Elsevier

International Journal of Cardiology

Volume 338, 1 September 2021, Pages 115-120
International Journal of Cardiology

Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure

https://doi.org/10.1016/j.ijcard.2021.06.041Get rights and content

Highlights

  • Urinary A1MG corrected for urinary creatinine concentration was strongly associated with tubular dysfunction rather than glomerular dysfunction, which implies increased A1MG levels likely reflect tubular damage in patients with AHF.

  • Increased A1MG was associated with an increased risk of all-cause mortality independently of other prognostic covariates, including glomerular function, and this association was almost linear.

  • A1MG yielded significant incremental prognostic information in addition to known risk factors.

  • This is the first study showing the clinical and prognostic values of urinary A1MG in patients with AHF.

Abstract

Background

Although urinary alpha-1-microglobulin has been used as a marker of tubular dysfunction, its clinical and prognostic values in patients with acute heart failure have not been validated.

Methods

We analyzed 623 patients (74 ± 13 years old, 60.0% male) with acute heart failure in whom urinary alpha-1-microglobulin (A1MG) levels were measured as tubular markers at the time of admission. The primary endpoint was all-cause mortality.

Results

The median levels of urinary alpha-1-microglobulin with and without correction for urinary creatinine concentration were 8.80 (interquartile range: 4.20–17.7) mg/dL and 12.9 (5.92–30.7) mg/gCr, respectively. Urinary A1MG levels were significantly correlated with all of beta-2-microglobulin (r = 0.77), N-acetyl-β-D-glucosaminidase (r = 0.51), and estimated glomerular filtration rate (r = −0.42); however, alpha-1-microglobulin was most often predicted using beta-2-microglobulin or N-acetyl-β-D-glucosaminidase. During the 488-day (interquartile range: 185–938 days) follow-up, 141 deaths occurred. Higher A1MG levels were associated with higher mortality even after adjustment for other covariates. Only A1MG, but not beta-2-microglobulin or N-acetyl-β-D-glucosaminidase, yielded incremental prognostic information in addition to the preexisting prognostic factors (net-reclassification improvement: 0.254, P = 0.023; integrated discrimination improvement: 0.015, P = 0.028).

Conclusions

In patients hospitalized due to acute heart failure, urinary alpha-1-microglobulin was a marker of tubular dysfunction. High alpha-1-microglobulin was associated with all-cause mortality independent of glomerular function and was a better predictor of mortality than urinary beta-2-microglobulin.

Introduction

Acute heart failure (AHF) is one of the main causes of mortality and hospital admission globally [1]. Despite recent developments of novel treatments, the prognosis of AHF is unacceptably poor. Renal dysfunction is a major comorbidity and powerful prognostic factor of both chronic heart failure and AHF [2,3], and there is a complicated interplay between the cardiovascular system and kidney function [4]. Therefore, comprehending this bidirectional relationship is crucial to improve management and prognosis of high-risk populations, including patients with AHF who have renal dysfunction. Renal dysfunction includes both glomerular and tubular dysfunction. Several biomarkers have been proposed to predict tubular dysfunction, such as urinary beta-2 microglobulin (B2MG) and urinary N-acetyl-β-D-glucosaminidase (NAG). Tubular dysfunction defined by these biomarkers has been shown to be associated with poor prognosis in patients with chronic heart failure [[5], [6], [7]]. However, a few studies have shown conflicting results regarding the effects of tubular dysfunction in patients with AHF [[8], [9], [10], [11], [12]].

Alpha-1 microglobulin (A1MG) is a small molecular weight protein (27 kDa) first identified more than 50 years ago. In a healthy kidney, A1MG proteins pass freely through the glomerular membranes, where approximately 99% are reabsorbed and catabolized by the proximal tubular cells [13]. Increased urinary A1MG is an early sign of renal damage, primarily in the proximal tubules, and has been used as a marker of tubular dysfunction due to its high stability in urine compared to other tubular markers [[14], [15], [16], [17], [18]]. Indeed, a previous study analyzing kidney biopsies found that urine A1MG was associated with tubulointerstitial fibrosis. Proximal tubular dysfunction evaluated by A1MG has been reported to be associated with cardiovascular mortality in patients with chronic kidney disease [19,20]. Moreover, in a study of 513 patients with type 2 diabetes mellitus, urinary A1MG normalized for urinary creatinine was superior to urinary neutrophil gelatinase-associated lipocalin in identifying patients with renal insufficiency [21].

Although A1MG is a traditional, inexpensive, and readily measurable biomarker that may be able to identify tubular dysfunction, to our knowledge, no study has evaluated its prognostic implications in patients with heart failure. Thus, we hypothesized that A1MG measured in patients with AHF would be associated with prognosis and would be a better predictor of prognosis compared to other tubular biomarkers.

Section snippets

Patients

We performed a retrospective analysis of the Juntendo database for acute heart failure (JEDI-AHF). All patients with AHF who were hospitalized in a high care unit or coronary care unit of Juntendo University Hospital in Japan from January 2015 to December 2019 were analyzed. Consecutive patients aged >18 years with a confirmed AHF diagnosis according to the Framingham criteria were included in the study [22]. We excluded cases in which brain natriuretic peptide (BNP) values at admission were <

Results

A total of 744 patients were eligible for inclusion. After excluding 121 patients (four were on dialysis; 117 had missing data on A1MG), we analyzed the records of the 623 remaining patients. The average age was 74 ± 13 years, and 62.4% of the patients were male. The median levels of urinary A1MG with and without correction for urinary creatinine were 8.80 (interquartile range [IQR]: 4.20–17.7) mg/dL and 12.9 (IQR: 5.92–30.7) mg/gCr, respectively. The patients were divided into four groups

Discussion

The findings of this study, which analyzed 623 patients hospitalized due to AHF, provided several novel insights into the relationship between A1MG and clinical outcome in patients with AHF. First, we found that urinary A1MG corrected for urinary creatinine concentration was strongly associated with tubular dysfunction rather than glomerular dysfunction, which implies increased A1MG levels likely reflect tubular damage in patients with AHF. Second, increased A1MG was associated with an

Disclosures

Dr. Sayaki Ishiwata, Yuya Matsue and Takatoshi Kasai are affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi, and Dr. Yuya Matsue received an honorarium from Otsuka Pharmaceutical Co and Novartis Japan. Other authors have nothing to declare.

Sources of funding

This work was partially supported by JSPS KAKENHI (Grant Number 18 K15862).

Acknowledgements

None.

References (38)

  • C. Ronco et al.

    Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative

    Eur. Heart J.

    (2010)
  • N. Hata et al.

    Acute kidney injury and outcomes in acute decompensated heart failure: evaluation of the RIFLE criteria in an acutely ill heart failure population

    Eur. J. Heart Fail.

    (2010)
  • A. Rastogi et al.

    The cardiorenal connection in heart failure

    Curr. Cardiol. Rep.

    (2008)
  • K. Damman et al.

    Clinical outcome of renal tubular damage in chronic heart failure

    Eur. Heart J.

    (2011)
  • S.H. Nymo et al.

    The association between neutrophil gelatinase-associated lipocalin and clinical outcome in chronic heart failure: results from CORONA*

    J. Intern. Med.

    (2012)
  • C.G. Jungbauer et al.

    Kidney injury molecule-1 and N-acetyl-beta-D-glucosaminidase in chronic heart failure: possible biomarkers of cardiorenal syndrome

    Eur. J. Heart Fail.

    (2011)
  • Y. Nakada et al.

    Prognostic value of urinary neutrophil gelatinase-associated Lipocalin on the first day of admission for adverse events in patients with acute decompensated heart failure

    J. Am. Heart Assoc.

    (2017)
  • A. Jouary et al.

    A 2D virtual reality system for visual goal-driven navigation in zebrafish larvae

    Sci. Rep.

    (2016)
  • S. Funabashi et al.

    Elevated admission urinary N-acetyl-beta-D-glucosamidase level is associated with worse long-term clinical outcomes in patients with acute heart failure

    Eur. Heart J. Acute Cardiovasc. Care

    (2020)
  • Cited by (0)

    View full text