PMID- 37726051 OWN - NLM STAT- MEDLINE DCOM- 20240201 LR - 20240312 IS - 1523-6838 (Electronic) IS - 0272-6386 (Print) IS - 0272-6386 (Linking) VI - 83 IP - 2 DP - 2024 Feb TI - Urinary Biomarkers and Kidney Injury in VA NEPHRON-D: Phenotyping Acute Kidney Injury in Clinical Trials. PG - 151-161 LID - S0272-6386(23)00804-1 [pii] LID - 10.1053/j.ajkd.2023.07.012 [doi] AB - RATIONALE & OBJECTIVE: Urinary biomarkers of injury, inflammation, and repair may help phenotype acute kidney injury (AKI) observed in clinical trials. We evaluated the differences in biomarkers between participants randomized to monotherapy or to combination renin-angiotensin-aldosterone system (RAAS) blockade in VA NEPHRON-D, where an increased proportion of observed AKI was acknowledged in the combination arm. STUDY DESIGN: Longitudinal analysis. SETTING & PARTICIPANTS: A substudy of the VA NEPHRON-D trial. PREDICTOR: Primary exposure was the treatment arm (combination [RAAS inhibitor] vs monotherapy). AKI is used as a stratifying variable. OUTCOME: Urinary biomarkers, including albumin, EGF (epidermal growth factor), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3-like protein 1), and KIM-1 (kidney injury molecule-1). ANALYTICAL APPROACH: Biomarkers measured at baseline and at 12 months in trial participants were compared between treatment groups and by AKI. AKI events occurring during hospitalization were predefined safety end points in the original trial. The results were included in a meta-analysis with other large chronic kidney disease trials to assess global trends in biomarker changes. RESULTS: In 707 participants followed for a median of 2.2 years, AKI incidence was higher in the combination (20.7%) versus the monotherapy group (12.7%; relative risk [RR], 1.64 [95% CI, 1.16-2.30]). Compared with the monotherapy arm, in the combination arm the urine biomarkers at 12 months were either unchanged (MCP-1: RR, -3% [95% CI, -13% to 9%], P(adj)=0.8; KIM-1: RR, -10% [95% CI, -20% to 1%], P(adj)=0.2; EGF, RR-7% [95% CI, -12% to-1%], P(adj)=0.08) or lower (albuminuria: RR, -24% [95% CI, -37% to-8%], P(adj)=0.02; YKL: RR, -40% to-44% [95% CI, -58% to-25%], P(adj)<0.001). Pooled meta-analysis demonstrated reduced albuminuria in the intervention arm across 3 trials and similar trajectories in other biomarkers. LIMITATIONS: Biomarker measurement was limited to 2 time points independent of AKI events. CONCLUSIONS: Despite the increased risk of serum creatinine-defined AKI, combination RAAS inhibitor therapy was associated with unchanged or decreased urinary biomarkers at 12 months. This suggests a possible role for kidney biomarkers to further characterize kidney injury in clinical trials. PLAIN-LANGUAGE SUMMARY: The VA NEPHRON-D trial investigated inhibition of the renin-angiotensin-aldosterone system (RAAS) hormonal axis on kidney outcomes in a large population of diabetic chronic kidney disease patients. The trial was stopped early due to increased events of serum creatinine-defined acute kidney injury in the combination therapy arm. Urine biomarkers can serve as an adjunct to serum creatinine in identifying kidney injury. We found that urinary biomarkers in the combination therapy group were not associated with a pattern of harm and damage to the kidney, despite the increased number of kidney injury events in that group. This suggests that serum creatinine alone may be insufficient for defining kidney injury and supports further exploration of how other biomarkers might improve identification of kidney injury in clinical trials. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Kiernan, Elizabeth A AU - Kiernan EA AD - Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. FAU - Hu, David AU - Hu D AD - Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. FAU - Philbrook, Heather Thiessen AU - Philbrook HT AD - Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. FAU - Ix, Joachim H AU - Ix JH AD - Division of Nephrology-Hypertension, University of California-San Diego, San Diego, California; Veterans Affairs San Diego Healthcare System, San Diego, CA. FAU - Bonventre, Joseph V AU - Bonventre JV AD - Renal Division, Brigham & Women's Hospital, Boston, Massachusetts. FAU - Coca, Steven G AU - Coca SG AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Moledina, Dennis G AU - Moledina DG AD - Section of Nephrology and Clinical and Translational Research Accelerator, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut. FAU - Fried, Linda F AU - Fried LF AD - Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. FAU - Shlipak, Michael G AU - Shlipak MG AD - Kidney Health Research Collaborative, Department of Medicine, University of California-San Francisco, San Francisco, California. FAU - Parikh, Chirag R AU - Parikh CR AD - Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Electronic address: chirag.parikh@jhmi.edu. LA - eng GR - U01 DK114866/DK/NIDDK NIH HHS/United States GR - UL1 TR001863/TR/NCATS NIH HHS/United States GR - R37 DK039773/DK/NIDDK NIH HHS/United States GR - R01 DK072381/DK/NIDDK NIH HHS/United States GR - U01 DK129984/DK/NIDDK NIH HHS/United States GR - K23 DK117065/DK/NIDDK NIH HHS/United States GR - R01 DK128087/DK/NIDDK NIH HHS/United States GR - U01 DK085660/DK/NIDDK NIH HHS/United States GR - R01 HL085757/HL/NHLBI NIH HHS/United States GR - R01 DK093770/DK/NIDDK NIH HHS/United States GR - P30 DK079310/DK/NIDDK NIH HHS/United States GR - U01 DK106962/DK/NIDDK NIH HHS/United States GR - U01 DK102730/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Meta-Analysis DEP - 20230917 PL - United States TA - Am J Kidney Dis JT - American journal of kidney diseases : the official journal of the National Kidney Foundation JID - 8110075 RN - 0 (Biomarkers) RN - AYI8EX34EU (Creatinine) RN - 62229-50-9 (Epidermal Growth Factor) SB - IM MH - Humans MH - *Acute Kidney Injury/diagnosis MH - Albuminuria MH - *Biomarkers/urine MH - Creatinine MH - Epidermal Growth Factor MH - Nephrons MH - Randomized Controlled Trials as Topic MH - Renal Insufficiency, Chronic MH - Clinical Trials as Topic PMC - PMC10841767 MID - NIHMS1933324 OTO - NOTNLM OT - AKI OT - RAAS-I OT - albuminuria OT - biomarkers OT - creatinine COIS- The other authors declare that they have no relevant financial interests. EDAT- 2023/09/20 00:43 MHDA- 2024/01/23 06:43 PMCR- 2025/02/01 CRDT- 2023/09/19 19:11 PHST- 2022/10/13 00:00 [received] PHST- 2023/06/23 00:00 [revised] PHST- 2023/07/02 00:00 [accepted] PHST- 2025/02/01 00:00 [pmc-release] PHST- 2024/01/23 06:43 [medline] PHST- 2023/09/20 00:43 [pubmed] PHST- 2023/09/19 19:11 [entrez] AID - S0272-6386(23)00804-1 [pii] AID - 10.1053/j.ajkd.2023.07.012 [doi] PST - ppublish SO - Am J Kidney Dis. 2024 Feb;83(2):151-161. doi: 10.1053/j.ajkd.2023.07.012. Epub 2023 Sep 17.