent human studies indicate that altered tubular mitochondrial nutrient metabolism, specifically higher levels of tricarboxylic acid (TCA) cycle intermediates, predicts progression of DKD. In contrast, lower urinary Tamm Horsfall Protein (THP) levels associate with human chronic kidney disease (CKD) progression, suggesting a protective role for THP. We also found that urinary THP is increased in a rodent hypoxia-induced kidney injury which exhibits mitochondrial damage, with increased levels of THP associated with protection from injury. In this proposal, we seek to link THP levels to mitochondrial function, identifying a protective role of THP on renal disease progression by utilizing complimentary rodent and human studies in DKD. These discovery studies will lay the groundwork for future large-scale prospective studies to identify the biomarker potential of urinary THP and tricarboxylic acid cycle metabolites and mechanistically define the link between THP and mitochondrial function. This work will further a collaborative infrastructure between PKUHSC and Michigan Medicine, and foster training of PKUHSC staff and graduate students in metabolomics.

Ganesh Palapattu, MD, FACS
George F and Sandy G Valassis Professor of Urology
Department Chair, Urology
University of Michigan Medical School
[email protected]

Kan Gong, MD, PhD
龚侃教授
Professor of Urology
Peking University First Hospital
[email protected]

JI Program: Renal

Status: Active/Ongoing

Summary

The long-term goal of our proposal is to improve the health of men diagnosed with renal cell carcinoma (RCC). To this end, we seek to understand the underlying molecular basis of recurrence and/or mortality following radical nephrectomy for RCC. Kidney cancer is one of the most common tumors worldwide, and the clinical trajectory of kidney cancer is extremely variable even within existing categories of risk. Current methods for risk stratification rely almost solely on tumor stage and grade and are used to drive the investigation of adjuvant therapies, including tyrosine kinase inhibitors (TKI) in high risk patients. Unlike for other tumor types (e.g., breast cancer, lung cancer, etc.), no comprehensive molecular assays are available to augment clinical decision-making for patients with kidney cancer after surgical removal. Recent exomic and transcriptomic profiling of diverse kidney cancer subtypes has begun to define the common molecular alterations in RCC and nominate potential DNA and RNA biomarkers that may be clinically useful. There is a pressing need for new ancillary studies to help guide the clinical management of patients with kidney cancer. Given recent advances in molecular profiling, a clear opportunity exists to leverage our emerging understanding of the molecular pathogenesis of kidney cancer to develop novel molecular biomarker assays. Our international research team, composed of experts in kidney cancer management and genomics, coupled with our distinctive and extensive access to relevant tissue resources, is uniquely poised to complete our stated research plan.

Celine Berthier, PhD
Assistant Research Scientist
Department of Internal Medicine - Nephrology
University of Michigan Medical School
[email protected]

Hong Zhang, MD
张宏教授
Professor of Internal Medicine
Peking University First Hospital

JI Program: Renal

Status: Active/Ongoing

Summary

IgA nephropathy (IgAN), lupus nephritis (LN), and Henoch-Schonlein purpura nephritis (HSPN) are three types of glomerulonephritis (GN) with high prevalence in both Chinese and American populations, leading to end-stage renal disease (ESRD), which means the requirement of organ replacement therapy, itself associated with high cost and unacceptable levels of mortality in both countries. Epidemiology studies show a significant contribution of ethnicity in the prevalence and severity of IgAN and LN diseases (e.g., African-American and Chinese are “sicker” than Europeans). The Michigan Medicine and PKUHSC renal divisions have joined their efforts recently in another collaborative study to develop non-invasive molecular markers for GN patients. This new unique opportunity to collaborate between our two countries and combine our complementary resources and expertise in both systems genetics and system biology will allow us to: 1) build and validate a fine mapping of the genetic variant regions associated with IgAN, LN, and HSPN; and 2) integrate the characterized putative functional variants into their disease functional context. Our pilot study will generate essential information towards the goal of customizing effective patient care with disease- and patient-specific therapies that are less toxic, thus minimally affecting the central immune mechanisms and reducing the treatment costs in both China and the U.S.

Outcome

• Completed imputation and statistical analysis of genome wide association studies (GWAS) from controls, IgAN, LN, and IgA vasculitis patients.  Our study is one of the largest IgAN GWAS up to date, and in the same center, avoiding diagnosis (renal biopsy) heterogeneity.
• Our study reveals additional loci and novel genes for genetic predisposition to IgAN, which may shed novel biological mechanism.
• Machine learning methods are being developed to support prediction analyses using GWAS data.

Wenjun Ju, PhD
Associate Research Scientist
Division of Nephrology
Department of Internal Medicine
Michigan Kidney Translational Core Center Deputy Director
University of Michigan Medical School
[email protected]

Min Chen, MD, PhD
陈旻教授
Professor
Renal Division
Peking University First Hospital
[email protected]

JI Program: Renal

Status: Active/Ongoing

Summary

Approximately 14% of the US’ and 11% of China’s adult population are affected by chronic kidney disease (CKD). Patients with CKD may progress to end stage kidney disease (ESKD) and require renal replacement therapy associated with high morbidity, mortality and expense. Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the US, accounting for approximately 50% of cases, and is predicted to be the major cause of ESKD in China in the very near future. DKD affects many aspects of kidney physiology and function. Current diagnostic biomarkers tend to capture only one aspect of renal function, and only are reliable at a relatively late disease stage, after substantial pathologicalb damage has already occurred. Our current inability to diagnose early-to-moderate DKD prevents early intervention. Our funded JI Discovery Award project (2013-2015) entitled, “Towards Molecular Prognosis of Chronic Kidney Disease in UMHS and PUHSC,” discovered and validated a new CKD biomarker epidermal growth factor (EGF), which appears to reflect the regenerative capacity of distal tubular cells in the kidney. Abnormally low levels of this novel biomarker predict CKD progression in both Chinese and US populations. Urinary EGF is the first CKD biomarker discovered in the last two decades that adds significantly and substantially to routine clinical markers in the prognostic assessment of CKD patients. We are now in the unique position to validate urinary EGF (uEGF) as a clinically applicable biomarker to improve patient care and discover novel disease mechanisms-associated biomarkers which could aid in early diagnosis and prognosis in DKD patients from both US and China. In addition, we also will identify and validate novel non-invasive biomarkers that are shared with other chronic kidney diseases or are specific for DKD progression using a systems biology approach.

Outcomes

• uEGF was validated in this study which can be used as a prognostic marker for DKD progression.
• One abstract was presented at American Society of Nephrology’s Annual Meeting 2018.
• One abstract was presented at the Michigan Diabetes Research Center Annual Diabetes Symposium 2019.
• 2500 subjects were enrolled from both sides into the study, with urine and plasma samples collected and biobanked.

Publications

1. Wu L, … Chen M, and Zhao M-H. Associations of urinary epidermal growth factor and monocyte chemotactic protein-1 with kidney involvement in patients with diabetic kidney disease. Nephrol Dial Transplant. 2018 Oct 23. doi: 10.1093/ndt/gfy314. [Epub ahead of print]

Extramural Funding

• Awarded $1.641 million dollars from Industrial funding generated from the JI project (Renal Pre-Competitive Consortium RPC2, $1,641,908).

Matthias Kretzler, MD
Warner-Lambert/Parke-Davis Professor of Medicine
Professor of Internal Medicine
Research Professor, Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Minghui Zhao, MD
赵明辉教授
Renal Division and Institute of Nephrology
Peking University First Hospital

JI Program: Renal

Status: Active/Ongoing

Summary

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is one of the common autoimmune diseases in adults. Left untreated, the prognosis is usually fatal, with a 1-year mortality rate of about 80%. Introduction of aggressive immunosuppressive therapy has improved outcomes. However, disease progression, treatment resistance and frequent relapse remain major challenges for clinicians. This is particularly challenging for renal disease in AAV, with the need to differentiate between ongoing immunological damage versus chronic progression of CKD. We will integrate data from the AAV patients across continents, using a data driven approach to identify pathways and networks that are AAV specific and those shared with other CKDs, identify non-invasive biomarker candidates that can monitor disease progression and propose disease targets that can serve as the basis for the creation of novel small molecules or that can be targeted through drug repurposing of FDA approved drugs/small molecules in a precision medicine manner to improve treatment options for patients with AAV.

Outcome

450 subjects have been enrolled in the study, with urine and plasma samples collected.
JAK-STAT pathway activation was identified as a mechanism shared between nephrotic syndrome and potential impact on health ANCA-associated vasculitis. Non-invasive biomarkers that represent the activation of this pathway were identified and we currently are validating the assays. A draft manuscript hasbeen deposited in bioarchives in advance of submission to Kidney International.
The bioinformatic result has been deposited in bioarchives in advance of submission to Kidney International: "Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome".

Publications

1. Li X-Q, Goyal T, Eddy S, Kretzler M, Ju WJ, Chen M, Zhao MH. Urinary epidermal growth factor predicts renal prognosis in antineutrophil cytoplasmic antibody associated vasculitis. Ann Rheum Dis. 2018 Sep;77(9):1339-1344. doi: 10.1136/annrheumdis-2017-212578. Epub 2018 May 3. PMID: 29724728 DOI: 10.1136/annrheumdis-2017-212578

Extramural Funding

Awarded $1 million dollars from NIH funding generated from the JI project.

Subramaniam Pennathur, MBBS
Norman Radin Professor of Nephrology
Professor of Internal Medicine
Professor of Molecular and Integrative Physiology
University of Michigan Medical School
[email protected]

Yuqing Chen, MD
陈育青教授
Professor of Nephrology
Peking University First Hospital

JI Program: Renal

Status: Completed

Summary

Chronic kidney disease (CKD) is a significant public health problem, and progression to end-stage renal disease (ESRD) leads to dramatic increases in morbidity and mortality. The mechanisms underlying progression of CKD are poorly defined, and current noninvasive markers incompletely correlate with disease progression. In this discovery proposal, we seek to discover global glycoprotein profiles that predict progression and we will explore specific glycosylation changes to UMOD that associates with progression. We propose to set up a case control discovery study from our existing biobank with 100 subjects at Peking University First Hospital. Utilizing shotgun glycoproteomics, we will determine urinary glycoprotein markers for progression. These discovery studies will lay the groundwork for future large-scale studies to identify biomarker potential of the identified markers. This work will establish a collaborative infrastructure between PUHSC and Michigan Medicine and foster training opportunities for PUHSC graduate students in renal glycoproteomics.

Outcomes

• 100 urine samples (50 IgA and 50 DKD) samples were collected in PKUHSC biorepository and shipped to Michigan Medicine. 100 samples were collected for the mass spectrometric analyses.
• 1 PhD student from PKUHSC received extensive training at Michigan Medicine mentored by Dr. Pennathur.
• Urine succinate and citrate predict pregression of kidney disease in the U.S. cohort. If confirmed in the PKUHSC cohort, these biomarkers could be used for prediction for DKD progression.
• The rodent studies are ongoing with development of rat diabetic kidney disease model in both wild type and THP null rats. Once completed (in summer 2019), these samples will be shipped to UM for metabolomics analysis. These studies will be pivotal in providing the mechanistic link between THP and mitochondrial nutrient metabolism and risk for DKD progression.

Publications

Manuscript in preparation

Roger Wiggins, M.B.,B.Chir
Professor Emeritus Internal Medicine
Division of Nephrology
University of Michigan Medical School
[email protected]

Jie Ding, MD
丁洁教授
Professor of Pediatrics
Vice President
Peking University First Hospital

JI Program: Renal

Status: Completed

Summary

Alport Syndrome (AS) is a major cause of end stage renal disease (ESRD) which is now a recognized public health issue worldwide and an important contributor to global disease burden. Early identification and intervention to prevent AS progression will improve outcomes. A novel Podometric technology developed by the Wiggins laboratory at Michigan Medicine has the potential to be able to define the risk for progression to ESRD. The Alport Syndrome Prevention of Progression (ASPOP) project will integrate a large well-characterized database-driven genetically-defined AS cohort developed and managed at a state-of-the-art facility at Peking University First Hospital under the direction of Dr. Jie Ding with novel podometric technology developed to identify and prevent progression of glomerular diseases developed by the Wiggins laboratory at Michigan medicine. It is anticipated that the combination of an unusually large cohort of AS patients managed by genetic and other approaches together with a novel technological approach towards preventative management will offer opportunities for obtaining competitive funding through national and international structures.

Outcomes

• 194 samples were collected from PKUHSC (133 urine samples, 61 kidney biopsies); all samples collected are kept in Beijing, only processed biopsy images and data from urine mRNA quantitation were sent to Ann Arbor for joint analyses.
• 1 PhD student from PKUHSC received extensive training at Michigan Medicine.
• 2 abstracts were presented at the American Society of Nephrology’s annual meeting and Chinese Pediatrics Society’s annual meeting.

Publications

1. Ding F, Wickman L, Wang SQ,… Ding J, Wiggins RC. (2017) Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome. Kidney Int. 2017 Jul 26. pii: S0085-2538(17)30357-5. doi: 10.1016/j.kint.2017.05.017

Jennifer Bragg-Gresham, PhD
Assistant Research Scientist
Internal Medicine
University of Michigan Medical School
[email protected]

Luxia Zhang, MD
张路霞教授
Professor of Renal Division
Peking University Institute of Nephrology
Peking University First Hospital

JI Program: Renal

Status: Completed

Summary

Chronic Kidney Disease (CKD) has emerged as a major non-communicable disease (NCD) with public health importance affecting more than 5% of the population around the world. In rapidly developing nations, such as China, risk factor profiles of the population are constantly evolving, resulting in the increasing likelihood of a rising burden of multiple comorbid conditions such as obesity, diabetes, hypertension, cardiovascular diseases, cancer and kidney disease. In an effort to control and manage kidney disease, many nations including both the U.S. and China have initiated comprehensive CKD surveillance. This collaborative study provides a unique opportunity for different countries to learn from each other’s experiences, while implementing country-specific public health strategies to stem the growing tide of NCDs, such as CKD and end stage renal disease (ESRD).

Outcomes

• 1 PKUHSC faculty member received extensive training at UMMS.
• 1 UMMS resident received Fogarty fellowship for a 11-month research training at PKUHSC.
• A research poster was presented at the World Congress of Nephrology conference in South Africa in March 2015.

Publications

1. Wang J, Wang F, Saran R, He Z, Zhao M, Li Y, Zhang L, Bragg-Gresham J. Mortality risk of chronic kidney disease: A comparison between the adult populations in urban China and the United States. Plos One. 2018 Mar 15. https://doi.org/10.1371/journal.pone.0193734
2. Under reviewer at KI Reports: Fang Wang, MD1, Zhi He, PhD2, Jinwei Wang, PhD1, Minghui Zhao, MD, PhD1, Yi. Li, PhD2, Luxia Zhang, MD, MPH1, Rajiv Saran, MD, MPH3, Jennifer L Bragg-Gresham, MS, PhD3. Prevalence and Risk Factors for Chronic Kidney Disease: A Comparison between the Adult Populations in China and the United States.

Matthias Kretzler, MD
Warner-Lambert/Parke-Davis Professor of Medicine
Professor of Internal Medicine
Research Professor, Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Minghui Zhao, MD
赵明辉教授
Renal Division and Institute of Nephrology
Peking University First Hospital

JI Program: Renal

Status: Completed

Summary

Patients with end stage renal disease (ERSD) who require renal replacement therapy are associated with high morbidity, mortality, and cost both in China and the U.S. The majority of ESRD originates from glomerular diseases. The Michigan Medicine and PKUHSC renal divisions are at the forefront of translational glomerular disease research in the U.S. and China. They have joined forces to address the most urgent unmet need in the field:  Early and accurate identification of patients at high risk to progress to ESRD for targeted treatments. The joint scientific expertise, unique resources (biobanks established by both divisions, hosting urine and plasma samples accumulated over years from patients with glomerular diseases – and samples linked with longitudinal clinical data), and the deep trust-based intensive cooperation and exchanges (including faculty training, multiple visits, shared seminars…etc.) position us strongly to meet this challenge. Together, we strive to develop non-invasive molecular markers to allow early detection of patients at high risk for progression, and identify molecular pathways that bridge the genotype-phenotype gap to identify molecular mechanisms driving glomerular disease progressions as targets for future interventional trials. Moreover, JI’s renal program provides a valuable platform to exchange research inspiration and to nurture new collaborations on renal diseases between both sides. We strongly believe that our joint effort will ultimately contribute to the improvement of patient care, and reduce financial burden in both the U.S. and China.

Outcomes

• 4 PKUHSC junior faculty members received extensive training at Michigan Medicine mentored by Dr. Matthias Kretzler and Dr. Wenjun Ju.
• 1 UMMS resident completed a one-month clinical rotation at PKUHSC with Dr. Minghui Zhao.
• One peer-reviewed publication was highlighted by the NIH director’s blog as an exemplary story on precision medicine: “Pursuing Precision Medicine for Chronic Kidney Disease”(https://directorsblog.nih.gov/2015/12/15/pursuing-precision-medicine-for-chronic-kidney-disease(link is external))
• One abstract was presented by American Society of Nephrology’s Annual Meeting.
• Awarded $2.524 million dollars from NIH and industrial funding generated from the JI project.

Publications

1. Ju W, Nair V, Smith S…Kretzler M. NEPTUNE and PKU-IgAN Consortium (2015) Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Sci Tansl Med. 2015; 7(316): 316ra193 DOI:10.1126/scitranslmed.aac7071.