Abstract
Rationale & Objective: Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. Study Design: Prospective, observational cohort study. Setting & Participants: 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposure: Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 levels in prospective analyses. Outcomes: Baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. Analytical Approach: Multivariable-adjusted linear regression models tested associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 levels with future kidney failure and death. Results: In the BKBC Study, higher plasma KIM-1 levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, CKD in 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, CKD in 1,153 participants progressed to kidney failure and 1,356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure after multivariable adjustment (hazard ratios of 1.19 [95% CI, 1.03-1.38] and 1.10 [95% CI, 1.06-1.15] for BKBC and CRIC, respectively). There was no statistically significant association of plasma KIM-1 levels with death in either cohort. Limitations: Generalizability and unmeasured confounding. Conclusions: Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in 2 cohort studies of individuals with kidney diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 231-243.e1 |
| Journal | American Journal of Kidney Diseases |
| Volume | 79 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2022 |
Funding
Dr Srivastava reports personal fees from Horizon Therapeutics, PLC, AstraZeneca, CVS Caremark, Bayer, and Tate & Latham (medicolegal consulting). Dr Bonventre is cofounder and holds equity in Goldfinch Bio, is coinventor on KIM-1 patents assigned to Partners Healthcare, received grant funding from Boehringer Ingelheim, and has received consulting income related to biomarkers from Biomarin, Aldeyra, Angion, PTC, Praxis, and Sarepta. Dr Waikar reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluwer, GE Health Care, GSK, Mass Medical International, Barron and Budd (vs Fresenius), JNJ, Venbio, Strataca, Takeda, Cerus, Pfizer, Bunch and James, and Harvard Clinical Research Institute (aka Baim), and grants and personal fees from Allena Pharmaceuticals. The remaining authors declare that they have no relevant financial interests. This work was supported by the CKD Biomarker Consortium by National Institutes of Health (NIH) grants U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689, DK072381, and R37DK39773; the National Center for Advancing Translational Sciences of the NIH (UL1TR000003); and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr Schmidt is supported by the American Philosophical Society Daland Fellowship in Clinical Investigation. Dr Srivastava is supported by NIH grant K23DK120811, an NIDDK Kidney Precision Medicine Project Opportunity Pool grant under U2CDK114886, and core resources from the George M. O’Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY) P30DK114857. Dr Waikar is also supported by NIH grants UH3DK114915, U01DK085660, U01DK104308, R01DK103784, and R21DK119751. Funding for the CRIC Study was obtained under a cooperative agreement from NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/ National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland , UL1TR000439 from the NCATS component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. Funding for the BKBC was supported by the NIH grant R01DK093574 (SSW). This work was conducted with support from Harvard Catalyst , the Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences , NIH award UL1TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. The funders of the studies had no role in study design; data collection, analysis, or reporting; or the decision to submit for publication. Aside from authors Vasan (Chair, Steering Committee), Bonventre (co-Principal Investigator [PI]), Waikar (co-PI), Sabbisetti, Hsu (PI), Liu (PI), Feldman (PI), Xie, Zhang, Mifflin (Laboratory), Nelson, Kimmel, and Kusek, the CKD Biomarkers Consortium Investigators comprise: Cedars Sinai Medical Center: Jennifer Van Eyk, PhD, Dawn Chen, PhD, Qin Fu, PhD; Cincinnati Children's Hospital Medical Center: Hermine Brunner, MD; Columbia University College of Physicians and Surgeons: Vivette D'Agati, MD, Jonathan Barasch, MD; Johns Hopkins University: Josef Coresh, MD, PhD (PI), Casey Rebholz, PhD; Division of Research, Kaiser Permanente Northern California: Alan S. Go, MD; Icahn School of Medicine at Mount Sinai: Erwin Bottinger, MD (PI), Avelino Teixeira, PhD, Ilse Daehn, PhD; Northwestern University: Mark Molitch, MD (PI), Daniel Batlle, MD; Ohio State University: Brad Rovin, MD (PI), Haifeng Wu, MD; Tufts Medical Center: Andrew S. Levey, MD, Lesley A. Inker, MD, MS, Meredith Foster, PhD; University of Louisville: Jon Klein, MD, PhD; University of Minnesota: Michael Mauer, MD (PI), Paola Fioretto, MD, PhD, Gary Nelsestuen, PhD, John H. Eckfeldt, MD, PhD, Amy Karger, MD, PhD; University of Padova: Paola Fioretto, MD, PhD; University of Pennsylvania (Coordinating Center): Shawn Ballard, MS, Krista Whitehead, MS, Phyllis Gimotty, PhD, Haochang Shou, PhD, Kellie Ryan; University of Utah: Tom Greene, PhD. Aside from authors Feldman, Chen, and Nelson, the CRIC Study Investigators comprise Lawrence J. Appel, MD, MPH, Alan S. Go, MD, James P. Lash, MD, Mahboob Rahman, MD, Panduranga S. Rao, MD, Vallabh O. Shah, PhD, MS, Raymond R. Townsend, MD, and Mark L. Unruh, MD, MS. Insa M. Schmidt, MD, MPH, Anand Srivastava, MD, MPH, Venkata Sabbisetti, PhD, Gearoid M. McMahon, MB, BCh, Jiang He, MD, PhD, Jing Chen, MD, MSc, John W. Kusek, PhD, Jonathan Taliercio, DO, Ana C. Ricardo, MD, MPH, MS, Chi-yuan Hsu, MD, MSc, Paul L. Kimmel, MD, Kathleen D. Liu, MD, PhD, Theodore E. Mifflin, PhD, Robert G. Nelson, MD, PhD, Ramachandran S. Vasan, MD, Dawei Xie, PhD, Xiaoming Zhang, MS, Ragnar Palsson, MD, Isaac E. Stillman, MD, Helmut G. Rennke, MD, Harold I. Feldman, MD, Joseph V. Bonventre, MD, PhD, and Sushrut S. Waikar, MD, MPH. Study concept and design: IMS, AS, SSW; adjudication of histopathology: IES, HGR; measured plasma KIM-1 in CRIC and BKBC samples: VS, JVB; statistical analysis: IMS, AS, SSW; data interpretation: IMS, AS, VS, GMM, JH, JC, JWK, JT, ACR, C-yH, PLK, KDL, TEM, RGN, RSV, DX, XZ, RP, IES, HGR, HIF, JVB, SSW. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This work was supported by the CKD Biomarker Consortium by National Institutes of Health (NIH) grants U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689, DK072381, and R37DK39773; the National Center for Advancing Translational Sciences of the NIH (UL1TR000003); and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr Schmidt is supported by the American Philosophical Society Daland Fellowship in Clinical Investigation. Dr Srivastava is supported by NIH grant K23DK120811, an NIDDK Kidney Precision Medicine Project Opportunity Pool grant under U2CDK114886, and core resources from the George M. O'Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY) P30DK114857. Dr Waikar is also supported by NIH grants UH3DK114915, U01DK085660, U01DK104308, R01DK103784, and R21DK119751. Funding for the CRIC Study was obtained under a cooperative agreement from NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the NCATS component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. Funding for the BKBC was supported by the NIH grant R01DK093574 (SSW). This work was conducted with support from Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH award UL1TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. The funders of the studies had no role in study design; data collection, analysis, or reporting; or the decision to submit for publication. Dr Srivastava reports personal fees from Horizon Therapeutics, PLC, AstraZeneca, CVS Caremark, Bayer, and Tate & Latham (medicolegal consulting). Dr Bonventre is cofounder and holds equity in Goldfinch Bio, is coinventor on KIM-1 patents assigned to Partners Healthcare, received grant funding from Boehringer Ingelheim, and has received consulting income related to biomarkers from Biomarin, Aldeyra, Angion, PTC, Praxis, and Sarepta. Dr Waikar reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluwer, GE Health Care, GSK, Mass Medical International, Barron and Budd (vs Fresenius), JNJ, Venbio, Strataca, Takeda, Cerus, Pfizer, Bunch and James, and Harvard Clinical Research Institute (aka Baim), and grants and personal fees from Allena Pharmaceuticals. The remaining authors declare that they have no relevant financial interests. The authors thank the staff and participants of the studies for their important contributions and invaluable assistance. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the NIH. Received October 9, 2020. Evaluated by 4 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Emmanuel Burdmann, MD, PhD). Accepted in revised form May 3, 2021. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
ASJC Scopus subject areas
- Nephrology
