To the Editor:
Sepsis is a leading cause of death, especially when complicated by acute kidney injury (AKI), a common clinical syndrome linked to chronic kidney disease progression,1 cardiovascular disease,2 and mortality.3 Approximately two-thirds of septic shock patients develop AKI, with nearly half presenting with it upon admission.4,5 However, it remains unclear why some septic patients develop AKI whereas others do not.
Septic AKI is often attributed to acute tubular necrosis, in which the tubules are the primary site of kidney injury. Tubular stress markers, including tissue inhibitor of metalloproteinases 2 (TIMP2) and insulin-like growth factor binding protein 7 (IGFBP7), rise during AKI owing to impaired filtration, reduced reabsorption, and leakage from tubular damage. We investigated whether these urine stress markers, used to detect AKI acutely,6 can also reflect long-term tubular health and predict septic AKI when measured in the ambulatory setting.
We performed a case-control study within the Reasons for Geographical Differences in Stroke (REGARDS), a national cohort, using baseline urine samples. Patients who developed septic AKI were matched 1:1 based on age, sex, race, and time to admission with sepsis patients without AKI. We used conditional logistic regression to assess associations among TIMP2, IGFBP7, and the odds of AKI during sepsis per doubling of each biomarker, separately, and in tertiles. Detailed methods are shown in Item S1.
This study included the following 490 participants: 245 with septic AKI and 245 who were admitted with severe infection but did not have AKI. Table 1 displays participant demographics and clinical characteristics, stratified based on AKI status. The mean age was 69 ± 8 years, 44% were women, and 39% were Black. The median (interquartile range) baseline estimated glomerular filtration rate (eGFR) for cases and controls was 73 (55-90) and 82 (65-92) mL/min/1.73 m2, respectively, whereas the median (interquartile range) albuminuria was 19 (8-87) versus 9 (5-22) mg/g. The median (interquartile range) time between the REGARDS baseline visit and their index hospitalization was 4.3 (2.5-6) years. Compared with controls, cases more often had diabetes, a lower eGFR, and higher albuminuria at baseline. During hospitalization for sepsis, cases had higher Sequential Organ Failure Assessment scores and mortality. TIMP2 was not, whereas IGFBP7 was, associated with a higher risk of septic AKI in the fully adjusted analysis (odds ratio, 1.27; 95% confidence interval, 1.01-1.60), which included the use of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, high-sensitivity C-reactive protein, Sequential Organ Failure Assessment score, hospital mortality, baseline eGFR, and urine albumin, as shown in Table 2. In sensitivity analyses, we indexed each biomarker to urine creatinine, rather than adjusting for urine creatinine as a separate covariate, yielding similar results (Table S1).
Table 1.
Baseline Characteristics of REGARDS Participants With Sepsis Based on AKI Status
| Controls (n = 245) | Cases (n = 245) | |
|---|---|---|
| Age, y (SD) | 69 (8) | 69 (8) |
| Female, n (%) | 107 (44) | 107 (44) |
| Race, n (%) | ||
| Black | 96 (39) | 96 (39) |
| White | 149 (61) | 149 (61) |
| Diabetes mellitus, n (%) | 81 (33) | 108 (44) |
| Mean systolic BP, mm Hg (SD) | 131 (19) | 133 (18) |
| Mean diastolic BP, mm Hg (SD) | 75 (10) | 75 (11) |
| Use of ACEi, n (%) | 78 (32) | 91 (37) |
| Use of ARBs, n (%) | 41 (17) | 59 (24) |
| Use of mineralocorticoids, n (%) | 10 (4) | 11 (4) |
| Use of NSAID, n (%) | 51 (21) | 62 (25) |
| Admission destination, n (%) | ||
| ICU | 23 (10) | 44 (18) |
| General ward | 196 (84) | 185 (78) |
| Other/unknown | 26 (11) | 16 (7) |
| Type of infection | ||
| Respiratory | 110 (45) | 120 (49) |
| Urinary tract | 34 (14) | 36 (15) |
| Abdominal | 53 (22) | 37 (15) |
| Skin | 22 (9) | 23 (9) |
| Other | 26 (11) | 28 (12) |
| Mean hsCRP at baseline, (SD) | 0.51 (0.50) | 0.56 (0.50) |
| SOFA score | ||
| 0 | 45 | 23 |
| 1 | 69 | 31 |
| 2 | 54 | 55 |
| 3-4 | 52 | 64 |
| ≥5 | 25 | 72 |
| Hospital mortality, n (%) | 10 (4.1) | 56 (22.9) |
| Median eGFR, (IQR) | 82 (65-92) | 73 (55-90) |
| Median urine ACR, mg/g (IQR) | 9 (5-22) | 19 (8-87) |
| Median urine TIMP2, ng/mL (IQR) | 1.4 (0.7-2.6) | 1.5 (0.8-2.7) |
| Median urine IGFBP7, ng/mL (IQR) | 99.6 (56.5-166.1) | 106.4 (55.1-197.6) |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ACR, albumin-creatinine ratio; AKI, acute kidney injury; ARBs, angiotensin II receptor blockers; BP, blood pressure; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein; ICU, intensive care unit; IGFBP7, insulin-like growth factor binding protein 7; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory drugs; REGARDS, Reasons for Geographical Differences in Stroke; SD, standard deviation: SOFA, Sequential Organ Failure Assessment; TIMP2, tissue inhibitor of metalloproteinases 2.
Table 2.
Association of Urine Tubular Stress Markers With Risk of Septic Acute Kidney Injury Adjusted to Urine Creatinine
| No. of Cases | TIMP2 |
No. of Cases | IGFBP7 |
|||
|---|---|---|---|---|---|---|
| Model 1a |
Model 2b |
Model 1a |
Model 2b |
|||
| OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |||
| Per doubling | 245 | 1.13 (0.96-1.34) | 1.12 (0.91-1.39) | 245 | 1.22 (1.02-1.46) | 1.27 (1.01-1.60) |
| Tertile 1 | 81/158 | Reference | Reference | 76/153 | Reference | Reference |
| Tertile 2 | 61/138 | 0.84 (0.51-1.37) | 0.82 (0.43-1.57) | 58/135 | 0.87 (0.51-1.48) | 0.85 (0.44-1.66) |
| Tertile 3 | 103/194 | 1.43 (0.80-2.57) | 1.13 (0.53-2.43) | 111/202 | 1.52 (0.89-2.60) | 1.80 (0.90-3.61) |
Note: Tertiles were created from the controls.
Abbreviations: CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; IGFBP7, insulin-like growth factor binding protein 7; OR, odds ratio; SOFA, Sequential Organ Failure Assessment; TIMP2, tissue inhibitor of metalloproteinases 2.
Model 1: urine creatinine, DM, systolic blood pressure, and diastolic blood pressure.
Model 2: model 1 + angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, C-reactive protein, SOFA score, hospital mortality, baseline eGFR, and urine albumin.
Our findings align with the evidence from other tubular biomarkers supporting the role of baseline tubular health in predicting kidney vulnerability to future insults. Urine uromodulin (uUMOD), the most abundant urine protein in healthy adults, is synthesized exclusively in the thick ascending limb of Henle loop and the distal convoluted tubule of the kidney.7 Higher uUMOD levels may serve as a surrogate for kidney tubule functional capacity.7 We have previously demonstrated that lower uUMOD and higher tubular reabsorption marker concentrations, such as alpha-1 microglobulin, are associated with increased risk of AKI, independent of eGFR and albuminuria.8 However, this study involved participants in the Systolic Blood Pressure Intervention Trial, in which over 80% of AKI events were linked to intravascular volume depletion or hypotension.9 In a subsequent study, we found no association between uUMOD or reabsorption markers and septic AKI.10 The pathophysiology of septic AKI is complex and includes intrarenal hemodynamic changes, endothelial dysfunction, infiltration of inflammatory cells in the renal parenchyma, intraglomerular thrombosis, and obstruction of tubules with necrotic cells and debris. In this study, IGFBP7 was associated with higher odds of septic AKI, suggesting that tubular dysfunction may increase susceptibility to septic AKI, despite being measured over 4 years before the insult. Prior research has highlighted the predictive value of tubular stress markers in acute settings such as surgery and critical illness. To the best of our knowledge, this study is the first to demonstrate their prognostic use when measured years before hospitalization.
This study demonstrates that abnormalities in tubular stress markers can be detected long before AKI occurs, suggesting a role for routine testing to complement eGFR and albuminuria in risk stratification. Whereas IGFBP7 emerged as a predictor, TIMP2 did not, potentially owing to differences in proximal versus distal tubular origin. However, when assessing the functional form of association based on tertiles, higher levels of both stress markers were associated with higher odds of AKI.
Strengths of this study include a large cohort with a significant prevalence of diabetes and hypertension, key risk factors for renal complications, and detailed information during hospitalization. Limitations include reliance on single baseline samples and the lack of long-term follow-up to assess prognosis in participants with higher levels of tubular stress markers.
In summary, when measured in high-risk community-dwelling patients during periods of health, a tubular stress marker, IGFBP7, was significantly associated with the future risk of septic AKI. These findings support our original hypothesis that markers of tubule dysfunction measured during times of health are associated with subsequent sepsis-associated AKI. More extensive studies could be considered to evaluate the use of IGFBP7 in screening individuals at high risk for AKI, in which preventive strategies may lead to a lower incidence of AKI.
Article Information
Authors’ Contributions
Research idea and study design: ALB, OMG. Data acquisition: ALB, OMG. Data analysis/interpretation: AW, ALB, MGS, OMG. Statistical analysis: ALB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Support
ALB is supported by the Department of Veterans Affairs Office of Research and Development Mentored Career Development Award IK2BX004986. OMG is supported by National Institute of Diabetes and Digestive and Kidney Diseases R01 DK128803. Representatives from the Department of Veterans Affairs, the University of Alabama at Birmingham, and University of California San Diego−O'Brien Center for Acute Kidney Injury Research or the National Institute of Diabetes and Digestive and Kidney Diseases did not have any role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation or approval of the manuscript. Reasons for Geographical Differences in Stroke is supported by cooperative agreement U01 NS041588 cofunded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging, National Institutes of Health, Department of Health and Human Services. This content is the sole responsibility of the authors. It does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, the National Institute of Health, the Department of Veterans Affairs or the US Government.
Financial Disclosure
OMG reports receiving honoraria from Amgen, Ardelyx, and Akebia. The remaining authors declare that they have no relevant financial interests.
Peer Review
Received September 19, 2025. Evaluated by 2 external peer reviewers, with direct editorial input from the Editor-in-Chief. Accepted in revised form January 26, 2026.
Footnotes
Item S1: Detailed Methods.
Table S1: Association of Urine Tubular Stress Markers Indexed to Urine Creatinine With Risk of Septic Acute Kidney Injury.
Supplementary Materials
Item S1; Table S1.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Item S1; Table S1.