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Marrapu S, Kumar R. Transition from acute kidney injury to chronic kidney disease in liver cirrhosis patients: Current perspective. World J Nephrol 2025; 14:102381. [DOI: 10.5527/wjn.v14.i1.102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/22/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025] Open
Abstract
In liver cirrhosis patients, acute kidney injury (AKI) is a common and severe complication associated with significant morbidity and mortality, often leading to chronic kidney disease (CKD). This progression reflects a complex interplay of renal and hepatic pathophysiology, with AKI acting as an initiator through maladaptive repair mechanisms. These mechanisms—such as tubular cell cycle arrest, inflammatory cascades, and fibrotic processes—are exacerbated by the hemodynamic and neurohormonal disturbances characteristic of cirrhosis. Following AKI episodes, persistent kidney dysfunction or acute kidney disease (AKD) often serves as a bridge to CKD. AKD represents a critical phase in renal deterioration, characterized by prolonged kidney injury that does not fully meet CKD criteria but exceeds the temporal scope of AKI. The progression from AKD to CKD is further influenced by recurrent AKI episodes, impaired renal autoregulation, and systemic comorbidities such as diabetes and metabolic dysfunction-associated steatotic liver disease, which compound kidney damage. The clinical management of AKI and CKD in cirrhotic patients requires a multidimensional approach that includes early identification of kidney injury, the application of novel biomarkers, and precision interventions. Recent evidence underscores the inadequacy of traditional biomarkers in predicting the AKI-to-CKD progression, necessitating novel biomarkers for early detection and intervention.
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Affiliation(s)
- Sudheer Marrapu
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Sethi S, Theis JD, Palma LM, Madden B. From Patterns to Proteins: Mass Spectrometry Comes of Age in Glomerular Disease. J Am Soc Nephrol 2024; 35:117-128. [PMID: 37749770 PMCID: PMC10786612 DOI: 10.1681/asn.0000000000000221] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 08/17/2023] [Indexed: 09/27/2023] Open
Abstract
Laser capture microdissection and mass spectrometry (LCM/MS) is a technique that involves dissection of glomeruli from paraffin-embedded biopsy tissue, followed by digestion of the dissected glomerular proteins by trypsin, and subsequently mass spectrometry to identify and semiquantitate the glomerular proteins. LCM/MS has played a crucial role in the identification of novel types of amyloidosis, biomarker discovery in fibrillary GN, and more recently discovery of novel target antigens in membranous nephropathy (MN). In addition, LCM/MS has also confirmed the role for complement proteins in glomerular diseases, including C3 glomerulopathy. LCM/MS is now widely used as a clinical test and considered the gold standard for diagnosis and typing amyloidosis. For the remaining glomerular diseases, LCM/MS has remained a research tool. In this review, we discuss the usefulness of LCM/MS in other glomerular diseases, particularly MN, deposition diseases, and diseases of complement pathways, and advocate more routine use of LCM/MS at the present time in at least certain diseases, such as MN, for target antigen detection. We also discuss the limitations of LCM/MS, particularly the difficulties faced from moving from a research-based technique to a clinical test. Nonetheless, the role of LCM/MS in glomerular diseases is expanding. Currently, LCM/MS may be used to identify the etiology in certain glomerular diseases, but in the future, LCM/MS can play a valuable role in determining pathways of complement activation, inflammation, and fibrosis.
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Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jason D. Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lilian M.P. Palma
- Pediatric Nephrology, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Benjamin Madden
- Mayo Clinic Proteomics Core, Mayo Clinic, Rochester, Minnesota
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Nadkarni GN, Stapleton S, Takale D, Edwards K, Moran K, Mosoyan G, Hansen MK, Donovan MJ, Heerspink HJL, Fleming F, Coca SG. Derivation and independent validation of kidneyintelX.dkd: A prognostic test for the assessment of diabetic kidney disease progression. Diabetes Obes Metab 2023; 25:3779-3787. [PMID: 37722962 DOI: 10.1111/dom.15273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/20/2023]
Abstract
AIMS To develop and validate an updated version of KidneyIntelX (kidneyintelX.dkd) to stratify patients for risk of progression of diabetic kidney disease (DKD) stages 1 to 3, to simplify the test for clinical adoption and support an application to the US Food and Drug Administration regulatory pathway. METHODS We used plasma biomarkers and clinical data from the Penn Medicine Biobank (PMBB) for training, and independent cohorts (BioMe and CANVAS) for validation. The primary outcome was progressive decline in kidney function (PDKF), defined by a ≥40% sustained decline in estimated glomerular filtration rate or end-stage kidney disease within 5 years of follow-up. RESULTS In 573 PMBB participants with DKD, 15.4% experienced PDKF over a median of 3.7 years. We trained a random forest model using biomarkers and clinical variables. Among 657 BioMe participants and 1197 CANVAS participants, 11.7% and 7.5%, respectively, experienced PDKF. Based on training cut-offs, 57%, 35% and 8% of BioMe participants, and 56%, 38% and 6% of CANVAS participants were classified as having low-, moderate- and high-risk levels, respectively. The cumulative incidence at these risk levels was 5.9%, 21.2% and 66.9% in BioMe and 6.7%, 13.1% and 59.6% in CANVAS. After clinical risk factor adjustment, the adjusted hazard ratios were 7.7 (95% confidence interval [CI] 3.0-19.6) and 3.7 (95% CI 2.0-6.8) in BioMe, and 5.4 (95% CI 2.5-11.9) and 2.3 (95% CI 1.4-3.9) in CANVAS, for high- versus low-risk and moderate- versus low-risk levels, respectively. CONCLUSIONS Using two independent cohorts and a clinical trial population, we validated an updated KidneyIntelX test (named kidneyintelX.dkd), which significantly enhanced risk stratification in patients with DKD for PDKF, independently from known risk factors for progression.
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Affiliation(s)
- Girish N Nadkarni
- Barbara T Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Division of Digital and Data Driven Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | | | - Kara Moran
- Renalytix AI, PLC, New York, New York, USA
| | - Gohar Mosoyan
- Barbara T Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael K Hansen
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | | | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
| | | | - Steven G Coca
- Barbara T Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Le D, Chen J, Shlipak MG, Ix JH, Sarnak MJ, Gutierrez OM, Schelling JR, Bonventre JV, Sabbisetti VS, Schrauben SJ, Coca SG, Kimmel PL, Vasan RS, Grams ME, Parikh C, Coresh J, Rebholz CM. Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes. Kidney Med 2023; 5:100719. [PMID: 37841418 PMCID: PMC10568645 DOI: 10.1016/j.xkme.2023.100719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023] Open
Abstract
Rationale & Objective Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Study Design Prospective observational cohort. Setting & Participants In the Atherosclerosis Risk in Communities) study, 948 participants were studied. Exposures The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Outcome Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to <60 mL/min/1.73 m2 or dialysis dependence through United States Renal Data System linkage. Analytical Approach Logistic regression and C statistics. Results There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 (P < 0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%. Limitations Biomarkers and creatinine were measured at one time point. Conclusions Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes. Plain-Language Summary For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease.
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Affiliation(s)
- Dustin Le
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
| | - Jingsha Chen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Michael G. Shlipak
- Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, California; Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California
| | - Joachim H. Ix
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California: Kidney Research Innovation Hub of San Diego, San Diego, California
| | - Mark J. Sarnak
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA
| | - Orlando M. Gutierrez
- Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Jeffrey R. Schelling
- Department of Physiology and Biophysics and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Joseph V. Bonventre
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Venkata S. Sabbisetti
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sarah J. Schrauben
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Steven G. Coca
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Paul L. Kimmel
- Division of Kidney Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Ramachandran S. Vasan
- Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA
| | - Morgan E. Grams
- Division of Precision Medicine, Department of Medicine, New York University, NY
| | - Chirag Parikh
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Casey M. Rebholz
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Chronic Kidney Disease Biomarkers Consortium
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
- Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, California; Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, California
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California: Kidney Research Innovation Hub of San Diego, San Diego, California
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA
- Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL
- Department of Physiology and Biophysics and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Division of Kidney Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
- Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA
- Division of Precision Medicine, Department of Medicine, New York University, NY
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Baidildinova G, Pallares Robles A, Ten Cate V, Kremers BMM, Heitmeier S, Ten Cate H, Mees BME, Spronk HMH, Wild PS, Ten Cate-Hoek AJ, Jurk K. Plasma protein signatures for high on-treatment platelet reactivity to aspirin and clopidogrel in peripheral artery disease. Thromb Res 2023; 230:105-118. [PMID: 37708596 DOI: 10.1016/j.thromres.2023.08.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/31/2023] [Accepted: 08/31/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND A significant proportion of patients with peripheral artery disease (PAD) displays a poor response to aspirin and/or the platelet P2Y12 receptor antagonist clopidogrel. This phenomenon is reflected by high on-treatment platelet reactivity (HTPR) in platelet function assays in vitro and is associated with an increased risk of adverse cardiovascular events. OBJECTIVE This study aimed to elucidate specific plasma protein signatures associated with HTPR to aspirin and clopidogrel in PAD patients. METHODS AND RESULTS Based on targeted plasma proteomics, 184 proteins from two cardiovascular Olink panels were measured in 105 PAD patients. VerifyNow ASPI- and P2Y12-test values were transformed to a continuous variable representing HTPR as a spectrum instead of cut-off level-defined HTPR. Using the Boruta random forest algorithm, the importance of 3 plasma proteins for HTPR in the aspirin, six in clopidogrel and 10 in the pooled group (clopidogrel or aspirin) was confirmed. Network analysis demonstrated clusters with CD84, SLAMF7, IL1RN and THBD for clopidogrel and with F2R, SELPLG, HAVCR1, THBD, PECAM1, TNFRSF10B, MERTK and ADM for the pooled group. F2R, TNFRSF10B and ADM were higher expressed in Fontaine III patients compared to Fontaine II, suggesting their relation with PAD severity. CONCLUSIONS A plasma protein signature, including eight targets involved in proatherogenic dysfunction of blood cell-vasculature interaction, coagulation and cell death, is associated with HTPR (aspirin and/or clopidogrel) in PAD. This may serve as important systems-based determinants of poor platelet responsiveness to aspirin and/or clopidogrel in PAD and other cardiovascular diseases and may contribute to identify novel treatment strategies.
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Affiliation(s)
- G Baidildinova
- Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - A Pallares Robles
- Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - V Ten Cate
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - B M M Kremers
- Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry, Cardiovascular Research, Maastricht University, Netherlands
| | - S Heitmeier
- Division Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - H Ten Cate
- Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands; Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht, Netherlands
| | - B M E Mees
- Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, Netherlands
| | - H M H Spronk
- Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands; Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht, Netherlands
| | - P S Wild
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany
| | - A J Ten Cate-Hoek
- Laboratory for Clinical Thrombosis and Hemostasis, Department of Biochemistry, Cardiovascular Research, Maastricht University, Netherlands; Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht, Netherlands
| | - K Jurk
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
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Vasquez-Rios G, Katz R, Levitan EB, Cushman M, Parikh CR, Kimmel PL, Bonventre JV, Waikar SS, Schrauben SJ, Greenberg JH, Sarnak MJ, Ix JH, Shlipak MG, Gutierrez OM. Urinary Biomarkers of Kidney Tubule Health and Mortality in Persons with CKD and Diabetes Mellitus. KIDNEY360 2023; 4:e1257-e1264. [PMID: 37533144 PMCID: PMC10547219 DOI: 10.34067/kid.0000000000000226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023]
Abstract
Key Points Among adults with diabetes and CKD, biomarkers of kidney tubule health were associated with a greater risk of death, independent of eGFR, albuminuria, and additional risk factors. Higher urine levels of YKL-40 and KIM-1 were associated with a greater risk of death. For cause-specific death, UMOD was independently and inversely associated with the risk of cardiovascular death. Background Kidney disease assessed by serum creatinine and albuminuria are strongly associated with mortality in diabetes. These markers primarily reflect glomerular function and injury. Urine biomarkers of kidney tubule health were recently associated with the risk of kidney failure in persons with CKD and diabetes. Associations of these biomarkers with risk of death are poorly understood. Methods In 560 persons with diabetes and eGFR ≤60 ml/min per 1.73 m2 from the Reasons for Geographic and Racial Differences in Stroke study (47% male, 53% Black), we measured urine biomarkers of kidney tubule health at baseline: monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin, kidney injury molecule-1 (KIM-1), EGF, chitinase-3-like protein 1 (YKL-40), and uromodulin (UMOD). Cox proportional hazards regression was used to examine the associations of urine biomarkers with all-cause and cause-specific mortality in nested models adjusted for urine creatinine, demographics, mortality risk factors, eGFR, and urine albumin. Results The mean (SD) age was 70 (9.6) years, and baseline eGFR was 40 (3) ml/min per 1.73 m2. There were 310 deaths over a mean follow-up of 6.5 (3.2) years. In fully adjusted models, each two-fold higher urine concentration of KIM-1 and YKL-40 were associated with all-cause mortality (hazard ratio [HR] 1.15, 95% confidence interval [CI], 1.01 to 1.31 and 1.13, 95% CI, 1.07 to 1.20, respectively). When examining cause-specific mortality, higher UMOD was associated with a lower risk of cardiovascular death (adjusted HR per two-fold higher concentration 0.87, 95% CI, 0.77 to 0.99), and higher MCP-1 was associated with higher risk of cancer death (HR per two-fold higher concentration 1.52, 95% CI, 1.05 to 2.18). Conclusion Among persons with diabetes and CKD, higher urine KIM-1 and YKL-40 were associated with a higher risk of all-cause mortality independently of established risk factors. Urine UMOD and MCP-1 were associated with cardiovascular and cancer-related death, respectively.
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Affiliation(s)
- George Vasquez-Rios
- Division of Nephrology , Department of Internal Medicine , Icahn School of Medicine at Mount Sinai , Manhattan , New York
| | - Ronit Katz
- Department of Obstetrics and Gynecology , University of Washington , Seattle , Washington
| | - Emily B Levitan
- Department of Epidemiology , University of Alabama at Birmingham , Birmingham , Alabama
| | - Mary Cushman
- Departments of Medicine and Pathology and Laboratory Medicine , Larner College of Medicine at the University of Vermont , Burlington , Vermont
| | - Chirag R Parikh
- Section of Nephrology , Department of Internal Medicine , Johns Hopkins School of Medicine , Baltimore , Maryland
| | - Paul L Kimmel
- National Institute of Diabetes and Digestive and Kidney Diseases , Bethesda , Maryland
| | - Joseph V Bonventre
- Division of Nephrology , Department of Medicine , Brigham and Women's Hospital , Boston , Massachusetts
| | - Sushrut S Waikar
- Section of Nephrology , Department of Medicine , Boston Medical Center , Boston , Massachusetts
| | - Sarah J Schrauben
- Department of Medicine , Perelman School of Medicine , Center for Clinical Epidemiology and Biostatistics at the Perelman School of Medicine at the University of Pennsylvania , Philadelphia , Pennsylvania
| | - Jason H Greenberg
- Section of Nephrology , Department of Pediatrics , Program of Applied Translational Research , Yale University School of Medicine , New Haven , Connecticut
| | - Mark J Sarnak
- Division of Nephrology , Department of Medicine , Tufts Medical Center , Boston , Massachusetts
| | - Joachim H Ix
- Division of Nephrology-Hypertension , Department of Medicine , University of California San Diego , San Diego , California
- Veterans Affairs San Diego Healthcare System , San Diego , California
| | - Michael G Shlipak
- Kidney Health Research Collaborative , San Francisco Veterans Affairs Healthcare System and University of California , San Francisco , California
| | - Orlando M Gutierrez
- Departments of Medicine and Epidemiology , University of Alabama at Birmingham , Birmingham , Alabama
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Wettersten N, Katz R, Greenberg JH, Gutierrez OM, Lima JAC, Sarnak MJ, Schrauben S, Deo R, Bonventre J, Vasan RS, Kimmel PL, Shlipak M, Ix JH. Association of Kidney Tubule Biomarkers With Cardiac Structure and Function in the Multiethnic Study of Atherosclerosis. Am J Cardiol 2023; 196:11-18. [PMID: 37086700 PMCID: PMC10204591 DOI: 10.1016/j.amjcard.2023.02.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 02/17/2023] [Accepted: 02/25/2023] [Indexed: 04/24/2023]
Abstract
Markers of glomerular disease, estimated glomerular filtration rate (eGFR) and albuminuria, are associated with cardiac structural abnormalities and incident cardiovascular disease (CVD). We aimed to determine whether biomarkers of kidney tubule injury, function, and systemic inflammation are associated with cardiac structural abnormalities. Among 393 Multi-Ethnic Study of Atherosclerosis participants without diabetes, CVD, or chronic kidney disease, we assessed the association of 12 biomarkers of kidney tubule injury, function, and systemic inflammation with the left ventricular mass/volume ratio (LVmvr) and left ventricular ejection fraction (LVEF) on cardiac magnetic resonance imaging using linear regression. The average age was 60 ± 10 years; 48% were men; mean eGFR was 96±16 ml/min/1.73 m2; mean LVmvr was 0.93±0.18 g/ml, and mean LVEF was 62±6%. Each twofold greater concentration of plasma soluble urokinase plasminogen activator receptor was associated with a 0.04 g/ml (95% confidence interval [CI] 0.01 to 0.08 g/ml) higher LVmvr and 2.1% (95% CI 0.6 to 3.5%) lower LVEF, independent of risk factors for CVD, eGFR, and albuminuria. Each twofold greater plasma monocyte chemoattractant protein 1 was associated with higher LVmvr with a similar coefficient to that of plasma soluble urokinase plasminogen activator receptor. Each twofold greater concentration of plasma chitinase-3-like protein 1 and urine alpha-1-microglobulin was associated with a 1.1% (95% CI 0.4 to 1.7%) and 1.2% (95% CI 0.2 to 2.2%) lower LVEF, respectively. In conclusion, abnormal kidney tubule health may lead to cardiac dysfunction above and beyond eGFR and albuminuria.
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Affiliation(s)
- Nicholas Wettersten
- Cardiology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California; Division of Cardiology, Department of Medicine, University of California San Diego, San Diego, California.
| | - Ronit Katz
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Jason H Greenberg
- Section of Nephrology, Department of Pediatrics, Clinical and Translational Research Accelerator, Yale University School of Medicine, New Haven, Connecticut
| | - Orlando M Gutierrez
- Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joao A C Lima
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland
| | - Mark J Sarnak
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts
| | - Sarah Schrauben
- Renal-Electrolyte and Hypertension Division, and Department of Epidemiology, Biostatistics and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rajat Deo
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joseph Bonventre
- Division of Renal Medicine and Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ramachandran S Vasan
- Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts; Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
| | - Paul L Kimmel
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Michael Shlipak
- Kidney Health Research Collaborative, Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, California
| | - Joachim H Ix
- Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California
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Sandokji I, Xu Y, Denburg M, Furth S, Abraham AG, Greenberg JH. Current and Novel Biomarkers of Progression Risk in Children with Chronic Kidney Disease. Nephron Clin Pract 2023; 148:1-10. [PMID: 37232009 PMCID: PMC10840447 DOI: 10.1159/000530918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 02/18/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials. SUMMARY Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD. KEY MESSAGES Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management.
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Affiliation(s)
- Ibrahim Sandokji
- Department of Pediatrics, Taibah University College of Medicine, Medina, Saudi Arabia,
| | - Yunwen Xu
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Michelle Denburg
- Division of Nephrology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Susan Furth
- Division of Nephrology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alison G Abraham
- Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jason H Greenberg
- Department of Pediatrics, Section of Nephrology, Clinical and Translational Research Accelerator, Yale School of Medicine, New Haven, Connecticut, USA
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Patel M, Gbadegesin RA. Update on prognosis driven classification of pediatric AKI. Front Pediatr 2022; 10:1039024. [PMID: 36340722 PMCID: PMC9634036 DOI: 10.3389/fped.2022.1039024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/03/2022] [Indexed: 11/29/2022] Open
Abstract
Acute kidney injury (AKI) affects a large proportion of hospitalized children and increases morbidity and mortality in this population. Initially thought to be a self-limiting condition with uniformly good prognosis, we now know that AKI can persist and progress to acute kidney disease (AKD) and chronic kidney disease (CKD). AKI is presently categorized by stage of injury defined by increase in creatinine, decrease in eGFR, or decrease in urine output. These commonly used biomarkers of acute kidney injury do not change until the injury is well established and are unable to detect early stage of the disease when intervention is likely to reverse injury. The kidneys have the ability to compensate and return serum creatinine to a normal or baseline level despite nephron loss in the setting of AKI possibly masking persistent dysfunction. Though these definitions are important, classifying children by their propensity for progression to AKD and CKD and defining these risk strata by other factors besides creatinine may allow for better prognosis driven discussion, expectation setting, and care for our patients. In order to develop a classification strategy, we must first be able to recognize children who are at risk for AKD and CKD based on modifiable and non-modifiable factors as well as early biomarkers that identify their risk of persistent injury. Prevention of initial injury, prompt evaluation and treatment if injury occurs, and mitigating further injury during the recovery period may be important factors in decreasing risk of AKD and CKD after AKI. This review will cover presently used definitions of AKI, AKD, and CKD, recent findings in epidemiology and risk factors for AKI to AKD to CKD progression, novel biomarkers for early identification of AKI and AKI that may progress to CKD and future directions for improving outcome in children with AKI.
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Affiliation(s)
- Mital Patel
- Department of Pediatrics, Division of Pediatric Nephrology, Duke University, Durham, NC, United State
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