IGFBP‑7 Biomarker Linked to Mortality, Readmission Risk in Acute Heart Failure

A recent study showed that kidney tubular injury and dysfunction biomarkers, including IGFBP-7, IGFBP-7*TIMP-2, KIM-1, and MCP-1, were independently associated with increased 1-year risk of death or heart failure (HF) readmission in patients hospitalized with acute heart failure (AHF).1

“…though only IGFBP‐7 remained associated after adjusting for multiple comparisons,” wrote investigator Nicholas Wettersten, MD, from the University of California, San Diego, and colleagues.1 “Nonetheless, all 5 of these may be of particular interest for future studies of tubular biomarkers in AHF.”

Kidney dysfunction in AHF is linked to greater readmission and mortality risks, traditionally assessed via serum creatinine, cystatin C, and albuminuria.2 Previous studies suggest kidney tubule markers may predict health outcomes, but research has inconsistently linked these biomarkers to worsening renal function, mortality, and HF readmission, often assessing only a narrow set of injury markers.1

In AKINESIS (Acute Kidney Injury Neutrophil Gelatinase‐Associated Lipocalin Evaluation of Symptomatic Heart Failure Study), investigators evaluated whether urine biomarkers of tubular function, injury, inflammation, and stress predicted 1-year death or HF readmission.1 The study enrolled 927 patients at 16 US and European sites, all of whom had AHF and were receiving or planning to receive intravenous diuretics. Exclusions included acute coronary syndrome, dialysis dependence, organ transplant, recent trial participation, and pregnancy.

A case-control subset of 436 participants with at least stage 1 acute kidney injury (AKI) was analyzed. Mean age was 71 years; 64% were men, 68% White, 79% had hypertension, 49% diabetes, and the mean eGFR was 55 mL/min/1.73 m². Urine samples were collected within 2 hours of the first loop diuretic dose and again 2–6 hours later.1

Fourteen kidney tubule biomarkers were assessed, including markers of function (α‑1‑microglobulin, uromodulin, EGF), injury (LFABP, NGAL, KIM-1, IGFBP-1), inflammation (YKL-40, IL-18, MCP-1, CCL-14), stress (IGFBP-7, TIMP-2), and neurohormonal activation (angiotensinogen).

The 14 biomarkers:

1. Tubular function (α‐1‐microglobulin; α‐1‐m
2. Uromodulin
3. Epidermal growth factor (EGF)
4. Tubular injury (liver fatty acid binding protein-1; LFABP)
5. Neutrophil gelatinase-associated lipocalin (NGAL)
6. Kidney injury molecule-1 (KIM-1)
7. Insulin-like growth factor-binding protein-1 (IGFBP-1)
8. Tubular inflammation (chitinase-3-like protein-1; YKL-40)
9. Interleukin-18 (IL-18)
10. Monocyte chemoattractant protein-1 (MCP-1)
11. C-C motif chemokine ligand-14 (CCL-14)
12. Tubular stress (insulin-like growth factor-binding-protein-7; IGFBP-7)
13. Tissue inhibitor of metalloproteinases-2 (TIMP-2)
14. Neurohormonal activation (angiotensinogen)

Most biomarkers showed weak positive correlations with serum creatinine (≤0.40) and urine albumin (≤0.39), and weak negative correlations with eGFR (≤–0.39). The strongest correlations were observed between IGFBP-7 and TIMP-2 (0.71), IGFBP-7 and KIM-1 (0.70), α-1-m and IGFBP-1 (0.68), and TIMP-2 and KIM-1 (0.65). The other urine biomarkers were weakly intercorrelated.1

In total, 87 deaths occurred within 1 year of follow-up, with 43 occurring in individuals with AKI and 44 occurring without. Greater levels of IGFBP‐7, IGFBP‐7*TIMP‐2, KIM‐1, MCP‐1, CCL‐14, and IGFBP‐1, along with lower levels of angiotensinogen, were all significantly associated with a greater risk of the composite death or HF readmission outcome.1

IGFBP-7 showed the strongest association, indicating a 36% greater risk of death or HF readmission per 2-fold increase and a 2.4-fold greater risk in the fourth versus first quartile. After adjustment for multiple comparisons, IGFBP-7 remained the only biomarker significantly associated with these outcomes (P =.015).1

NGAL (P =.019) and IGFBP‐1 (P =.001) showed significant effect modification by case–control status, with higher levels more strongly linked to adverse outcome in patients with AKI. Only IGFBP‑7 was significantly associated with death alone, though not after multiple comparison adjustment (P =.51).1

Regarding HF readmission, there were 38 cases in individuals with AKI vs 54 without. No biomarkers independently predicted HF readmission after adjustment. However, after adjusting for confounders, each 2-fold greater MCP1 and CCl-14 level was associated with a 24% and 11% greater risk of HF readmission, respectively.1

“Our findings demonstrate that the net relationship of the kidney with adverse outcomes in AHF may have previously been underestimated, because we demonstrate that kidney tubule health is associated with outcomes in AHF independent of glomerular health and cardiac risk biomarkers,” investigators wrote.1

References

1. Wettersten N, Duff S, Horiuchi Y, et al. Kidney Tubular Biomarkers Predict Risk of Death and Heart Failure Readmission in Acute Heart Failure. J Am Heart Assoc. 2025;14(18):e042880. doi:10.1161/JAHA.125.042880

2. Ix JH, Shlipak MG. The Promise of Tubule Biomarkers in Kidney Disease: A Review. Am J Kidney Dis. 2021;78(5):719-727. doi:10.1053/j.ajkd.2021.03.026