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Huang L, Wang F. Identification of L-shaped curve association between serum bicarbonate concentrations and short-term outcomes in patients with acute kidney injury: a retrospective cohort study. Ren Fail 2025; 47:2462264. [PMID: 39962718 PMCID: PMC11837928 DOI: 10.1080/0886022x.2025.2462264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/21/2025] Open
Abstract
OBJECTIVE This study aims to investigate the association between serum bicarbonate levels and short-term outcomes in patients with acute kidney injury (AKI), with a focus on 14-day mortality and AKI progression within a 14-day period. METHODS We conducted a secondary analysis using data from the Electronic Alerts for Acute Kidney Injury Amelioration (ELAIA) study. Serum bicarbonate levels and their associated outcomes were collected for all participants. Cox regression analysis and smooth curve fitting methods were employed to achieve the research objectives. RESULTS A total of 5,835 patients with AKI were included in the study. After adjustment for confounding factors, patients with serum bicarbonate concentrations below 22 mmol/L had a higher risk of both 14-day mortality and AKI progression compared to those with levels between 22 and 26 mmol/L (hazard ratio [HR] 1.90; 95% confidence interval [CI], 1.51-1.83 for mortality and HR 1.45; 95% CI, 1.23-1.71 for AKI progression, respectively). In contrast, patients with bicarbonate concentrations above 26 mmol/L had a lower risk of 14-day mortality (HR 0.70; 95% CI, 0.53-0.94) and AKI progression (HR 0.90; 95% CI, 0.74-1.10). Subsequent exploratory subgroup analyses revealed no statistically significant interactions (all p-values for interaction > 0.05) between 14-day mortality and serum bicarbonate levels. CONCLUSIONS In this cohort of AKI patients, serum bicarbonate concentrations below 22 mmol/L were associated with increased risks of 14-day mortality and AKI progression, while concentrations above 26 mmol/L were linked to a reduced risk of 14-day mortality.
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Affiliation(s)
- Lu Huang
- Department of Critical Care Medicine of Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Luoyang, Henan, China
| | - Fengying Wang
- Department of Critical Care Medicine of Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Luoyang, Henan, China
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2
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Liu J, Shi Y, Duan H, Shi X, Zhang Y, Zhao M. Association between hemoglobin glycation index and poor prognosis in patients with AKI: a retrospective cohort analysis of the MIMIC-IV database. Ren Fail 2025; 47:2499232. [PMID: 40356360 PMCID: PMC12077456 DOI: 10.1080/0886022x.2025.2499232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 04/18/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND There have been no investigations on the relationship between hemoglobin glycation index (HGI) and poor prognosis in patients with acute kidney injury (AKI). METHODS Patients were enrolled from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The HGI was calculated using a linear regression model fitted to glycosylated hemoglobin and fasting plasma glucose (FPG). Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were performed based on HGI quartiles to determine the independent association between HGI and mortality risk. A restricted cubic spline (RCS) was employed to assess the potential nonlinear relationship between HGI and mortality risk. A two-piecewise linear regression model was developed to identify the threshold effect. Additionally, a linear regression model was applied to evaluate the association between HGI and the length of hospital stays. RESULTS A total of 3684 patients with AKI were included in this study. Among them, 486 patients died within 28 days, and 673 patients died within 90 days. Multivariate Cox regression analysis identified HGI as an independent risk factor for both 28-day mortality (hazard ratio [HR], 1.65 [95% CI 1.26 to 2.16], p < 0.001) and 90-day mortality (HR, 1.45 [95% CI 1.16 to 1.82], p < 0.001) in AKI. The RCS analysis revealed a significant L-shaped association between HGI and both 28-day (nonlinear p < 0.001) and 90-day mortality (nonlinear p < 0.001). For 28-day mortality, the inflection point was 1.09 (HR = 0.72, 95% CI: 0.65 to 0.805). For 90-day mortality, the inflection point was 1.14 (HR = 0.76, 95% CI: 0.69 to 0.84). Notably, the association between HGI and outcomes was more significant in nondiabetic patients (p < 0.05). Additionally, HGI was found to be significantly and inversely associated with the length of hospital stays. CONCLUSION In patients with AKI, a low HGI is an independent risk factor for 28-day and 90-day mortality, exhibiting an L-shaped association. HGI may serve as a potential predictor of mortality risk.
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Affiliation(s)
- Jing Liu
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Yue Shi
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Duan
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiujie Shi
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu Zhang
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Mingming Zhao
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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3
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Ajay AK, Akinfolarin AA, Gifford CC, Sabbisetti VS, Bonventre JV. Breast cancer gene-1 (BRCA1) potentiates maladaptive repair after kidney injury. J Exp Med 2025; 222:e20231107. [PMID: 40152784 PMCID: PMC11951932 DOI: 10.1084/jem.20231107] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/17/2024] [Accepted: 12/06/2024] [Indexed: 03/29/2025] Open
Abstract
Maladaptive repair following kidney tubular injury leads to the development of interstitial fibrosis, a pathology common to chronic kidney diseases (CKD). Dysfunctional DNA damage response plays an important role in the progression of CKD. We found that BRCA1 expression was increased in the kidneys of patients with CKD and fibrotic kidneys of mice. Exon 11 deletion of Brca1 in proximal tubule cells (PTCs) of mice subjected to ischemic or nephrotoxic (aristolochic acid) injury resulted in a reduced number of senescent cells, as assessed by a decrease in phospho-histone H3, p16INK4a, RAD51 recruitment, G2/M cell cycle phase cells, GATA4, and senescence-associated β-galactosidase. There was less production of inflammatory profibrotic mediators and reduced kidney fibrosis. After cisplatin exposure in vitro, human PTCs with reduced BRCA1 had increased apoptosis, decreased RAD51 nuclear foci, and fewer cells in the G2/M cell cycle phase, with reduced IL-6 and sonic hedgehog production. Thus, BRCA1 regulates nonmalignant tissue responses to kidney injury, a role hitherto unrecognized.
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Affiliation(s)
- Amrendra K. Ajay
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Akinwande A. Akinfolarin
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Cody C. Gifford
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Venkata S. Sabbisetti
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Joseph V. Bonventre
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
- Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA, USA
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Tang K, Ye T, He Y, Ba X, Xia D, Peng E, Chen Z, Ye Z, Yang X. Ferroptosis, necroptosis, and pyroptosis in calcium oxalate crystal-induced kidney injury. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167791. [PMID: 40086520 DOI: 10.1016/j.bbadis.2025.167791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/24/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025]
Abstract
Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.
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Affiliation(s)
- Kun Tang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Ye
- Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaozhuo Ba
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Xia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ejun Peng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiqiang Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangqun Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqi Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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5
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Khoo B, Friedrich JO, Lebovic G, Hiremath S, Fishman G, Wing S, Meraz-Munoz A, Harel Z, Goder N, Gal-Oz A, Bagshaw SM, Wald R. Kidney recovery after iodinated contrast administration in patients with acute kidney injury receiving renal replacement therapy. J Crit Care 2025; 87:155015. [PMID: 39889644 DOI: 10.1016/j.jcrc.2025.155015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/03/2025] [Accepted: 01/03/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND Acute kidney injury (AKI) is common in hospitalized patients. Administration of iodinated contrast may impede kidney recovery but avoiding contrast may delay diagnosis and therapeutic interventions. There is limited data on the impact of contrast exposure in patients with established AKI receiving renal replacement therapy (RRT). METHODS We conducted a retrospective cohort study which included all patients with AKI who received RRT at St Michael's Hospital in Toronto, Canada, from January 2007 to December 2022. The exposure was the receipt of iodinated contrast during the 14 days following RRT initiation and while the patient was still RRT-dependent. The primary outcome was RRT dependence at hospital discharge. RESULTS 1597 patients with AKI received RRT and 754 patients were included in our analysis. Of these, 185 patients received iodinated contrast. After propensity score weighting, the exposure to contrast was associated with a higher likelihood of RRT dependence at hospital discharge (Odds Ratio 1.73, 95 % confidence interval 1.13-2.53). CONCLUSION The receipt of contrast in patients with AKI receiving RRT was associated with an increased risk of RRT dependence at hospital discharge. Contrast exposure in RRT-dependent patients may delay recovery from AKI. The benefits of contrast should be carefully weighed against this risk in patients with AKI receiving RRT.
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Affiliation(s)
- Benjamin Khoo
- Department of Nephrology, Tan Tock Seng Hospital, Singapore, 11 Jln Tock Seng, 308433, Singapore.
| | - Jan O Friedrich
- Departments of Critical Care and Medicine, Unity Health Toronto-St. Michael's Hospital, Toronto, ON, 36 Queen St E, M5B 1W8, Canada
| | - Gerald Lebovic
- Division of Nephrology, St. Michael's Hospital, 61 Queen St E, Toronto, ON M5B 1W8, Canada
| | - Swapnil Hiremath
- Division of Nephrology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8 L6, Canada
| | - Guy Fishman
- Departments of Critical Care and Medicine, Unity Health Toronto-St. Michael's Hospital, Toronto, ON, 36 Queen St E, M5B 1W8, Canada; Department of Critical Care, Rabin Medical Center, Zeev Jabotinsky St 39, Petah Tikva 4,941,492, Israel
| | - Sara Wing
- Division of Nephrology, St. Michael's Hospital, 61 Queen St E, Toronto, ON M5B 1W8, Canada
| | - Alejandro Meraz-Munoz
- Division of Nephrology, St. Boniface General Hospital, 409 Tache Ave, Winnipeg, MB R2H 2A6, Canada
| | - Ziv Harel
- Division of Nephrology, St. Michael's Hospital, 61 Queen St E, Toronto, ON M5B 1W8, Canada
| | - Noam Goder
- Department of Critical Care Medicine, Tel Aviv Sourasky Medical Center, Weizman St 6, Tel Aviv-Yafo 46,239, Israel; Faculty of Medicine, Tel Aviv University, Chaim Levanon St 55, Tel Aviv-Yafo 6,997,801, Israel
| | - Amir Gal-Oz
- Department of Critical Care Medicine, Tel Aviv Sourasky Medical Center, Weizman St 6, Tel Aviv-Yafo 46,239, Israel; Faculty of Medicine, Tel Aviv University, Chaim Levanon St 55, Tel Aviv-Yafo 6,997,801, Israel
| | - Sean M Bagshaw
- Department of Critical Care Medicine, University of Alberta, and Alberta Health Services, 116 St & 85 Ave, Edmonton, AB T6G 2R3, Canada
| | - Ron Wald
- Division of Nephrology, St. Michael's Hospital, 61 Queen St E, Toronto, ON M5B 1W8, Canada; Department of Nephrology and Hypertension, Tel Aviv Sourasky Medical Center, Weizman St 6, Tel Aviv-Yafo, 46,239, Israel
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Stannard B, Epstein RH, Gabel E, Nadkarni GN, Ouyang Y, Lin HM, Salari V, Hofer IS. Postoperative acute kidney injury is associated with persistent renal dysfunction: a multicentre propensity-matched cohort study. BJA OPEN 2025; 14:100384. [PMID: 40129614 PMCID: PMC11930183 DOI: 10.1016/j.bjao.2025.100384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 02/10/2025] [Indexed: 03/26/2025]
Abstract
Background The risk of developing a persistent reduction in renal function after postoperative acute kidney injury (pAKI) is not well established. The goal of this investigation was to evaluate whether patients who develop pAKI have a greater decline in long-term renal function than patients who do not. Methods In this multicentre retrospective propensity-matched study, anaesthesia data warehouses at three tertiary care hospitals were queried. Adult patients undergoing surgery with available preoperative and postoperative creatinine results and without baseline haemodialysis requirements were included. Patients were stratified by occurrence of pAKI as defined by the Acute Kidney Injury Network classification. The primary outcome was a decline in follow-up glomerular filtration rate (GFR) of 40% relative to baseline, based on follow-up outpatient visits from 0 to 36 months after hospital discharge. A propensity score-matched sample was used in Kaplan-Meier analysis and a piecewise Cox model to compare the time to reach a 40% decline in GFR for patients with and without pAKI. Results In 95 213 patients, the rate of pAKI ranged from 9.9% to 13.7%. In the piecewise Cox model, pAKI was associated with a significantly increased hazard of a 40% decline in GFR. The common-effect hazard ratio was 13.35 (95% confidence interval [CI] 10.79-16.51, P<0.001) for 0-6 months, 7.07 (5.52-9.05, P<0.001) for 6-12 months, 6.02 (4.69-7.74, P<0.001) for 12-24 months, and 4.32 (2.65-7.05, P<0.001) for 24-36 months. Conclusions pAKI is associated with a significantly increased hazard of a 40% decline in GFR up to 36 months after surgery across three institutions.
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Affiliation(s)
- Blaine Stannard
- Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Richard H. Epstein
- Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Eilon Gabel
- Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Girish N. Nadkarni
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Division of Data Driven and Digital Medicine (D3M), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Barbara T. Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuxia Ouyang
- Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hung-Mo Lin
- Department of Anesthesiology and Yale Center for Analytical Sciences, Yale School of Medicine, New Haven, NY, USA
| | - Valiollah Salari
- Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Ira S. Hofer
- Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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7
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Karmakar S, Dasgupta D, Akhtar S, Poddar S, Giri PP, Tse Y, Sinha R. Progression of acute kidney injury to chronic kidney disease: a prospective cohort study. Pediatr Nephrol 2025:10.1007/s00467-025-06810-5. [PMID: 40397129 DOI: 10.1007/s00467-025-06810-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 04/03/2025] [Accepted: 04/29/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Prospective studies on kidney outcomes in critically ill children with acute kidney injury (AKI) are scarce from low- and middle-income countries (LMIC). We conducted a pilot study to evaluate the continuum of transient AKI-persistent AKI-acute kidney disease (AKD) and chronic kidney disease (CKD). METHODS Children (1-18 years) admitted to our tertiary Pediatric Intensive Care Unit (PICU) and developing AKI with no known pre-existing kidney co-morbidities from January 2021 to June 2022 were included with follow up visits at 1 and 3 months after AKI onset. AKI and CKD were defined as per KDIGO 2012. At risk of CKD was defined by albuminuria, hypertension, estimated glomerular filtration rate (eGFR) 60-90 ml/kg/1.73 m2 or hyperfiltration (eGFR ≥ 150 ml/kg/1.73 m2). RESULTS Of 390 children, 15% (n = 57) developed AKI. 75% (n = 43) with AKI had underlying primarily non-kidney systemic etiology. Fourteen (25%) died at median 5 days (IQR 4-7) after admission, and three were lost to follow up after discharge. For the 40 AKI survivors with three months data, incidence of transient AKI was 40% (n = 16), persistent AKI 20% (n = 8), AKD 32% (n = 13), and CKD 8% (n = 3). In addition, 18% (n = 7) were at risk of CKD. 38% with AKI for > 48 h vs. 6% with AKI < 48 h developed CKD or were at risk of CKD (p = 0.025). All three AKI survivors who progressed to CKD had an underlying primarily kidney etiology and progressed from AKD to CKD. CONCLUSIONS In this LMIC study, kidney sequelae were high at 3 months among PICU AKI survivors. This pilot supports the need and feasibility of larger prospective trials in LMIC settings to understand outcomes for all children with AKI.
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Affiliation(s)
- Shreyashi Karmakar
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Deblina Dasgupta
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Shakil Akhtar
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Sanjukta Poddar
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Prabhas Prasun Giri
- Division of Pediatric Intensive Care, Institute of Child Health, Kolkata, India
| | - Yincent Tse
- Division of Pediatric Nephrology, Great North Children Hospital, Newcastle, UK
| | - Rajiv Sinha
- Division of Pediatric Intensive Care, Institute of Child Health, Kolkata, India.
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8
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Rizzari C, Schwartz S. Reply to: Methotrexate toxicity and glucarpidase: A call for dose optimization. Koppen A, et al. Br J Clin Pharmacol. 2025;91(5):1289-1292 doi:10.1002/bcp.70044. Br J Clin Pharmacol 2025. [PMID: 40394902 DOI: 10.1002/bcp.70105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Affiliation(s)
- Carmelo Rizzari
- Pediatric Hematology-Oncology Unit, Department of Pediatrics, IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Stefan Schwartz
- Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany
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9
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Kooijmans ECM, Mulder RL, Marks SD, Pavasovic V, Motwani SS, Walwyn T, Larkins NG, Kruseova J, Constine LS, Wallace WH, Green DM, Bökenkamp A, van der Pal HJH, van den Heuvel-Eibrink MM, Hjorth L, Andrés-Jensen L, Bardi E, van Dalen EC, Demoor-Goldschmidt C, Becktell K, Grönroos M, Kieran K, Mironova D, Terenziani M, Veening MA, Zieg J, Onder S, Onder AM, Routh JC, Thompson J, Hudson MM, Kremer LCM, Skinner R, Ehrhardt MJ. Nephrotoxicity Surveillance for Childhood and Young Adult Survivors of Cancer: Recommendations From the International Late Effects of Childhood Cancer Guideline Harmonization Group. J Clin Oncol 2025:JCO2402534. [PMID: 40393013 DOI: 10.1200/jco-24-02534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/24/2025] [Accepted: 04/03/2025] [Indexed: 05/22/2025] Open
Abstract
PURPOSE Childhood, adolescent, and young adult (CAYA) survivors of cancer are at risk of nephrotoxicity. Surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could slow the progression to higher stages of kidney dysfunction. METHODS The International Late Effects of Childhood Cancer Guideline Harmonization Group established a multidisciplinary panel of 34 experts from 11 countries. The panel performed systematic literature reviews for articles published between 1990 and June 2023, graded the evidence using Grading of Recommendations Assessment, Development, and Evaluation methodology, and formulated recommendations based on evidence, clinical judgment, and consideration of benefits and harms of surveillance. Recommendations were critically appraised by two independent external experts and patient representatives. RESULTS Glomerular dysfunction surveillance is recommended every 2-5 years for survivors treated with ifosfamide, cisplatin, abdominal radiotherapy, total body irradiation, or nephrectomy and is reasonable after carboplatin treatment. We recommend screening for glomerular dysfunction using an estimated glomerular filtration rate (eGFR) equation that includes serum creatinine, preferably combined with serum cystatin C if available. Tubular dysfunction surveillance is recommended once at entry into long-term follow-up and with follow-up as clinically indicated for survivors treated with ifosfamide and is reasonable after cisplatin treatment. CONCLUSION These recommendations inform routine, uniform long-term follow-up care for CAYA survivors of cancer at risk of nephrotoxicity.
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Affiliation(s)
- Esmee C M Kooijmans
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Renée L Mulder
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Vesna Pavasovic
- Department of Malignant Paediatric Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Shveta S Motwani
- Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Thomas Walwyn
- Department of Oncology, Haematology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, WA
- Discipline of Paediatrics, Medical School, University of Western Australia, Perth, WA, Australia
| | - Nicholas G Larkins
- Discipline of Paediatrics, Medical School, University of Western Australia, Perth, WA, Australia
- Department of Nephrology, Perth Children's Hospital, Perth, WA, Australia
| | - Jarmila Kruseova
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Louis S Constine
- Departments of Radiation Oncology and Pediatrics, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - W Hamish Wallace
- Department of Paediatric Haematology and Oncology, Royal Hospital for Children and Young People, and University of Edinburgh, Edinburgh, United Kingdom
| | - Daniel M Green
- Department of Oncology and Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN
| | - Arend Bökenkamp
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | | | - Marry M van den Heuvel-Eibrink
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Division of Child Health, Wilhelmina Children's Hospital, Utrecht, the Netherlands
| | - Lars Hjorth
- Department of Clinical Sciences Lund, Paediatrics, Skane University Hospital, Lund University, Lund, Sweden
| | - Liv Andrés-Jensen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark
| | - Edit Bardi
- St Anna Childrens Hospita and St Anna Children's Cancer Research Institute, Vienna, Austria
- Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Kepler University Hospital, Linz, Austria
| | | | - Charlotte Demoor-Goldschmidt
- Department of Pediatric Oncology, University Hospital of Angers, Angers, France
- Department of Pediatric Oncology, University Hospital of Caen, Caen, France
- Cancer and Radiation Team, Gustave Roussy, U1018 Inserm, Villejuif, France
| | - Kerri Becktell
- Division of Pediatric Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
| | - Marika Grönroos
- Department of Pediatric and Adolescent Medicine, Turku University Hospital, Turku, Finland
| | - Kathleen Kieran
- Division of Pediatric Urology, Seattle Children's Hospital, Seattle, WA
- Department of Urology, University of Washington, Seattle, WA
| | - Denitza Mironova
- Department of Oncology, Haematology, Blood and Marrow Transplantation, Perth Children's Hospital, Perth, WA
| | - Monica Terenziani
- Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Margreet A Veening
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Jakub Zieg
- Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Songul Onder
- Department of Nephrology, University of Tennessee, School of Medicine, Memphis, TN
| | - Ali Mirza Onder
- Department of Pediatric Nephrology, Nemours Children's Hospital, Wilmington, DE
| | - Jonathan C Routh
- Department of Urology, Duke University School of Medicine, Durham, NC
| | - Joel Thompson
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Division of Pediatric Hematology/Oncology/BMT, Children's Mercy Hospitals and Clinics, Kansas City, MO
| | - Melissa M Hudson
- Department of Oncology and Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN
| | - Leontien C M Kremer
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Division of Child Health, Wilhelmina Children's Hospital, Utrecht, the Netherlands
| | - Roderick Skinner
- Department of Paediatric and Adolescent Haematology/Oncology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, and Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Matthew J Ehrhardt
- Department of Oncology and Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN
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10
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Perez-Moreno E, de la Peña A, Toledo T, Saez J, Pérez-Molina F, Espinoza S, Metz C, Díaz-Valdivia N, Azócar L, Prado C, Pacheco R, Segovia-Miranda F, Godoy AS, Amador CA, Feuerhake T, González A, Soza A. Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury. Mol Med 2025; 31:192. [PMID: 40375122 DOI: 10.1186/s10020-025-01245-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin-8 (Gal-8), a tandem-repeat β-galactoside-binding lectin, plays a role in epithelial cell proliferation, epithelial-mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal-8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear. METHODS To investigate the endogenous role of Gal-8 in AKI, we compared the responses of Gal-8 knockout (Gal-8-KO; Lgals8-/- bearing a β-gal cassette under the Lgals8 gene promoter) and wild-type (Lgals8+/+) mice in a nephrotoxic folic acid (FA)-induced AKI model. Renal Gal-8 expression was assessed by β-galactosidase staining, lectin-marker colocalization, and RT-qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro-inflammatory T cells. RESULTS Galectin-8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8+/+ and Lgals8-/- mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8+/+ mice showed slightly worse damage. By the fibrotic phase, Lgals8-/- mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8+/+ mice. CONCLUSIONS Endogenous Gal-8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating extracellular matrix homeostasis and mitigating fibrosis. Additionally, Gal-8 contributes to inflammation resolution by limiting persistent immune cell infiltration, particularly IL-17-secreting cells.
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Affiliation(s)
- Elisa Perez-Moreno
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Facultad de Medicina, Universidad San Sebastián, Santiago, Chile
| | - Adely de la Peña
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
| | - Tomás Toledo
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Javiera Saez
- Laboratorio de Fisiopatología Renal, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Francisca Pérez-Molina
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Sofía Espinoza
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Claudia Metz
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Nicole Díaz-Valdivia
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Lorena Azócar
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Carolina Prado
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Laboratorio de Neuroinmunología, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Rodrigo Pacheco
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile
- Laboratorio de Neuroinmunología, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Fabian Segovia-Miranda
- Department of Cell Biology, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile
| | - Alejandro S Godoy
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Cristian A Amador
- Laboratorio de Fisiopatología Renal, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile
| | - Teo Feuerhake
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alfonso González
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
- Facultad de Medicina, Universidad San Sebastián, Santiago, Chile.
| | - Andrea Soza
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile.
- Centro Científico Tecnológico de Excelencia Ciencia y Vida, Fundación Ciencia y Vida, Santiago, Chile.
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11
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Morimoto K, Nakashima A, Ishiuchi N, Miyasako K, Tanaka Y, Sasaki K, Matsuda G, Maeda S, Miyaki S, Masaki T. Renal protective effects of extracellular vesicle-encapsulated tumor necrosis factor-α-induced protein 6 derived from mesenchymal stem cells. Stem Cells 2025; 43:sxaf022. [PMID: 40249362 DOI: 10.1093/stmcls/sxaf022] [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: 12/04/2024] [Accepted: 04/04/2025] [Indexed: 04/19/2025]
Abstract
Acute kidney injury (AKI) is involved in subsequent chronic kidney disease (CKD) development, and effective treatments to prevent AKI to CKD progression are lacking. Mesenchymal stem cells (MSCs) are emerging as a promising cellular therapy to impede such progression through the secretion of various humoral factors. Among these factors, tumor necrosis factor-α-induced protein 6 (TSG-6) has a central role in the anti-inflammatory effects of MSCs. However, the mechanisms by which MSCs secrete TSG-6 and exert anti-inflammatory effects are not fully clarified. Here, we investigated these mechanisms using TSG-6-overexpressing MSCs (TSG-6 MSCs) with an adeno-associated virus. Extracellular vesicles (EVs) were isolated from MSC culture supernatants by ultracentrifugation. MSCs were injected through the abdominal aorta into rats with ischemia-reperfusion injury (IRI) to evaluate their anti-inflammatory and anti-fibrotic effects. Additionally, we explored natural compounds that increased TSG-6 expression in MSCs. Most TSG-6 was immediately secreted in EVs and was not stored intracellularly. Administration of TSG-6 MSCs strongly suppressed renal fibrosis and inflammation in IRI rats. Although EVs and conditioned medium from TSG-6 MSCs (TSG-6 MSC-CM) strongly promoted polarization of M2 macrophages, TSG-6 MSC-CM after EV depletion promoted it only slightly. Moreover, TSG-6 MSC-CM enhanced regulatory T-cell induction. MSCs treated with indole-3-carbinol had enhanced TSG-6 expression and markedly suppressed IRI-induced renal fibrosis. Taken together, TSG-6 is secreted in EVs from MSCs and exerts potent anti-inflammatory effects by promoting M2 macrophage polarization and regulatory T-cell induction. Administration of MSCs with enhanced TSG-6 secretion is a promising therapeutic strategy to impede AKI to CKD progression.
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Affiliation(s)
- Keisuke Morimoto
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Nephrology, Graduate School of Medicine, University of Yamanashi, Yamanashi, 409-3898, Japan
| | - Naoki Ishiuchi
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Kisho Miyasako
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Yoshiki Tanaka
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Kensuke Sasaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
| | - Go Matsuda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Research and Development, TWOCELLS Company, Limited, Hiroshima, 732-0816, Japan
| | - Satoshi Maeda
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan
- Department of Research and Development, TWOCELLS Company, Limited, Hiroshima, 732-0816, Japan
| | - Shigeru Miyaki
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
- Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan
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12
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Hong Y, An Q, Wang Z, Hu B, Yang Y, Zeng R, Yao Y. Multi-omics Analysis Reveals the Propagation Mechanism of Ferroptosis in Acute Kidney Injury. Inflammation 2025:10.1007/s10753-025-02311-7. [PMID: 40358793 DOI: 10.1007/s10753-025-02311-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 04/01/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
Acute kidney injury (AKI) is a prevalent and critical clinical condition characterized by high morbidity and mortality. Recently, numerous studies have implicated ferroptosis, an iron-dependent programmed cell death process, in the pathophysiology of AKI. Despite this, the mechanism underlying the widespread occurrence of ferroptosis in AKI remains elusive. To address this, our study analyzed snRNA-seq data from AKI and healthy renal tissues. The analysis revealed notable differences in ferroptosis activity within proximal tubule (PT) cells of AKI patients, specifically highlighting a strong correlation between ferroptosis and the expression of genes GPX4, FTH1, and FTL. Spatial transcriptomics confirmed that the genes GPX4, FTH1, and FTL play a crucial role in driving ferroptosis propagation in AKI. Furthermore, utilizing a mouse model of bilateral renal ischemia-reperfusion injury, we validated the emergence of ferroptosis mediated by these key genes following AKI. The findings from our in vivo experiments were consistent with the spatial transcriptomics data. Chromatin accessibility and transcription factor analysis identified KLF6 as a repressor of ferroptosis-related genes. An in-depth analysis of PT revealed a subpopulation closely associated with ferroptosis. The cellular microenvironment within this subpopulation may regulate ferroptosis through the SPP1 signaling pathway, ultimately influencing the outcome of PT following AKI. In conclusion, this study elucidates the crucial role of GPX4, FTH1, and FTL in ferroptosis propagation during AKI and underscores the potential therapeutic benefits of targeting ferroptosis in the management of AKI.
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Affiliation(s)
- Yu Hong
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Qi An
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zheng Wang
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Bin Hu
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Yi Yang
- Department of Public Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Rui Zeng
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
| | - Ying Yao
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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13
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Wang H, Deng L, Li T, Liu K, Mao H, Wu B. The influence of electronic AKI alert on prognosis of adult hospitalized patients: a systematic review and meta-analysis. Crit Care 2025; 29:189. [PMID: 40355901 PMCID: PMC12070640 DOI: 10.1186/s13054-025-05402-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/02/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a critical yet frequently under diagnosed condition in hospitalized patients, impacting morbidity and mortality. Electronic alerts for AKI aimed to assist physicians in early diagnosis and intervention, though evidence for their effectiveness is inconsistent. MATERIALS AND METHODS A systematic search was conducted in PubMed, the Cochrane Central Register of Controlled Trials, Cochrane Library, and Web of Science from inception to November 2024. Eligible studies included randomized controlled trials (RCTs), before-and-after analyses, and stepped-wedge designs involving hospitalized patients. The primary outcomes were mortality and renal replacement therapy (RRT) rates, Secondary outcomes included hospital length of stay (LoS), AKI progression and recovery. Care-centered outcomes encompassed nephrologist consultation, nephrotoxic medication discontinuation and medication review. Subgroup analysis examined the impact of response intensity, hospital type and geographic region on these outcomes. RESULTS Twenty-two studies involving 170,696 participants were included: 8 RCTs (n = 21,710) and 14 non-RCTs or observational studies (n = 148,986). RCTs showed no effect on mortality (RR 1.02; 95% CI 0.97-1.07) or LoS (mean difference 0.04; 95% CI - 0.13 to 0.22) but a significant increase in RRT use (RR 1.13; 95% CI 1.02-1.26) with AKI alert systems. Non-RCTs, however, reported reduced mortality (RR 0.92; 95% CI 0.88-0.96), less AKI progression (RR 0.85; 95% CI 0.77-0.94), enhanced kidney recovery (RR 1.65; 95% CI 1.56-1.75), increased nephrotoxic drug discontinuation (RR 1.20; 95% CI 1.13-1.28), and higher drug review rates (RR 1.19; 95% CI 1.17-1.21), with no impact on RRT use (RR 1.08; 95% CI 0.87-1.36). Subgroup analysis revealed an increased in-hospital mortality in low response intensity (RR 1.15; 95% CI 1.00-1.32), reduced mortality in moderate response intensity (RR 0.93; 95% CI 0.89-0.97), and unclear effects in high response intensity (RR 0.88; 95% CI 0.70-1.09). AKI alert was also favored in teaching hospitals and in several regions (Europe, North America and South America). CONCLUSION The efficacy of AKI alerts remains inconclusive. Current evidence do not support or refute their effectiveness. Variability in response intensity, hospital type and geographic region may help explaining discrepancies, underscoring the need for further research to optimize AKI alert systems with more effective action in clinical practice.
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Affiliation(s)
- Han Wang
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
| | - Lingling Deng
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
| | - Ting Li
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
| | - Kang Liu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
| | - Huijuan Mao
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
| | - Buyun Wu
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
- Critical Care Center, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China.
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14
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Clark AJ, Flores BM, Saade MC, Vu KQ, Pence IJ, Berg A, Parikh SM. Pediatric acute kidney injury is associated with impairment in nicotinamide adenine dinucleotide (NAD+) metabolism. Pediatr Nephrol 2025:10.1007/s00467-025-06791-5. [PMID: 40353859 DOI: 10.1007/s00467-025-06791-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 04/12/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Acute kidney injury (AKI) is highly prevalent among hospitalized children, but there is no treatment. Impaired de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis measured via elevation of the urine quinolinic acid-to-tryptophan ratio (uQ:T) is a feature of AKI that has been described in preclinical models and humans with AKI. Small prospective trials to restore NAD+ abundance with NAD+ precursor supplementation have shown promise in the prevention and treatment of AKI. It is not known whether pediatric patients also develop suppression of NAD+ biosynthesis during AKI, but such information will be critical before children can be included in NAD+ -based clinical trials to treat or prevent AKI. METHODS An observational cross-sectional study was performed on convenience urine samples from children hospitalized in a tertiary care children's hospital. Samples were split into five groups: outpatient controls, floor controls, ICU controls, floor AKI, and ICU AKI. Clinical data were collected from the medical record, and metabolites were measured using targeted mass spectrometry. Patients with AKI were compared to their respective controls. A multivariate linear regression was used to assess whether demographic variables were independently associated with uQ:T, and odds of AKI were assessed in serial uQ:T tertiles using multivariate logistic regression models that adjusted for patient variables. RESULTS Sixty-nine control patients (39 outpatient, 10 floor, and 20 ICU controls) and 22 AKI patients (12 floor and 10 ICU) were enrolled. uQ:T was elevated in patients with AKI compared to their respective controls. No demographic variables were independently associated with uQ:T, and when adjusting for patient demographic and clinical variables, the odds of AKI increased serially with uQ:T tertile. CONCLUSIONS Elevated uQ:T is a feature of pediatric AKI. The present results warrant further exploration in observational and potentially interventional studies with NAD+ precursor therapies.
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Affiliation(s)
- Amanda J Clark
- Pediatrics, Pediatric Nephrology and Children's Medical Center Dallas, University of Texas Southwestern, Dallas, USA.
| | - Brenda Mendoza Flores
- Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, USA
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
| | | | - Kyle Q Vu
- Pediatrics, Pediatric Nephrology and Children's Medical Center Dallas, University of Texas Southwestern, Dallas, USA
| | - Isaac J Pence
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
- Biomedical Engineering, University of Texas Southwestern, Dallas, USA
| | - Anders Berg
- Pathology, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Samir M Parikh
- Internal Medicine, Nephrology, University of Texas Southwestern, Dallas, USA
- Pharmacology, University of Texas Southwestern, Dallas, USA
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15
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Hao H, Bao F, Wang Y, Li N, Gong Y. Peptide therapy: new promising therapeutics for acute kidney injury. Drug Discov Today 2025:104377. [PMID: 40348078 DOI: 10.1016/j.drudis.2025.104377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 04/01/2025] [Accepted: 05/06/2025] [Indexed: 05/14/2025]
Abstract
Acute kidney injury (AKI) is a common fatal condition among hospitalized patients. AKI may be induced by a variety of complicating factors such as sepsis, ischemia-reperfusion injury, nephrotoxic substances, and rhabdomyolysis. At present, symptomatic treatment is mainly used, and there are no US Food and Drug Administration (FDA)-approved drugs for the prevention or treatment of AKI. Peptides have become a promising area of research in AKI treatment because of their high efficiency and low toxicity. In this paper, we systematically review the experimental advancements of peptide therapy for AKI, analyze the mechanism of peptide action in different pathological models, discuss the challenges facing peptide therapy, and provide a scientific basis for further clinical research.
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Affiliation(s)
- Herui Hao
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China; Faculty of Medicine, Tianjin University, China
| | - Fengjiao Bao
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China; Faculty of Medicine, Tianjin University, China
| | - Yuru Wang
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China; Faculty of Medicine, Tianjin University, China
| | - Ning Li
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China; Faculty of Medicine, Tianjin University, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
| | - Yanhua Gong
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China; Faculty of Medicine, Tianjin University, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China.
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16
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Patel SS, Raman VK, Zhang S, Sheriff HM, Fonarow GC, Heidenreich PA, Faselis C, Lam PH, Morgan CJ, Moore H, Atkins D, Cheng Y, Shao Y, Deedwania P, Palant CE, Sauer BC, Mehta RL, Love TE, Allman RM, Heimall MS, Wu WC, Zeng-Treitler Q, Ahmed A. Renin Angiotensin Inhibition and Lower Risk of Kidney Failure in Patients with Heart Failure: Subtitle: RAS inhibition and kidney failure in heart failure. Am J Med 2025:S0002-9343(25)00285-2. [PMID: 40345511 DOI: 10.1016/j.amjmed.2025.04.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 04/29/2025] [Accepted: 04/29/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Renin-angiotensin system (RAS) inhibitors reduce risk of kidney failure in patients with chronic kidney disease, but worsen kidney function in heart failure patients, especially in those with chronic kidney disease. Less is known about risk of kidney failure in heart failure patients receiving RAS inhibitors. METHODS We used propensity score matching for outcome-blinded assembly of 168,860 Veterans with heart failure phenotyped by artificial intelligence who were balanced on 77 baseline characteristics and initiated on RAS inhibitors. Hazard ratio (95% CI) for 5-year kidney failure in high-dose (versus low-dose) RAS inhibitor group was estimated, accounting for competing risk of death. Kidney failure was defined as kidney replacement therapy or estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2. RESULTS New-onset kidney failure occurred in 4.1% (3455/84,430) and 3.5% (2966/84,430) of patients in low-dose and high-dose RAS inhibitor groups, respectively (HR, 0.85; 95%CI, 0.81-0.89). Respective HRs (95%CIs) in eGFR subgroups ≥60, 45-59 and 15-44 mL/min/1.73m2 were 1.21 (1.08-1.36), 0.93 (0.82-1.05) and 0.82 (0.77-0.87). The association was similar across ejection fraction subgroups. There was a lower risk of death in the subgroup with ejection fraction ≤40%. CONCLUSIONS Patients with heart failure receiving high-dose (versus low-dose) RAS inhibitors had a lower associated risk of kidney failure, which was driven by the subgroup with chronic kidney disease. This new information may help to inform future guideline recommendations and clinical practice regarding RAS inhibitor use in these patients. Future studies need to examine this association in those with normal kidney function.
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Affiliation(s)
- Samir S Patel
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Venkatesh K Raman
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | | | - Helen M Sheriff
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | | | - Paul A Heidenreich
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; Stanford University School of Medicine, Stanford, CA
| | - Charles Faselis
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC; Uniformed Services University, Washington, DC
| | - Phillip H Lam
- Georgetown University, Washington, DC; MedStar Washington Hospital Center, Washington, DC
| | - Charity J Morgan
- Veterans Affairs Medical Center, Washington, DC; University of Alabama at Birmingham, Birmingham, AL
| | - Hans Moore
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC; Georgetown University, Washington, DC; Uniformed Services University, Washington, DC
| | | | - Yan Cheng
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Yijun Shao
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Prakash Deedwania
- Veterans Affairs Medical Center, Washington, DC; University of California, San Francisco, CA
| | | | - Brian C Sauer
- Veterans Affairs Medical Center, Salt Lake City, Utah; University of Utah, Salt Lake City, Utah
| | | | | | - Richard M Allman
- George Washington University, Washington, DC; MedStar Washington Hospital Center, Washington, DC; Wake Forest University, Winston-Salem, NC
| | - Michael S Heimall
- Veterans Affairs Medical Center, Washington, DC; HealthWell Foundation, Germantown, MD
| | - Wen-Chih Wu
- Veterans Affairs Medical Center, Providence, RI; Brown University, Providence, RI
| | - Qing Zeng-Treitler
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | - Ali Ahmed
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC; Georgetown University, Washington, DC.
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Shahrahmani F, Badamchizadeh S, Kaihani F, Alavi-Moghadam S, Keshtkari S, Rezaei-Tavirani M, Arjmand R, Larijani B, Arjmand B. Platinum-based chemotherapies-induced nephrotoxicity: mechanisms, potential treatments, and management. Int Urol Nephrol 2025; 57:1563-1583. [PMID: 39630371 DOI: 10.1007/s11255-024-04303-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/20/2024] [Indexed: 04/17/2025]
Abstract
Platinum-based chemotherapies are essential in the treatment of several malignancies. However, such medications can damage the kidneys, frequently leading to both acute and chronic kidney disease. Treatment becomes more difficult for such problems. Physicians may alter chemotherapy regimens and utilize kidney-protecting medications to lessen renal damage. New imaging techniques and biomarkers also aid in the early detection of renal issues. To effectively handle the mentioned situation, oncologists, nephrologists, and pharmacists must collaborate. However, additional study is still required to develop customized therapies, discover strategies to minimize kidney injury and produce new platinum medicines. Hereupon, the present review's authors are being sought to address the causes, prospective treatments, and management of nephrotoxicity caused by platinum-based chemotherapy.
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Affiliation(s)
- Fatemeh Shahrahmani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sana Badamchizadeh
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Keshtkari
- Department of Internal Medicine, AJA University of Medical Sciences, Tehran, Iran
| | | | - Rasta Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Pruna A, Monaco F, Asiller ÖÖ, Delrio S, Yavorovskiy A, Bellomo R, Landoni G. How Would We Prevent Our Own Acute Kidney Injury After Cardiac Surgery? J Cardiothorac Vasc Anesth 2025; 39:1123-1134. [PMID: 39922732 DOI: 10.1053/j.jvca.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/28/2024] [Accepted: 01/12/2025] [Indexed: 02/10/2025]
Abstract
Acute Kidney Injury (AKI) is a common complication after cardiac surgery affecting up to 40% leading to increased morbidity and mortality. To date, there is no specific treatment for AKI, thus, clinical research efforts are focused on preventive measures. The only pharmacological preventive intervention that has demonstrated a beneficial effect on AKI in a high-quality, double-blind, randomized controlled trial is a short perioperative infusion of a balanced mixture of amino acid solution. Amino acid infusion reduced the incidence of AKI by recruiting renal functional reserve and, therefore, increasing the glomerular filtration rate. The beneficial effect of amino acids was further confirmed for severe AKI and applied to patients with chronic kidney disease. Among non-pharmacological interventions, international guidelines on AKI suggest the implementation of a bundle of good clinical practice measures to reduce the incidence of perioperative AKI or to improve renal function whenever AKI occurs. The Kidney Disease Improving Global Outcomes (KDIGO) bundle includes the discontinuation of nephrotoxic agents, volume status and perfusion pressure assessment, renal functional hemodynamic monitoring, serum creatine, and urine output monitoring, and the avoidance of hyperglycemia and radiocontrast procedures. However, pooled data from a meta-analysis did not find a significant reduction in AKI. The aim of this review is to delineate the most appropriate evidence-based approach to prevent AKI in cardiac surgery patients.
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Affiliation(s)
- Alessandro Pruna
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabrizio Monaco
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Özgün Ömer Asiller
- Department of Anesthesia and Intensive Care, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Silvia Delrio
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Andrey Yavorovskiy
- I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Moscow, Russia
| | - Rinaldo Bellomo
- Department of Critical Care, The University of Melbourne, Melbourne, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia; Data Analytics Research and Evaluation Centre, Austin Hospital, Melbourne, Australia; Department of Intensive Care, Austin Hospital, Melbourne, Australia; Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
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19
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Baiardo Redaelli M, Monaco F, Bradic N, Scandroglio AM, Ti LK, Belletti A, Viscido C, Licheri M, Guarracino F, Pruna A, Pisano A, Pontillo D, Federici F, Losiggio R, Serena G, Tomasi E, Silvetti S, Ranucci M, Brazzi L, Cortegiani A, Landoni G, Mastroroberto P, Paternoster G, Gaudino MFL, Zangrillo A, Bellomo R. Amino Acid Infusion for Kidney Protection in Cardiac Surgery Patients with Chronic Kidney Disease: A Secondary Analysis of the PROTECTION Trial. Anesthesiology 2025; 142:818-828. [PMID: 39705670 DOI: 10.1097/aln.0000000000005336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2024]
Abstract
BACKGROUND In the PROTECTION trial (Intravenous Amino Acid Therapy for Kidney Protection in Cardiac Surgery), intravenous amino acids decreased the occurrence of acute kidney injury in cardiac surgery patients with cardiopulmonary bypass. Recruitment of renal functional reserve may be responsible for such protection. However, patients with chronic kidney disease have diminished renal functional reserve, and amino acids may be less protective in such patients. Thus, a separate investigation of such patients is warranted. METHODS For this study chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml · min -1 · 1.73 m -2 , and patients with estimated glomerular filtration rates greater than or equal to 60 ml · min -1 · 1.73 m -2 served as controls. The primary outcome was the occurrence of acute kidney injury. Secondary outcomes included severity of acute kidney injury, need for and duration of renal replacement therapy, and all-cause mortality. RESULTS Among chronic kidney disease patients (n = 812), compared with placebo, amino acids significantly decreased the rate of acute kidney injury (43.1% vs 50.3%; relative risk, 0.86; 95% CI, 0.74 to 0.99; P = 0.041; number needed to treat = 14) with a median percentage increase in estimated glomerular filtration rate from baseline to postoperative day 3 of 12.7% versus 6.5% ( P = 0.002). In estimated glomerular filtration rate-based chronic kidney disease subgroups (30 to 39, 40 to 49, and 50 to 59 ml · min -1 · 1.73 m -2 ), the amino acid effect was similar (interaction P = 0.50). Finally, amino acid infusion decreased the occurrence of severe (stage 3) acute kidney injury (2.7% vs . 5.6%; relative risk 0.48; 95% CI, 0.24 to 0.98; P = 0.038). CONCLUSIONS Amino acid infusion protected chronic kidney disease patients undergoing cardiopulmonary bypass from developing acute kidney injury, with an absolute risk reduction of 7% and a number needed to treat of 14 in a cohort with a greater than 45% rate of acute kidney injury. Moreover, it delivered a greater than 50% relative risk reduction in severe acute kidney injury.
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Affiliation(s)
- Martina Baiardo Redaelli
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabrizio Monaco
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nikola Bradic
- Clinic of Anesthesiology, Resuscitation and Intensive Care, University Hospital Dubrava, Zagreb, Croatia; University North, Department of Nursing, Varazdin, Croatia
| | - Anna Mara Scandroglio
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lian Kah Ti
- Department of Anaesthesia, National University Hospital, Singapore
| | - Alessandro Belletti
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Cristina Viscido
- Department of Cardiovascular Anesthesia and Intensive Care, Ordine Mauriziano Umberto I Hospital, Turin, Italy
| | - Margherita Licheri
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabio Guarracino
- Department of Cardiothoracic and vascular Anaesthesia and Intensive Care, Pisa University Hospital, Pisa, Italy
| | - Alessandro Pruna
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Pisano
- Cardiac Anesthesia and ICU, AORN "Dei Colli," Monaldi Hospital, Naples, Italy
| | - Domenico Pontillo
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Federici
- Department of Anesthesia and Intensive Care, Sant'Andrea University Hospital, Rome, Italy
| | - Rosario Losiggio
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giovanni Serena
- University Hospital of Central Friuli, Department of Emergency "Santa Maria Della Misericordia," University Hospital of Udine, Udine, Italy
| | - Enrico Tomasi
- Hospital Pharmacy, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Simona Silvetti
- Department of Cardiac Anesthesia and Intensive Care, IRCCS San Martino Polyclinic Hospital, IRCCS Cardiovascular Network, Genova, Italy
| | - Marco Ranucci
- Department of Cardiovascular Anesthesia and Intensive Care, IRCCS San Donato Polyclinic, San Donato Milanese, Italy
| | - Luca Brazzi
- Department of Surgical Sciences, University of Turin, Turin, Italy; and Department of Anesthesia, Intensive Care and Emergency, "Città Della Salute e Della Scienza" Hospital, Turin, Italy
| | - Andrea Cortegiani
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy; and Department of Anesthesia, Analgesia, Intensive Care and Emergency. "Paolo Giaccone" Polyclinic University Hospital, Palermo, Italy
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; and School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Pasquale Mastroroberto
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Gianluca Paternoster
- Cardiovascular Anesthesia and Intensive Care Unit, San Carlo Hospital, Potenza, Italy
| | - Mario F L Gaudino
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York
| | - Alberto Zangrillo
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; and School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Rinaldo Bellomo
- Department of Critical Care, University of Melbourne, Melbourne, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia; Data Analytics Research and Evaluation Centre, Austin Hospital, Melbourne, Australia; Department of Intensive Care, Austin Hospital, Melbourne, Australia; and Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia
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20
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Tsuji T, Casula A, Tomlinson L, Nitsch D, Hole B. Acute kidney injury does not explain sex differences in kidney replacement therapy initiation or death amongst individuals with chronic kidney disease reported to the UK Renal Registry. Clin Kidney J 2025; 18:sfaf105. [PMID: 40376306 PMCID: PMC12080223 DOI: 10.1093/ckj/sfaf105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Indexed: 05/18/2025] Open
Abstract
Background Why more males than females start kidney replacement therapy (KRT) is incompletely understood. Acute kidney injury (AKI) is a possible factor underlying sex differences in chronic kidney disease (CKD) progression, but previous studies regarding this have been inconclusive. We investigated sex differences in the association between AKI and CKD progression in UK nephrology care. Methods This cohort study uses UK Renal Registry data. Adults with CKD stages 4/5 in 14 nephrology centres in England were followed from January 2018 to December 2021. We compared their baseline characteristics by sex and calculated cause specific hazard ratio (HR) for outcomes: time to AKI stage 2/3 (AKI2/3), initiation of chronic KRT and death by all causes. Results A total of 15 547 patients were included. Fewer females (43.8%) were seen in renal centres than males (56.2%). During follow-up, 3909 (25.1%) AKI2/3 episodes, 3510 (22.6%) KRT initiations, and 7293 (46.9%) deaths were observed. Males were more likely than females to experience each outcome: AKI2/3 [adjusted HR 1.39, 95% confidence interval (CI) 1.31-1.49], KRT initiation (adjusted HR 1.51, 95% CI 1.39-1.65) and death (adjusted HR 1.11, 95% CI 1.05-1.16). Adjustment for AKI2/3 did not change the association between being male and the higher risk of KRT initiation. Conclusion Being male was associated with a higher risk of AKI2/3, KRT initiation and death. Fewer females appeared in nephrology care data than expected from population CKD prevalence. However, no evidence was found to support the hypothesis that AKI2/3 explains the higher KRT initiation rates seen amongst males.
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Affiliation(s)
- Takahiro Tsuji
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Anna Casula
- UK Renal Registry, UK Kidney Association, Bristol, UK
| | - Laurie Tomlinson
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Dorothea Nitsch
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- UK Renal Registry, UK Kidney Association, Bristol, UK
- Renal Unit, Royal Free London NHS Foundation Trust, London, UK
| | - Barnaby Hole
- UK Renal Registry, UK Kidney Association, Bristol, UK
- Population Health, University of Bristol, Bristol, UK
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21
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Kamla CE, Meersch-Dini M, Palma LMP. Kidney Injury Following Cardiac Surgery: A Review of Our Current Understanding. Am J Cardiovasc Drugs 2025; 25:337-348. [PMID: 39799538 PMCID: PMC12014718 DOI: 10.1007/s40256-024-00715-8] [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] [Accepted: 12/15/2024] [Indexed: 01/15/2025]
Abstract
Around one-quarter of all patients undergoing cardiac procedures, particularly those on cardiopulmonary bypass, develop cardiac surgery-associated acute kidney injury (CSA-AKI). This complication increases the risk of several serious morbidities and of mortality, representing a significant burden for both patients and the healthcare system. Patients with diminished kidney function before surgery, such as those with chronic kidney disease, are at heightened risk of developing CSA-AKI and have poorer outcomes than patients without preexisting kidney injury who develop CSA-AKI. Several mechanisms are involved in the development of CSA-AKI; injury is primarily thought to result from an amplification loop of inflammation and cell death, with complement and immune system activation, cardiopulmonary bypass, and ischemia-reperfusion injury all contributing to pathogenesis. At present there are no effective, targeted pharmacological therapies for the prevention or treatment of CSA-AKI, although several preclinical trials have shown promise, and clinical trials are under way. Progress in the understanding of the complex pathophysiology of CSA-AKI is needed to improve the development of successful strategies for its prevention, management, and treatment. In this review, we outline our current understanding of CSA-AKI development and management strategies and discuss potential future therapeutic targets under investigation.
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Affiliation(s)
| | - Melanie Meersch-Dini
- Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany
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22
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Qiao C, Zhou J, Wei C, Cao J, Zheng K, Lv M. Cardiac surgery-associated acute kidney injury: a decade of research trends and developments. Front Med (Lausanne) 2025; 12:1572338. [PMID: 40351461 PMCID: PMC12062005 DOI: 10.3389/fmed.2025.1572338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/09/2025] [Indexed: 05/14/2025] Open
Abstract
Background Cardiac surgery-associated acute kidney injury (CSA-AKI) significantly increases postoperative mortality and healthcare costs. Despite the growing volume of CSA-AKI research, the field remains fragmented, with challenges in identifying high-impact studies, collaborative networks, and emerging trends. Bibliometric analysis addresses these gaps by systematically mapping knowledge structures, revealing research priorities, and guiding resource allocation for both researchers and clinicians. Method We analyzed 4,474 CSA-AKI-related publications (2014-2023) from the Web of Science Core Collection (WoSCC) using VOSviewer, CiteSpace, the Bibliometrix Package in R, and the bibliometric online analysis platform. Results Annual publications increased steadily, with the USA and China leading productivity. The Journal of Cardiothoracic and Vascular Anesthesia serves as the foremost preferred journal within this domain. Critical Care (IF = 15.1) has the highest impact factor. Yunjie Li published the most papers. John A Kellum has the highest H-index. The definition, pathogenesis or etiology, diagnosis, prediction, prevention and treatment, which are the research basis in CSA-AKI. Machine learning (ML) and prediction models emerged as dominant frontiers (2021-2023), reflecting a shift toward personalized risk stratification and real-time perioperative decision-making. These advancements align with clinical demands for early AKI detection and precision prevention. Conclusion This study not only maps the evolution of CSA-AKI research but also identifies priority areas for innovation: multicenter validation of predictive models to strengthen generalizability, preventive nephrology frameworks for long-term AKI survivor monitoring, and randomized controlled trials to confirm efficacy of machine learning-based CSA-AKI prediction tools.
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Affiliation(s)
- Changlong Qiao
- Department of Anesthesiology, Shandong Provincial Clinical Research Center for Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Anesthesia and Respiratory Critical Medicine, Jinan, Shandong, China
| | - Jing Zhou
- Laboratory of Laparoscopic Technology, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Chuansong Wei
- Department of Anesthesiology, Shandong Provincial Clinical Research Center for Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Anesthesia and Respiratory Critical Medicine, Jinan, Shandong, China
| | - Jing Cao
- Department of Anesthesiology, Shandong Provincial Clinical Research Center for Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Anesthesia and Respiratory Critical Medicine, Jinan, Shandong, China
| | - Ke Zheng
- Graduate School, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Meng Lv
- Department of Anesthesiology, Shandong Provincial Hospital of Shandong First Medical University, Jinan, Shandong, China
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Esposito P, Cappadona F, Prenna S, Marengo M, Fiorentino M, Fabbrini P, Quercia AD, Naso E, Garzotto F, Russo E, Zanetti V, Piscia R, Capponi A, Castellano G, Cantaluppi V. Acute kidney injury in hospitalized patients with real-life analysis of incidence and clinical impact in Italian hospitals (the SIN-AKI study). Sci Rep 2025; 15:14261. [PMID: 40274969 PMCID: PMC12022043 DOI: 10.1038/s41598-025-96236-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 03/25/2025] [Indexed: 04/26/2025] Open
Abstract
Acute Kidney Injury (AKI) is a common condition with significant impact on morbidity, mortality, and healthcare costs. This study explores the epidemiology of AKI, highlighting key factors and outcomes. In a retrospective study we evaluated patients admitted to hospital from 2016 to 2019, excluding those with pre-existing chronic kidney disease (CKD) stages 4-5. Data were extracted from hospital databases, with AKI defined by changes in serum creatinine (sCr) according to KDIGO criteria. Additionally, AKI was classified as "de novo" or as AKI on CKD in the subgroup of patients with available pre-hospital eGFR. Outcomes included mortality, hospital stay duration (LOS), AKI recovery, and persistent AKI. Of 87,087 patients, 17,946 (20.6%) developed AKI. AKI patients were older, with more comorbidities, and had significantly higher mortality (17.7% vs. 4.3%, p < 0.001). AKI was associated with in-hospital mortality (HR 1.23, 95% CI 1.16-1.30), longer LOS, and ICU admission. Mortality increased with AKI severity. Considering the 34,285 patients (39% of the total cohort) with pre-hospital eGFR, AKI occurred in 17.3% patients without previous CKD and in 31.1% of patients with previous CKD. These patients presented higher incidence of ICU admission and mortality. Additionally, 17.6% of AKI patients had persistent kidney dysfunction at discharge, often requiring extended hospitalization and ICU care. The substantial impact of AKI on both short- and potentially long-term health emphasizes the importance of early detection, personalized management, and structured follow-up to enhance outcomes and reduce CKD progression risk.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine and and Medical Specialties (DIMI), University of Genova, Genova, Italy.
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy.
| | - Francesca Cappadona
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Stefania Prenna
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), AOU Maggiore Della Carità, Novara, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Marita Marengo
- Nephrology and Dialysis Unit, Aslcn1, Cuneo, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Marco Fiorentino
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Paolo Fabbrini
- Nephrology and Dialysis Unit, ASST Nord Milano, Milano, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Alessandro Domenico Quercia
- Nephrology and Dialysis Unit, Aslcn1, Cuneo, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Erika Naso
- Nephrology and Dialysis Unit, Aslcn1, Cuneo, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Francesco Garzotto
- Department of Cardiac Thoracic Vascular Sciences and Public Health, Unit of Biostatistics, Epidemiology and Public Health, University of Padua, Padua, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Elisa Russo
- Department of Internal Medicine and and Medical Specialties (DIMI), University of Genova, Genova, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Valentina Zanetti
- Department of Internal Medicine and and Medical Specialties (DIMI), University of Genova, Genova, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Riccardo Piscia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), AOU Maggiore Della Carità, Novara, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Andrea Capponi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), AOU Maggiore Della Carità, Novara, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), AOU Maggiore Della Carità, Novara, Italy
- The AKI and Extracorporeal Blood Purification Therapies Project Group, Italian Society of Nephrology (SIN), Rome, Italy
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Meng XM, Wang L, Nikolic-Paterson DJ, Lan HY. Innate immune cells in acute and chronic kidney disease. Nat Rev Nephrol 2025:10.1038/s41581-025-00958-x. [PMID: 40263532 DOI: 10.1038/s41581-025-00958-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/24/2025]
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-related clinical and pathophysiological disorders. Cells of the innate immune system, such as granulocytes and macrophages, can induce AKI through the secretion of pro-inflammatory mediators such as cytokines, chemokines and enzymes, and the release of extracellular traps. In addition, macrophages and dendritic cells can drive the progression of CKD through a wide range of pro-inflammatory and pro-fibrotic mechanisms, and by regulation of the adaptive immune response. However, innate immune cells can also promote kidney repair after acute injury. These actions highlight the multifaceted nature of the way by which innate immune cells respond to signals within the kidney microenvironment, including interaction with the complement and coagulation cascades, cells of the adaptive immune system, intrinsic renal cells and infiltrating mesenchymal cells. The factors and mechanisms that underpin the ability of innate immune cells to contribute to renal injury or repair and to drive the progression of CKD are of great interest for understanding disease processes and for developing new therapeutic approaches to limit AKI and the AKI-to-CKD transition.
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Affiliation(s)
- Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - David J Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre and Monash University Centre for Inflammatory Diseases, Melbourne, Victoria, Australia
| | - Hui-Yao Lan
- Research Center of Integrated Traditional Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
- Departments of Medicine & Therapeutics, the Chinese University of Hong Kong, Hong Kong, and Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China.
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Adamowicz K, Lima Ribeiro AS, Golda A, Wadowska M, Potempa J, Schmaderer C, Anders HJ, Koziel J, Lech M. Bidirectional Interaction Between Chronic Kidney Disease and Porphyromonas gingivalis Infection Drives Inflammation and Immune Dysfunction. J Immunol Res 2025; 2025:8355738. [PMID: 40276114 PMCID: PMC12021489 DOI: 10.1155/jimr/8355738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 04/26/2025] Open
Abstract
Introduction: Chronic kidney disease (CKD) is characterized by a decline in renal function, increased mortality, and significant impairments in the immune system and function of immune cells. These alterations are often derived by uremic toxins, which, in turn, modify the immune system's response to infections. Our research investigates the progression of Porphyromonas gingivalis (P. gingivalis) infection during CKD and its subsequent impact on kidney failure. Methods: We utilized two infectious models, a chamber model representing short-term local inflammation and alveolar bone loss that mimic chronic infection of periodontium, both in conjunction with a CKD model. Additionally, our in vitro studies employed primary macrophages, osteoclasts, and lymphocytes to characterize the immune responses to P. gingivalis and pathogen-associated molecular patterns (PAMPs) in the presence of uremic toxins. Results and Conclusion: Our findings demonstrate that uremic toxins, such as indoxyl sulfate (IS), alter responses of macrophages and lymphocytes to P. gingivalis. In vivo, CKD significantly enhanced P. gingivalis survival and infection-induced alveolar bone loss. The increased distribution of pathogen within peripheral tissues was associated with altered inflammatory responses, indicating that CKD promotes infection. Moreover, P. gingivalis-infected mice exhibited a marked increase in renal inflammation, suggesting that the relationship between uremia and infection is bidirectional, with infection exacerbating kidney dysfunction. Furthermore, we observed that infected CKD mice exhibit decreased serum immunoglobulin G (IgG) levels compared to infected mice without CKD, implying that uremia is associated with immune dysfunction characterized by immunodepression and impaired B lymphocyte function.
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Affiliation(s)
- Karina Adamowicz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Andrea Sofia Lima Ribeiro
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- TUM University Hospital, Technical University Munich (TUM), Munich, Germany
| | - Anna Golda
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Marta Wadowska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
- Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | | | - Hans-Joachim Anders
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Joanna Koziel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Maciej Lech
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
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Araoka T, Toyohara K, Ryosaka M, Inui C, Matsuura M, Ma C, Watahiki J, Li Z, Iwasaki M, Watanabe A, Yokokawa R, Tabata Y, Izpisua Belmonte JC, Osafune K. Human iPSC-derived nephron progenitor cells treat acute kidney injury and chronic kidney disease in mouse models. Sci Transl Med 2025; 17:eadt5553. [PMID: 40173262 DOI: 10.1126/scitranslmed.adt5553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/12/2025] [Indexed: 04/04/2025]
Abstract
The number of patients requiring dialysis therapy continues to increase worldwide because of the lack of effective treatments for chronic kidney disease (CKD). Furthermore, no curative treatments for acute kidney injury (AKI) have been established. The therapeutic effects of human induced pluripotent stem cell-derived nephron progenitor cells (hiPSC-NPCs) on AKI have been reported in mice but not clinically confirmed. There are also no reports examining the therapeutic potential of hiPSC-NPCs on CKD. Although large numbers of uniform hiPSC-NPCs are required for cell therapies for AKI and CKD, effective expansion cultures remain to be developed. Here, we established a culture medium for cells that enabled more than 100-fold proliferation of hiPSC-NPCs from multiple hiPSC lines in two passages. We demonstrated that hiPSC-NPCs expanded by our medium named CFY or by their conditioned medium alone attenuated kidney injury and improved survival in cisplatin-induced AKI mice. We also observed that hiPSC-NPCs prevented kidney functional decline, interstitial fibrosis, and senescence in aristolochic acid-induced CKD mice. In addition, we found c-MET to be a specific cell surface marker for hiPSC-NPCs and confirmed that purified c-MET+ hiPSC-NPCs had therapeutic effects on AKI and CKD mice. Furthermore, we found that hiPSC-NPCs exerted their therapeutic effects in AKI and CKD mice by secreting vascular endothelial growth factor A. Expanded hiPSC-NPCs may be useful cell therapies for AKI and CKD and may open avenues for treating kidney diseases.
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Affiliation(s)
- Toshikazu Araoka
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Kosuke Toyohara
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Makoto Ryosaka
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Chihiro Inui
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Maasa Matsuura
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Cheng Ma
- Department of Micro Engineering, Kyoto University, Kyoto 615-8540, Japan
| | - Jun Watahiki
- Medical Innovation Center (MIC), Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Zhongwei Li
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Mio Iwasaki
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Akira Watanabe
- Medical Innovation Center (MIC), Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Ryuji Yokokawa
- Department of Micro Engineering, Kyoto University, Kyoto 615-8540, Japan
| | - Yasuhiko Tabata
- Cell Biotechnology Group, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | | | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
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Guerra G, Preczewski L, Gaynor JJ, Morsi M, Tabbara MM, Mattiazzi A, Vianna R, Ciancio G. Multivariable Predictors of Poorer Renal Function Among 1119 Deceased Donor Kidney Transplant Recipients During the First Year Post-Transplant, With a Particular Focus on the Influence of Individual KDRI Components and Donor AKI. Clin Transplant 2025; 39:e70080. [PMID: 40226903 PMCID: PMC11995677 DOI: 10.1111/ctr.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 04/15/2025]
Abstract
Given our desire to reduce kidney transplant waiting times by utilizing more difficult-to-place ("higher-risk") DD kidneys, we wanted to better understand post-transplant renal function among 1119 adult DD recipients consecutively transplanted during 2016-2019. Stepwise linear regression of eGFR (CKD-EPI formula) at 3-, 6-, and 12-months post-transplant (considered as biomarkers for longer-term outcomes), respectively, was performed to determine the significant multivariable baseline predictors, using a type I error ≤ 0.01 to avoid spurious/weak associations. Three unfavorable characteristics were selected as highly significant in all three models: Older DonorAge (yr) (p < 0.000001), Longer StaticColdStorage Time (hr) (p < 0.000001), and Higher RecipientBMI (p ≤ 0.00003). Other significantly unfavorable characteristics included: Shorter DonorHeight (cm) (p ≤ 0.00001), Higher Natural Logarithm {Initial DonorCreatinine} (p ≤ 0.001), Longer MachinePerfusion Time (p ≤ 0.003), Greater DR Mismatches (p = 0.01), DonorHypertension (p ≤ 0.004), Recipient HIV+ (p ≤ 0.006), DCD Kidney (p = 0.002), Cerebrovascular DonorDeath (p = 0.01), and DonorDiabetes (p = 0.01). Variables not selected into any model included DonorAKI Stage (p ≥ 0.24), Any DonorAKI (p ≥ 0.04), and five KDRI components: two DonorAge splines at 18 years (p ≥ 0.52) and 50 years (p ≥ 0.28), BlackDonor (p ≥ 0.08), DonorHCV+ (p ≥ 0.06), and DonorWeight spline at 80 kg (p ≥ 0.03), indicating that DonorAKI and the weaker KDRI components have little, if any, prognostic impact on renal function during the first 12 months post-transplant. Additionally, biochemical determinations with skewed distributions such as DonorCreatinine are more accurately represented by natural logarithmic transformed values. In conclusion, one practical takeaway is that donor AKI may be ignored when evaluating DD risk.
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Affiliation(s)
- Giselle Guerra
- Department of MedicineDivision of NephrologyMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Luke Preczewski
- Executive Office DepartmentMiami Transplant InstituteJackson Memorial HospitalMiamiFloridaUSA
| | - Jeffrey J. Gaynor
- Department of SurgeryDivision of TransplantationMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Mahmoud Morsi
- Department of SurgeryDivision of TransplantationMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Marina M. Tabbara
- Department of SurgeryDivision of TransplantationMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Adela Mattiazzi
- Department of MedicineDivision of NephrologyMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Rodrigo Vianna
- Department of SurgeryDivision of TransplantationMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Gaetano Ciancio
- Department of SurgeryDivision of TransplantationMiami Transplant InstituteUniversity of Miami Miller School of MedicineMiamiFloridaUSA
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Arakawa H, Matsushita K, Ishiguro N. Advanced in vitro evaluation of drug-induced kidney injury using microphysiological systems in drug discovery and development. Drug Metab Pharmacokinet 2025; 61:101056. [PMID: 40088574 DOI: 10.1016/j.dmpk.2025.101056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 03/17/2025]
Abstract
Drug-induced kidney injury (DIKI) is a major cause of acute kidney injury (AKI). Given concerns about animal welfare and the need for more accurate prediction of human events, there is an urgent need to develop an in vitro evaluation method for DIKI using human cells. Renal proximal tubular epithelial cells (RPTECs) are the main targets of DIKI in drug discovery and development because of their abundant expression of drug transporters that contribute to renal-specific drug distribution. In general, physiological kidney function is significantly reduced in primary cell monolayer culture systems. However, with recent advances in cell engineering and regenerative medicine, human kidney-derived cell culture systems, with higher kidney function compared to conventional systems, have been established. For example, three-dimensional cultured RPTECs show enhanced expression of drug transporters and higher predictive performance than monolayer culture systems. The use of organs-on-a-chip with liver and kidney co-cultures also allows the detection of drug metabolite-induced nephrotoxicity. Kidney organoids differentiated from induced pluripotent stem cells (iPS) have also been established. In this review, we introduce a recently established renal cell culture system that includes a microphysiological system, and review the in vitro methods used to evaluate DIKI in RPTECs.
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Affiliation(s)
- Hiroshi Arakawa
- Faculty of Pharmaceutical Sciences, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
| | - Kohei Matsushita
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
| | - Naoki Ishiguro
- Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan
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Li H, Ouyang Y, Lv H, Liang H, Luo S, Zhang Y, Mao H, Chen T, Chen W, Zhou Y, Liu Q. Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells. Biomaterials 2025; 315:122926. [PMID: 39500111 DOI: 10.1016/j.biomaterials.2024.122926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/05/2024] [Accepted: 10/27/2024] [Indexed: 12/09/2024]
Abstract
Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.
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Affiliation(s)
- Hongyu Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Yuying Ouyang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Haoran Lv
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Hanzhi Liang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Siweier Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yating Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Haiping Mao
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China
| | - Tianfeng Chen
- Department of Chemistry, Jinan University, Guangzhou, 510632, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China.
| | - Yiming Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Basic and Translational Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Qinghua Liu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China; Department of Nephrology, Jieyang People's Hospital, Jieyang, 522000, China.
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Strader M, Friedman G, Benain X, Camerlingo N, Sultana S, Shapira S, Aber N, Murray PT. Early and Sensitive Detection of Cisplatin-Induced Kidney Injury Using Novel Biomarkers. Kidney Int Rep 2025; 10:1175-1187. [PMID: 40303198 PMCID: PMC12034874 DOI: 10.1016/j.ekir.2025.01.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 01/10/2025] [Accepted: 01/27/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction We evaluated a panel of novel urinary and serum biomarkers (BMs) for early and sensitive detection of cisplatin drug-induced kidney injury (DIKI) in patients with cancer, comparing their diagnostic accuracy with standard BMs (SBMs). Methods In this prospective exploratory observational study, 105 patients treated with cisplatin ("treated" with > 65 mg/m2/cycle), 20 non-cisplatin treated cancer controls ("nontreated"), and 34 "healthy" controls were enrolled. The treated group's serum and urine samples were collected predose, after 12 hours, and on days 1, 2, 4, 7, 14, and 21. SBMs and novel BMs (NBMs; 8 urinary, 1 serum) were measured, comparing accuracy, percent changes from baseline (PCFBs), and median time to peak values between treated patients and nontreated cancer controls. Blinded adjudication of the treated group's BM profiles occurred at 2 stages for DIKI diagnosis. Results All urinary NBMs had significant PCFBs in the treated group compared with the nontreated cancer control group; most accurately detected cisplatin exposure (area under the receiver operating characteristics [ROC] curve [AUROC] > 0.8). NBMs peaked earlier. In stage 1 adjudication (SBMs) of the treated group, PCFB of urinary NBMs showed no difference between DIKI (n = 24) and no-DIKI (n = 71) groups except for neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CYSC). In treated participants, all BMs showed greater PCFBs than control groups, regardless of stage 1 DIKI adjudication. Stage 2 (SBMs and NBMs), DIKI incidence (n = 63) increased by 41%, with most BMs having an AUROC > 0.80 compared with the nontreated cancer control group. Conclusion NBMs accurately and timely detected cisplatin exposure and identified "sub-clinical" DIKI undetected by standard acute kidney injury (AKI) criteria, highlighting the limitations of current functional BMs in estimating the true DIKI incidence.
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Affiliation(s)
- Michael Strader
- Department of Medicine, School of Medicine, University College Dublin, Dublin, Ireland
| | - Gary Friedman
- Global Biometrics and Data Management, Pfizer, Inc., Cambridge, Massachusetts, USA
| | - Xavier Benain
- Biostastics and Programming, Sanofi S.A., Paris, France
| | - Nunzio Camerlingo
- Global Biometrics and Data Management, Pfizer, Inc., Cambridge, Massachusetts, USA
| | - Stefan Sultana
- Patient Safety Center of Excellence, AstraZeneca PLC, Cambridge, UK
| | - Shiran Shapira
- Health Promotion Center and Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv, Israel
| | - Nadir Aber
- Health Promotion Center and Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv, Israel
| | - Patrick T. Murray
- Department of Medicine, School of Medicine, University College Dublin, Dublin, Ireland
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Gallop L, Hickey J, Johnson R, Secombe P. Severe sepsis-associated acute kidney injury and outcomes: a longitudinal cohort study. Intern Med J 2025; 55:630-636. [PMID: 39821592 DOI: 10.1111/imj.16633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/03/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Sepsis-associated acute kidney injury (SA-AKI) is common among patients admitted to the intensive care unit (ICU) with sepsis. AIMS This study aimed to demonstrate an association between an episode of SA-AKI and progression to dialysis dependence, with a view to identifying a cohort who may be suitable for intensive nephrology follow-up. METHODS Design: Retrospective data-linkage cohort study. SETTING Alice Springs Hospital ICU, 10-bed regional facility, housed in a 200-bed regional hospital, located in Central Australia. PARTICIPANTS All patients admitted with a diagnosis code associated with sepsis between 2015 and 2017. MAIN OUTCOME MEASURES Primary outcome was a composite measure comprising death or initiation of maintenance dialysis within 5 years of the index case of sepsis leading to ICU admission. RESULTS The unadjusted risk of the composite outcome was significantly higher in the SA-AKI group (odds ratio (OR) 3.22, 95% confidence interval (CI) 1.81-5.74, P < 0.01). This effect remains after adjustment for age, illness severity and co-morbidities (adjusted OR (aOR) 2.64, 95% CI 1.22-5.68, P = 0.01). Progression to maintenance dialysis was the primary driver of this effect (OR 7.56, 95% CI 2.23-25.65, P = 0.02), although it was modified by the effect of confounders (aOR 7.3, 95% CI 0.7-75.94, P = 0.10). CONCLUSIONS These results demonstrate an association between an index episode involving SA-AKI and the composite outcome in a defined population. Identification of this group may allow intensive nephrology follow-up and secondary prevention with the goal of mitigating the risk of progression of disease with significant economic and personal benefits.
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Affiliation(s)
- Laura Gallop
- Medical Retrieval and Consultation Centre, Alice Springs Hospital, Alice Springs (Mparntwe), Northern Territory, Australia
| | - Jack Hickey
- Research Unit, Alice Springs Hospital, Alice Springs (Mparntwe), Northern Territory, Australia
| | - Richard Johnson
- Director Research, Alice Springs Hospital, Alice Springs (Mparntwe), Northern Territory, Australia
- School of Medicine, Flinders University, Adelaide, South Australia, Australia
- School of Medicine, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Paul Secombe
- School of Medicine, Flinders University, Adelaide, South Australia, Australia
- Intensive Care Unit, Alice Springs Hospital, Alice Springs (Mparntwe), Northern Territory, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Centre For Outcome and Resource Evaluation, Australian and New Zealand Intensive Care Society, Melbourne, Victoria, Australia
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32
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Chee BRK, Quah ESH, Zhao CXS, Tan KGP, Thwin L. The Addition of a Nonsteroidal Anti-inflammatory Drug in Local Infiltration Analgesia During Total Knee Arthroplasty Increases the Risk of Acute Kidney Injury in Patients Who Have Renal Impairment: A Propensity-Matched Retrospective Cohort Study. J Arthroplasty 2025; 40:916-922. [PMID: 39447933 DOI: 10.1016/j.arth.2024.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/02/2024] [Accepted: 10/07/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Local infiltration analgesia (LIA) is a crucial component of pain management during total knee arthroplasty (TKA), Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly included in the drug cocktail. The use of NSAIDs are associated with adverse renal, gastrointestinal, and cardiovascular effects. This study aimed to investigate whether the addition of an NSAID in LIA affects the incidence of acute kidney injury (AKI) in TKA patients, especially those who have pre-existing renal impairment. The secondary aim was to determine overall AKI incidence. METHODS A retrospective cohort study was conducted on elective, primary TKA patients in a single tertiary institution between January 2020 and April 2024. Patients were administered LIA intraoperatively, with or without an NSAID (30 mg of ketorolac). Patients who did or did not have chronic kidney disease (CKD) were analyzed separately. Propensity matching was performed on the CKD group, correcting for age, sex, body mass index, American Society of Anesthesiologists score, and presence of diabetes mellitus/hypertension. The outcome of interest was the incidence of AKI. We used t-tests or Chi-square tests to determine the statistical significance of the results. RESULTS In patients who had CKD (n = 114), the presence of ketorolac in LIA was associated with a higher AKI incidence (12.7 versus 2.0%, P = 0.041). In patients who did not have CKD (n = 870), the presence of ketorolac in LIA was not associated with a higher AKI incidence (2.0 versus 1.9%, P = 1.0). Overall AKI incidence was 2.6%. CONCLUSIONS In patients who have CKD, orthopaedic surgeons should be highly cautious of administering ketorolac in LIA during TKA, as it is associated with a higher risk of AKI. Patients who have normal renal function can be safely given ketorolac in LIA without an elevated risk of AKI. Further studies are needed to examine AKI incidence when other NSAIDs are used in LIA.
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Affiliation(s)
- Brian R K Chee
- Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore
| | - Emrick S H Quah
- Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore
| | - Carol X S Zhao
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Kelvin G P Tan
- Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore
| | - Lynn Thwin
- Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore
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Kannan S, Phan TT, Creed HA, Reyna AJ, Baranwal G, Rich AL, Weiss DL, Rutkowski JM. Therapeutically Induced Lymphangiogenesis Is Ineffective in Resolving Established Kidney Disease in Mice. KIDNEY360 2025; 6:509-520. [PMID: 39689345 PMCID: PMC12045517 DOI: 10.34067/kid.0000000671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/27/2024] [Indexed: 12/19/2024]
Abstract
Key Points CKD is a state of unresolved kidney inflammation. Lymphatic vessels and lymphangiogenesis regulate inflammation, and thus, more lymphatics could potentially resolve inflammation and CKD progression. Induction of kidney-specific lymphangiogenesis in three mouse CKD models did not improve kidney function and has the potential to worsen CKD. Background CKD counts AKI as one of its many underlying causes. Lymphatic vessels are important in modulating inflammation postinjury. Manipulating lymphatic vessel expansion thus has the potential to alter CKD progression. Previously, we demonstrated that renal lymphatic expansion before injury reduced CKD progression after an AKI. Here, we test whether inducing lymphangiogenesis affects established CKD. Methods After CKD progression, kidney lymphatics were expanded by transgenic induction of kidney-specific overexpression of vascular endothelial growth factor-D in aristolochic acid (AA) nephropathy and cisplatin injury aggravated with chronic high phosphate diet (CisPi) models or by infusion of kidney-targeting nanoparticles loaded with the vascular endothelial growth factor receptor-3 specific ligand vascular endothelial growth factor-C C156S in a progressive proteinuria (POD) model. Renal fibrosis and lymphatic density were determined by picrosirius red staining and immunofluorescence, respectively. Renal function was assessed by creatinine clearance rate, serum creatinine, BUN, and urinary albumin-creatinine ratio. Renal proinflammatory and fibrotic markers expression were measured by quantitative RT-PCR. Results Kidney-specific overexpression of vascular endothelial growth factor-D+ mice demonstrated expanded renal lymphatics, while nanoparticles treatment minimally expanded lymphatics. In neither the AA nor POD model did lymphangiogenesis improve renal function or fibrosis. AA mice showed decreased Tgfb1 expression and POD mice showed increased Col4a1 expression. Expansion worsened function in CisPi CKD and increased fibrosis. CisPi kidneys also demonstrated increased expression of Mcp-1 , Il1b , Col1a1 , and Tgfb1 and increased macrophage numbers. Conclusions Therapeutically induced lymphatic expansion is ineffective in resolving established CKD and has the potential to further worsen CKD progression.
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Affiliation(s)
- Saranya Kannan
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, Texas
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Rane RP, Soundranayagam S, Shade DA, Nauer K, DuMont T, Nashar K, Balaan MR. Renal Involvement in Sepsis: Acute Kidney Injury. Crit Care Nurs Q 2025; 48:100-108. [PMID: 40009857 DOI: 10.1097/cnq.0000000000000553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Acute kidney injury (AKI) is a common complication of sepsis due to a myriad of contributing factors and leads to significant morbidity and mortality in critically ill patients. Prompt identification and management are vital to reverse and/or prevent the worsening of AKI. When renal function is severely compromised, there may be a need for dialytic therapy to meet the metabolic needs of patients. This article will review the definition of AKI, epidemiology, risk factors, and pathophysiology of AKI in sepsis, along with both non-dialytic and dialytic treatment strategies. We will also review landmark trials in fluid resuscitation in sepsis.
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Affiliation(s)
- Rahul Prakash Rane
- Author Affiliations: Division of Pulmonary and Critical Care, Medicine Institute, Allegheny Health Network, Pittsburgh, Pennsylvania (Dr Rane, Dr Shade, Mr Nauer, Dr DuMont, and Dr Balaan); Division of Nephrology and Critical Care, Medicine Institute, Allegheny Health Network, Pittsburgh, Pennsylvania (Dr Soundranayagam); and Division of Nephrology, Medicine Institute, Allegheny Health Network , Pittsburgh, Pennsylvania (Dr Nashar)
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Zong C, Xu GL, Ning M, Li JY, Wang X, Guo HJ, Zhang LH, Zhou L, Xu C, Yang ZH, Lu LM, Niu JY. PU.1/Spi1 exacerbates ischemia-reperfusion induced acute kidney injury via upregulating Gata2 and promoting fibroblast activation. Acta Pharmacol Sin 2025:10.1038/s41401-025-01530-w. [PMID: 40169783 DOI: 10.1038/s41401-025-01530-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/02/2025] [Indexed: 04/03/2025]
Abstract
Previous studies on acute kidney injury (AKI) have predominantly focused on renal tubular cells, while the specific role of fibroblasts has been largely neglected. Recent evidence shows that PU.1/Spi1, a transcription factor, is an important modulator of fibroblast activation, whereas pharmacological and genetic silencing of PU.1/Spi1 disrupts the fibrotic network and reprograms activated fibroblasts into quiescent fibroblasts. In this study we investigated whether and how PU.1/Spi1 regulated renal fibroblast activation during AKI. An AKI model was established in male mice by clamping bilateral renal arteries for 30 min. Mice were sacrificed and blood and kidney samples were collected 48 h after the surgery. We showed that the expression level of PU.1/Spi1 was significantly upregulated in ischemia/reperfusion (I/R)-induced AKI and PU.1/Spi1 was specifically localized in fibroblasts. Meanwhile, we observed that a massive activation of fibroblasts occurred at the early stage of AKI. PU.1/Spi1 knockout significantly attenuated the activation of fibroblasts along with the decreased release of inflammatory factors and tubular injury. Bioinformatic analysis revealed that GATA binding protein 2 (Gata2), an evolutionarily conserved gene, might be a downstream target gene of PU.1/Spi1. In primary cultured mouse kidney fibroblasts subjected to hypoxia/reoxygenation (H/R), the expression levels of PU.1/Spi1, Gata2 and α-SMA were significantly upregulated. Activated fibroblasts exhibited elevated proliferative capacity, evidenced by upregulated proliferating cell nuclear antigen (PCNA) and cell cycle proteins such as cyclin B1 and cyclin D3. The secretion of inflammatory factors was increased in the activated fibroblasts. Conditioned medium from H/R-treated fibroblasts induced tubular cell injury and increased apoptosis. Using chromatin immunoprecipitation and promoter-luciferase assays, we demonstrated that PU.1/Spi1 was able to bind to the promoter region of Gata2 and enhanced its transcription. Our results show that interstitial fibroblasts are activated at the early stage of I/R-induced AKI and involved in renal injury. Upregulated PU.1/Spi1 stimulates fibroblast activation by upregulating its downstream gene Gata2. Inhibiting the activation of fibroblasts may have a beneficial effect on AKI.
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Affiliation(s)
- Chen Zong
- Department of Nephrology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Guo-Li Xu
- Department of Nephrology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Ming Ning
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jing-Yao Li
- Department of Nephrology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China
| | - Xin Wang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, 201103, China
| | - Heng-Jiang Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Li-Hong Zhang
- Department of Nephrology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Li Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Chen Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhen-Hao Yang
- Department of Nephrology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Li-Min Lu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Jian-Ying Niu
- Department of Nephrology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.
- Center of Community-based Health Research, Fudan University, Shanghai, 200240, China.
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Wing S, Neto AS, Bellomo R, Clark EG, Gallagher M, Liangos O, Prasad B, Silver SA, Tolwani A, Bagshaw S, Wald R. CKD Progression after Acute Kidney Injury: A Secondary Analysis of the Standard versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury Trial. KIDNEY360 2025; 6:636-644. [PMID: 39625781 PMCID: PMC12045516 DOI: 10.34067/kid.0000000663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/21/2024] [Indexed: 04/25/2025]
Abstract
Key Points Development or progression of CKD occurred in almost 40% of patients after an episode of severe AKI. Receipt of KRT, regardless of allocation to an accelerated or standard initiation strategy, was associated with development or progression of CKD. This study helps identify a subset of patients at risk of CKD after severe AKI who would benefit from dedicated kidney follow-up after discharge. Background CKD is a common complication after AKI. We aimed to evaluate whether a KRT initiation strategy had an effect on CKD progression. Secondarily, we aimed to identify factors that influenced the development or progression of CKD after severe AKI. Methods This secondary analysis of the Standard versus Accelerated Initiation of Renal Replacement Therapy in AKI trial included patients with outpatient serum creatinine values available in the year before hospitalization and who were alive at 90 days after randomization. Our main analysis focused on patients who had definitive assessment of kidney function at 90 days after randomization. Predictor markers included patient demographics, comorbidities, markers of acute illness, laboratory values, receipt of KRT, and KRT treatment strategy (accelerated versus standard). The primary outcome was CKD progression, a composite of de novo CKD, defined as new eGFR <60 ml/min per 1.73 m2 if baseline eGFR was ≥60 ml/min; a decline in eGFR ≥25% if baseline eGFR was <60 ml/min; or KRT dependence at day 90. The association of KRT treatment strategy with CKD progression was assessed in an unadjusted mixed-effect logistic regression model. Results Of the 401 surviving patients with a baseline serum creatinine, 39% experienced CKD progression. KRT initiation strategy had no effect on CKD progression (accelerated arm [41%], versus the standard arm [38%], odds ratio, 1.13 [95% confidence interval, 0.75 to 1.72]). Receipt of KRT and aortic surgery were the most potent risks of CKD progression. Conclusions These findings suggest that CKD progression is common after severe AKI. Risk factors of CKD progression included receipt of KRT and aortic surgery, suggesting that these patients should be prioritized for dedicated kidney follow-up after hospital discharge. Clinical Trial registry name and registration number: NCT01557361 .
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Affiliation(s)
- Sara Wing
- Division of Nephrology, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada
| | - Ary Serpa Neto
- Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia
- Department of Critical Care, Melbourne Medical School, Austin Hospital, University of Melbourne, Melbourne, Victoria, Australia
- Department of Critical Care Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia
- Department of Critical Care, School of Medicine, University of Melbourne, Parkville, Victoria, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
- Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Edward G. Clark
- Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Martin Gallagher
- Renal Division, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Orfeas Liangos
- Faculty of Medicine, University of Würzburg, Würzburg, Germany
| | - Bhanu Prasad
- Faculty of Medicine, Regina General Hospital, Regina, Saskatchewan, Canada
| | - Samuel A. Silver
- Division of Nephrology, Kingston Health Sciences Center, Queen's University, Kingston, Ontario, Canada
| | - Ashita Tolwani
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Sean Bagshaw
- Department of Critical Care Medicine, Alberta Health Services, Edmonton, Alberta, Canada
| | - Ron Wald
- Division of Nephrology, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada
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Ulrich EH, Yordanova M, Morgan C, Benisty K, Riglea T, Huynh L, Crépeau-Hubert F, Hessey E, McMahon K, Cockovski V, Wang S, Zappitelli M. Kidney and blood pressure outcomes 11 years after pediatric critical illness and longitudinal impact of AKI: a prospective cohort study. Pediatr Nephrol 2025; 40:1111-1120. [PMID: 39585355 DOI: 10.1007/s00467-024-06586-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 10/10/2024] [Accepted: 10/23/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Acute kidney injury (AKI) is common in critically ill children and associated with adverse short-term outcomes; however, long-term outcomes are not well described. METHODS This longitudinal prospective cohort study examined the prevalence of chronic kidney disease (CKD) and hypertension (HTN) 11 vs. 6 years after pediatric intensive care unit (PICU) admission and association with AKI. We examined children (age < 19 years) without pre-existing kidney disease 11 ± 1.5 years after PICU admission at a single center. AKI was defined using serum creatinine criteria. The primary outcome was a composite of CKD or HTN. CKD was defined as estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or albuminuria. Multivariable analyses compared outcomes at 11- vs. 6-year follow-up and association with AKI during PICU admission. RESULTS Of 96 children evaluated 11 years after PICU admission, 16% had evidence of CKD or HTN (vs. 28% at 6 years, p < 0.05). Multivariable analysis did not show improvement in outcomes from 6- to 11-year follow-up. eGFR decreased from 6- to 11-year follow-up (adjusted coefficient - 11.7, 95% CI - 17.6 to - 5.9) and systolic and diastolic blood pressures improved. AKI was associated with composite outcome at 6-year (adjusted odds ratio (aOR) 12.7, 95% CI 3.2-51.2, p < 0.001), but not 11-year follow-up (p = 0.31). AKI was associated with CKD (aOR 10.4, 95% CI 3.1-34.7) at 11 years. CONCLUSIONS This study provides novel data showing that adverse kidney and blood pressure outcomes remain highly prevalent 10 years after critical illness in childhood. The association with AKI wanes over time.
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Affiliation(s)
- Emma H Ulrich
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Mariya Yordanova
- Faculty of Medicine and Dentistry, McGill University Health Centre, Montreal, QC, Canada
| | - Catherine Morgan
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Kelly Benisty
- Faculty of Medicine and Dentistry, McGill University Health Centre, Montreal, QC, Canada
| | - Teodora Riglea
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | - Louis Huynh
- Faculty of Medicine and Dentistry, McGill University Health Centre, Montreal, QC, Canada
| | | | - Erin Hessey
- Department of Pediatrics, Toronto Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, University of Toronto, 686 Bay Street, Room 11.9722, Toronto, ON, M5G 0A4, Canada
| | - Kelly McMahon
- Faculty of Medicine and Dentistry, McGill University Health Centre, Montreal, QC, Canada
| | - Vedran Cockovski
- Department of Pediatrics, Toronto Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, University of Toronto, 686 Bay Street, Room 11.9722, Toronto, ON, M5G 0A4, Canada
| | - Stella Wang
- Department of Pediatrics, Toronto Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, University of Toronto, 686 Bay Street, Room 11.9722, Toronto, ON, M5G 0A4, Canada
| | - Michael Zappitelli
- Department of Pediatrics, Toronto Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, University of Toronto, 686 Bay Street, Room 11.9722, Toronto, ON, M5G 0A4, Canada.
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Gao YX, Kou C, Tan X. Association of joint exposure to multiple brominated flame retardants with kidney impairment risk among adult population: Evidence from non-pooled samples of NHANES. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 294:118070. [PMID: 40120486 DOI: 10.1016/j.ecoenv.2025.118070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/07/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
Although previous studies showed toxicity of brominated flame retardants (BFRs) in human kidney cells in vitro, less is known about actual effects of BFRs exposure on kidney impairment. This study aims to examine associations of joint exposure to multiple BFRs with kidney impairment risk among adults, and with all-cause mortality risk among kidney impairment adults. Information on study participants and their serum concentrations of eleven BFRs (ten PBDEs and one PBB) were obtained from NHANES 2003-2004 and National Death Index. Factor analysis was applied to identify BFR exposure patterns. Data were analyzed using weighted multivariate logistic and Cox proportional regressions to examine the associations of BFR exposure patterns with kidney impairment risk and with all-cause mortality risk, respectively. Results showed concentrations of PBDE-28, PBDE-47, PBDE-85, PBDE-100, PBDE-154 and PBDE-66 among participants with kidney impairment were significantly higher than those without kidney impairment (all p < 0.050). Three exposure patterns were identified under an eigenvalue of ≥ 1.0 (p of Bartlett's test: <0.001; KMO value: 0.787), and one pattern of them, which was characterized by high exposure to PBDE-28, PBDE-47, PBDE-85, PBDE-99, PBDE-154 and PBDE-66, was positively associated with kidney impairment risk (weighted covariates-adjusted OR: 1.317; 95 % CI: 1.031-1.683). The median of follow-up period was 190.0 months. All patterns were not significantly associated with all-cause mortality risk during the follow-up period (all p > 0.050). In conclusion, this study found for the first time that high exposure to some PBDEs may increase kidney impairment risk, but not directly affect prognosis of kidney impairment among adult population.
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Affiliation(s)
- Yi-Xiong Gao
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Peking, China.
| | - Chen Kou
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Peking, China.
| | - Xin Tan
- School of Life Science, Beijing Institute of Technology, Peking, China.
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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. [PMID: 40134649 PMCID: PMC11755238 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: 10/16/2024] [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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40
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Tang H, Qu M, Xin M, He T. Association between lactate-albumin ratio and 28-day mortality in patients with sepsis-associated acute kidney injury: a retrospective cohort study. Sci Rep 2025; 15:10087. [PMID: 40128268 PMCID: PMC11933315 DOI: 10.1038/s41598-025-94753-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/17/2025] [Indexed: 03/26/2025] Open
Abstract
The aim of this study was to investigate the correlation between lactate-albumin ratio (LAR) and 28-day mortality in patients with sepsis combined with acute kidney failure (SA-AKI). The study was based on the eICU database and collected data from 1855 patients with SA-AKI. The relationship between LAR and 28-day in-hospital mortality was assessed using multivariate Cox regression models and Kaplan-Meier survival analysis. A generalised summation model was also used to analyse the non-linear relationship between LAR and mortality. The results showed that the 28-day in-hospital mortality rate of the patients was 19.46% (361/1,855), with a significant positive correlation between LAR and mortality (HR: 1.26, 95% CI: 1.18-1.35, p < 0.001). The Kaplan-Meier survival curve showed that the highest quartile of LAR (Q4) had the lowest survival rate. Non-linear analysis showed that when the LAR ratio was less than 2.1, mortality increased with each 1-unit increase in the LAR ratio, with an adjusted hazard ratio of 1.48 (95% CI 1.20, 1.84, p < 0.001). For patients with SA-AKI, a nonlinear relationship between LAR and 28-day risk of death was observed, with higher LAR associated with higher risk of mortality.
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Affiliation(s)
- Huizhen Tang
- Department of Transfusion, Northwest Women's and Children's Hospital, Xi'an, China
| | - Mingli Qu
- Department of Transfusion, Northwest Women's and Children's Hospital, Xi'an, China
| | - Miaomiao Xin
- Reproductive Center, Northwest Women's and Children's Hospital, Xi'an, China
| | - Tongqiang He
- Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, China.
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Mboni-Johnston IM, Hartmann S, Kroll C, Berndt C, Adjaye J, Schupp N. Impact of nephrotoxins and oxidants on survival and transport function of hiPSC-derived renal proximal tubular cells. Arch Toxicol 2025:10.1007/s00204-025-04015-1. [PMID: 40119912 DOI: 10.1007/s00204-025-04015-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/27/2025] [Indexed: 03/25/2025]
Abstract
Due to their role in excretion, renal proximal tubular cells are susceptible to damage by toxic metabolites and xenobiotics. The regenerative capacity of the kidney allows for the replacement of damaged cells, a process involving differentiation programs. However, kidney function tends to decline, suggesting that the replacement cells may not achieve full functionality. To understand possible causes of this decline, we investigated effects of nephrotoxins and oxidants on the differentiation of induced pluripotent stem cells (iPSC) into proximal tubular epithelial-like cells (PTELC). Proliferation, apoptosis, senescence, and expression of oxidative defense genes were analyzed in iPSC, differentiating and differentiated cells treated with cisplatin (CisPt, up to 45 µM), cyclosporin A (CycA, up to 12 µM), and the oxidants menadione (Mena, up to 50 µM) and tert-butylhydroquinone (tBHQ, up to 50 µM). We found that differentiating cells were most sensitive to oxidants and showed increased sensitivity to CisPt, whereas all differentiation stages showed similar sensitivity to CycA. Both oxidative stress and CisPt triggered apoptosis in all differentiation stages, whereas CycA mainly induced senescence. Treatment during differentiation resulted in long-term effects on gene expression in differentiated cells. While oxidants had no effect on transport function of differentiated cells, CisPt and CycA impaired albumin uptake. Our data suggest a substantial sensitivity of differentiating cells to nephrotoxins and oxidants, an aspect that could potentially interfere with regenerative processes.
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Affiliation(s)
- Isaac Musong Mboni-Johnston
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sören Hartmann
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Christian Kroll
- Department of Neurology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Carsten Berndt
- Department of Neurology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, University Hospital Düsseldorf, University of Düsseldorf, 40225, Düsseldorf, Germany
- Zayed Centre for Research into Rare Diseases in Children (ZCR), EGA Institute for Women'S Health, University College London (UCL), 20 Guilford Street, London, WC1N 1DZ, UK
| | - Nicole Schupp
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
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Assante W, Kore S, Alavi R, Foroshani S, Andrabi S, Kichloo A, Chugh S. Evaluating outcomes in critically ill patients with undiagnosed acute kidney injury: a comparison of the incidence of physician-diagnosed vs KDIGO criteria-diagnosed acute kidney injury. Proc AMIA Symp 2025; 38:266-271. [PMID: 40291098 PMCID: PMC12026081 DOI: 10.1080/08998280.2025.2475427] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 02/04/2025] [Accepted: 02/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background Acute kidney injury (AKI) independently predicts adverse outcomes, including morbidity, mortality, and prolonged hospital stays. Historically, inconsistent diagnostic criteria hindered the assessment of its prevalence. To address this, criteria such as Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO) were developed. Applying these criteria remains challenging, especially in critical care settings, leading to underdiagnosis and poorer outcomes. Methods This retrospective cohort study examined AKI incidence in critically ill patients by applying KDIGO criteria to charts of patients in the intensive care unit (ICU), comparing them to physician-diagnosed AKI. We examined the consequences for physician-undiagnosed AKI patients by analyzing variables such as mortality and hospital/ICU length of stay. Results Of the 1063 patients meeting KDIGO AKI criteria, physicians diagnosed 486 cases, missing 54% of AKI cases identified by KDIGO criteria. AKI was associated with longer hospital and ICU stays and higher mortality. Early stage AKI was particularly prone to underdiagnosis. Discussion This study reveals the underdiagnosis of AKI by ICU physicians. This significantly impacts patients with cardiovascular disease, complicating recovery from cardiac procedures and affecting both short-term and long-term outcomes. Enhancing early AKI surveillance offers an opportunity to optimize care and improve outcomes.
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Affiliation(s)
- William Assante
- Division of Nephrology, Westchester Medical Center, Valhalla, New York, USA
| | - Shruti Kore
- Division of Nephrology, Westchester Medical Center, Valhalla, New York, USA
- Division of Nephrology, New York Medical College, Valhalla, New York, USA
| | - Reza Alavi
- Division of Nephrology, Westchester Medical Center, Valhalla, New York, USA
| | - Saam Foroshani
- Division of Nephrology, New York Medical College, Valhalla, New York, USA
| | - Suhaib Andrabi
- Division of Nephrology, NYC Health + Hospitals/Harlem, New York, New York, USA
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Asim Kichloo
- Department of Internal Medicine and Sub-Specialties, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, Texas, USA
| | - Savneek Chugh
- Division of Nephrology, Westchester Medical Center, Valhalla, New York, USA
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Baker ML, Cantley LG. Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury. J Clin Invest 2025; 135:e188358. [PMID: 40091836 PMCID: PMC11910233 DOI: 10.1172/jci188358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025] Open
Abstract
Acute kidney injury (AKI) encompasses pathophysiology ranging from glomerular hypofiltration to tubular cell injury and outflow obstruction. This Review will focus on the tubulointerstitial processes that underlie most cases of AKI. Tubular epithelial cell (TEC) injury can occur via distinct insults, including ischemia, nephrotoxins, sepsis, and primary immune-mediated processes. Following these initial insults, tubular cells can activate survival and repair responses or they can develop mitochondrial dysfunction and metabolic reprogramming, cell-cycle arrest, and programmed cell death. Developing evidence suggests that the fate of individual tubular cells to survive and proliferate or undergo cell death or senescence is frequently determined by a biphasic immune response with initial proinflammatory macrophage, neutrophil, and lymphocyte infiltration exacerbating injury and activating programmed cell death, while alternatively activated macrophages and specific lymphocyte subsets subsequently modulate inflammation and promote repair. Functional recovery requires that this reparative phase supports proteolytic degradation of tubular casts, proliferation of surviving TECs, and restoration of TEC differentiation. Incomplete resolution or persistence of inflammation can lead to failed tubular repair, fibrosis, and chronic kidney disease. Despite extensive research in animal models, translating preclinical findings to therapies remains challenging, emphasizing the need for integrated multiomic approaches to advance AKI understanding and treatment.
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Martin L, Martin C, Peine A, Imöhl M, Kersten A, Kramann R, Saritas T, Marx N, Dreher M, Marx G, Simon TP. Implementation and One-Year Evaluation of Proenkephalin A in Critical Care. Int J Mol Sci 2025; 26:2602. [PMID: 40141244 PMCID: PMC11942029 DOI: 10.3390/ijms26062602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Proenkephalin A 119-159 (PENK) is a promising functional kidney biomarker, evaluated in various clinical settings. In critical care medicine, early diagnosis of acute kidney injury (AKI) is crucial; however, to date, the diagnosis and the assessment of kidney function is still based on serum creatinine (sCr) and urine output, both associated with several limitations. Between November 2020 and March 2022, we implemented PENK in our daily practice on our intensive care units (ICU). PENK, sCr, AKI stage, and the start and duration of renal replacement therapy (RRT) were documented. Almost 18,000 PENK measurements from 4169 patients were analyzed, and the glomerular filtration rate (GFR) was estimated with the new PENK-GFR formula. PENK outperformed sCR in the kidney function assessment and sCR trajectory over time. Moreover, PENK predicted the use of RRT and thus showed its usefulness in critical care daily practice.
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Affiliation(s)
- Lukas Martin
- Department of Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Caren Martin
- Department of Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Arne Peine
- Department of Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Matthias Imöhl
- Laboratory Diagnostic Center, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Alexander Kersten
- Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
- Department of Cardiology, Angiology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Rafael Kramann
- Department of Nephrology, Rheumatology, Clinical Immunology and Hypertension, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Turgay Saritas
- Department of Nephrology, Rheumatology, Clinical Immunology and Hypertension, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Nikolaus Marx
- Department of Cardiology, Angiology and Internal Intensive Care Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Michael Dreher
- Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Gernot Marx
- Department of Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Tim-Philipp Simon
- Department of Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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45
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Yang H, Chen Y, He J, Li Y, Feng Y. Advances in the diagnosis of early biomarkers for acute kidney injury: a literature review. BMC Nephrol 2025; 26:115. [PMID: 40045274 PMCID: PMC11884078 DOI: 10.1186/s12882-025-04040-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
Acute kidney injury (AKI) is a critical condition with diverse manifestations and variable outcomes. Its diagnosis traditionally relies on delayed indicators such as serum creatinine and urine output, making early detection challenging. Early identification is essential to improving patient outcomes, driving the need for novel biomarkers. Recent advancements have identified promising biomarkers across various biological processes. Tubular injury markers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and liver-type fatty acid-binding protein (L-FABP), offer insights into early tubular damage. Inflammatory and repair-associated biomarkers, such as interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), osteopontin (OPN), and C-C motif chemokine ligand 14 (CCL14), reflect ongoing injury and recovery processes. Additionally, stress and repair markers like tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP-7), alongside filtration markers such as cystatin C (CysC) and proenkephalin (PenKid®) e.tal, further enhance diagnostic precision. Oxidative stress-related markers, including Superoxide Dismutase 1 (SOD1), also contribute valuable information. Emerging candidates, such as microRNAs, soluble urokinase plasminogen activator receptor (SuPAR), and chitinase-3-like protein 1 (CHI3L1), hold substantial promise for AKI detection and prognosis. This review summarizes the progress in AKI biomarker research, highlighting their clinical utility and exploring their potential to refine early diagnosis and management strategies. These findings offer a new perspective for integrating novel biomarkers into routine clinical practice, ultimately improving AKI care.
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Affiliation(s)
- Hongsha Yang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Yanqin Chen
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Jiajia He
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China
| | - Yi Li
- Department of Nephrology, Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Centre for Kidney Diseases, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yunlin Feng
- Department of Nephrology, Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan Clinical Research Centre for Kidney Diseases, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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46
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Lu R, Dismorr M, Hertzberg D, Glaser N, Sartipy U. Early Creatinine Changes After Aortic Valve Replacement and Late Survival, Heart Failure, and Chronic Kidney Disease in a National Registry. Ann Thorac Surg 2025; 119:577-584. [PMID: 38971227 DOI: 10.1016/j.athoracsur.2024.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 07/08/2024]
Abstract
BACKGROUND The impact of small increases in serum creatinine after surgical aortic valve replacement (SAVR) that fail to meet the acute kidney injury stage 1 criteria is unknown. The aim of this study was to investigate prognosis after primary SAVR in patients with small increases in postoperative serum creatinine. METHODS This observational cohort study included all adult patients who underwent primary SAVR in Sweden from 2009 to 2022. The primary outcome was all-cause mortality. Secondary outcomes were chronic kidney disease and heart failure. Regression standardization addressed confounding. RESULTS In 16,766 patients, 4074 (24.2%) had no change in postoperative serum creatinine, 5764 (34.3%) had a small increase in postoperative serum creatinine (0.06 mg/dL ≤ Δserum creatinine <0.3 mg/dL), and 2753 (16.4%) fulfilled the Kidney Disease Improving Global Outcomes acute kidney injury stage 1 criteria. The mean age was 67 years, and 31% of patients were female. No significant difference in long-term all-cause mortality was observed in the no change group at 13 years compared with the small increase group (absolute survival difference, 2.3% [95% CI, 0%-4.6%]). A stepwise increase in the risk of 30-day mortality was observed with increasing changes in serum creatinine. At 13 years of follow-up, there was a significant difference in the risk of chronic kidney disease (absolute difference, 2.8% [95% CI, 1.0%-4.5%]) and heart failure (absolute difference, 3.5% [95% CI, 1.3%-5.7%]) between the no change and small increase groups. CONCLUSIONS A small increase in postoperative serum creatinine after SAVR was associated with an increased risk of adverse outcomes. The acute kidney injury definition may benefit from including more reliable and specific biomarkers together with small creatinine increases to detect kidney injury.
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Affiliation(s)
- Ruixin Lu
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Michael Dismorr
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
| | - Daniel Hertzberg
- Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Natalie Glaser
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Cardiology, Stockholm South General Hospital, Stockholm, Sweden
| | - Ulrik Sartipy
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden
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47
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Madesh S, Palaniappan S, Aravind A, Sau A, Almutairi MH, Almutairi BO, Soundharrajan I, Namasivayam SKR, Kumaradoss KM, Arockiaraj J. Mitigation of gentamycin induced acute kidney injury due to benzothiazole derivatives N1 and N5: Antioxidant and renoprotective mechanisms in-vivo zebrafish. Toxicol Lett 2025; 405:30-40. [PMID: 39921194 DOI: 10.1016/j.toxlet.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 12/20/2024] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
Acute kidney injury (AKI) is marked by a rapid decline in renal function, often caused by oxidative stress and nephrotoxic agents. Complications limit current therapeutic strategies, and no specific drugs are available to prevent renal injury or accelerate recovery. In the present research, we investigated the therapeutic efficacy of synthesized 2-aminobenzothiazole derivatives, N1 and N5, in mitigating Gentamicin (Gen) -induced renal damage in vivo zebrafish. The preliminary work of radical scavenging and hemolysis inhibition assay revealed that, both compounds exhibited strong antioxidant and anti-inflammatory activities. Furthermore, acute toxicity assays in zebrafish embryo/larvae revealed no adverse effects at concentrations up to 200 μM were tested, highlighting the safety of these compounds. In the zebrafish AKI model, Gen exposure led to oxidative stress, inflammation, and impaired glomerular filtration with tissue damage. Treatment with N1 and N5 significantly reduced ROS levels, apoptosis, and lipid peroxidation and restored antioxidant enzyme activities. Furthermore, N5 treatment improved renal filtration and reduced proteinuria levels, indicating its ability to mitigate nephrotoxic effects. Gene expression analysis showed that N1 and N5 downregulated pro-inflammatory markers (cox-2, tnfα, mpo) and angiogenic mediators (vegf, vegfr2), demonstrating anti-inflammatory and anti-angiogenic properties. Histological analyses revealed that N1 and N5 attenuated glomerular and tubular damage, reduced necrosis, and promoted tissue repair. These findings highlight the potential of 2-aminothiazole derivatives as effective therapeutic agents for AKI, offering antioxidant, anti-inflammatory, and cytoprotective benefits and warranting further investigation into their long-term efficacy in chronic kidney disease models.
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Affiliation(s)
- S Madesh
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu 603203, India
| | - Senthilkumar Palaniappan
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu 641021, India; Center for Active Pharmaceutical Ingredients, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu 641021, India
| | - Anand Aravind
- Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu 641021, India
| | - Avra Sau
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu 603203, India
| | - Mikhlid H Almutairi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Bader O Almutairi
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Ilavenil Soundharrajan
- Grassland and Forages Division, National Institute of Animal Science, Rural Development Administration, Cheonan 31000, Republic of Korea
| | - S Karthick Raja Namasivayam
- Centre for Applied Research, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 602105, India.
| | - Kathiravan Muthu Kumaradoss
- Dr APJ Abdul Kalam Research Lab, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu 603203, India.
| | - Jesu Arockiaraj
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, Tamil Nadu 603203, India.
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48
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Fogo AB, Harris RC. Crosstalk between glomeruli and tubules. Nat Rev Nephrol 2025; 21:189-199. [PMID: 39643696 DOI: 10.1038/s41581-024-00907-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2024] [Indexed: 12/09/2024]
Abstract
Models of kidney injury have classically concentrated on glomeruli as the primary site of injury leading to glomerulosclerosis or on tubules as the primary site of injury leading to tubulointerstitial fibrosis. However, current evidence on the mechanisms of progression of chronic kidney disease indicates that a complex interplay between glomeruli and tubules underlies progressive kidney injury. Primary glomerular injury can clearly lead to subsequent tubule injury. For example, damage to the glomerular filtration barrier can expose tubular cells to serum proteins, including complement and cytokines, that would not be present in physiological conditions and can promote the development of tubulointerstitial fibrosis and progressive decline in kidney function. In addition, although less well-studied, increasing evidence suggests that tubule injury, whether primary or secondary, can also promote glomerular damage. This feedback from the tubule to the glomerulus might be mediated by changes in the reabsorptive capacity of the tubule, which can affect the glomerular filtration rate, or by mediators released by injured proximal tubular cells that can induce damage in both podocytes and parietal epithelial cells. Examining the crosstalk between the various compartments of the kidney is important for understanding the mechanisms underlying kidney pathology and identifying potential therapeutic interventions.
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Affiliation(s)
- Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Raymond C Harris
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Tennessee Department of Veterans Affairs, Nashville, TN, USA.
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49
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Manis MM, Wallace JL, Boyd EF, Abebe KZ, Fried L, Palevsky PM, Conway PT, Horwitz EJ, Liu KD, Parikh CR, Poggio E, Siew ED, Neyra JA, Weir MR, Wilson FP, Kane-Gill SL. Postdischarge Care of Acute Kidney Injury Survivors: An Opportunity for Targeted Nurse and Pharmacist Interventions. ADVANCES IN KIDNEY DISEASE AND HEALTH 2025; 32:154-161. [PMID: 40222802 DOI: 10.1053/j.akdh.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 12/25/2024] [Accepted: 01/13/2025] [Indexed: 04/15/2025]
Abstract
The incidence of acute kidney injury (AKI) is increasing, and with it, the population of individuals requiring post-AKI care. Postdischarge follow-up for AKI survivors is recommended within 90 days of an AKI episode to promote kidney recovery and potentially prevent progression of kidney disease. However, timely postdischarge care is often lacking or fragmented and poses a missed opportunity to prevent long-term complications of this condition. Suggested elements of follow-up care begin with a scheduled appointment with a physician and involve a bundled approach to care with health care providers' communicating across sites, remote patient monitoring devices, review of medications, education, access, kidney care evaluation, and interdisciplinary collaboration to achieve these patient care goals. This article provides an overview of guidance documents for post-AKI care and the roles of the nurse and pharmacist as part of an interdisciplinary team in postdischarge care after a patient incurs an episode of AKI.
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Affiliation(s)
- Melanie M Manis
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | - Jessica L Wallace
- Department of Pharmacy and Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN; Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN; Division of Nephrology, Tennessee Valley Healthcare System (TVHS), Veterans Health Administration, Nashville, TN
| | - Emily F Boyd
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN
| | - Kaleab Z Abebe
- Center for Clinical Trials and Data Coordination, Division of General Internal Medicine, University of Pittsburgh School of Medicine
| | - Linda Fried
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine; Kidney Medicine Section, VA Pittsburgh Healthcare System
| | - Paul M Palevsky
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine; Kidney Medicine Section, VA Pittsburgh Healthcare System
| | - Paul T Conway
- Policy and Global Affairs, American Association of Kidney Patients (AAKP), Tampa, FL
| | - Edward J Horwitz
- Department of Nephrology, Metrohealth Medical Center, Cleveland, OH
| | - Kathleen D Liu
- Departments of Medicine and Anesthesia, University of California, San Francisco, CA
| | - Chirag R Parikh
- Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Emilio Poggio
- Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH
| | - Edward D Siew
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN; Division of Nephrology, Tennessee Valley Healthcare System (TVHS), Veterans Health Administration, Nashville, TN
| | - Javier A Neyra
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - F Perry Wilson
- Clinical and Translational Research Accelerator, Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Sandra L Kane-Gill
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA; Department of Pharmacy, UPMC, Pittsburgh, PA; Department of Critical Care Medicine, Program of Critical Care Nephrology, Pittsburgh, PA
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50
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Birkelo BC, Barreto EF, Siew ED. Care That Fits: Optimizing Value-Based Care for Acute Kidney Injury Survivors. ADVANCES IN KIDNEY DISEASE AND HEALTH 2025; 32:133-143. [PMID: 40222800 PMCID: PMC11999245 DOI: 10.1053/j.akdh.2024.10.010] [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: 02/28/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 04/15/2025]
Abstract
Acute kidney injury (AKI) survivors are at risk for substantial adverse outcomes, and the post-AKI setting is a source of high health care utilization. Kidney health is often not prioritized after discharge from an AKI hospitalization and can be complicated by patient and process-related barriers. Improving kidney care for AKI survivors has the potential to improve outcomes, though data on which care models are optimal for this population are lacking. Care models utilized in other patient populations, as well as prior trials of AKI survivor clinics, can provide insight as to how these models could be implemented in the post-AKI setting to improve outcomes in a cost-effective way. Potential care models range on a spectrum from the least specialized, most highly scalable, and cost-effective options, such as patient engagement programs and home health, to more generally accessible models including allied health-driven models, and primary care-embedded programs, to highly specialized and less scalable options, such as nephrology-led survivor clinics. Each has potential applications and limitations in the post-AKI setting. Ongoing studies that incorporate elements of multiple care models may have the most promise to improve value-based care in the care of AKI survivors.
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Affiliation(s)
- Bethany C Birkelo
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN.
| | | | - Edward D Siew
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN; Tennessee Valley Health Systems (TVHS), Nashville Veterans Affairs, Nashville, TN
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