Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement

doi:10.1016/j.healun.2014.06.007

The Journal of Heart and Lung Transplantation

Volume 33, Issue 12, December 2014, Pages 1215-1222

https://doi.org/10.1016/j.healun.2014.06.007 Get rights and content

Background

Progressive renal dysfunction develops in patients with advanced HF. We evaluated neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C compared with established markers of renal function in patients with heart failure (HF) because they might improve prognostic assessment of patients with HF.

Methods

Serum samples were collected from 40 patients with stable HF (age: 58 ± 8 years, body mass index [BMI]: 28.4 ± 6.4 kg/m²), 40 HF patients undergoing ventricular assist device (VAD) implantation (age: 53 ± 11 years, BMI: 26.8 ± 5.5 kg/m²), 40 patients undergoing VAD removal at cardiac transplantation, and 24 controls (age: 48 ± 7 years, BMI: 29.4 ± 4.2 kg/m²). Clinical data were collected from institutional medical records. NGAL and cystatin C levels were measured by enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease formula.

Results

Patients with stable HF showed elevated NGAL and cystatin C levels compared with controls (NGAL: 114.9 ± 48.3 ng/mL vs 72.0 ± 36.6 ng/mL, p < 0.0001; cystatin C: 1490.4 ± 576.1 ng/mL vs 954.7 ± 414.2 ng/mL, p = 0.0026). Unlike cystatin C, NGAL increased in advanced HF patients requiring VAD implantation (158.7 ± 74.8 ng/mL, p < 0.001). On VAD support, NGAL levels decreased (127.1 ± 80.4 ng/mL, p = 0.034). NGAL was higher in patients who developed right ventricular failure (187.8 ± 66.0 vs 130.9 ± 67.0 ng/mL, p = 0.03) and irreversible renal dysfunction (190.0 ± 73.8 ng/mL vs 133.8 ± 54.2 ng/mL, p < 0.05), whereas cystatin C, creatinine, and eGFR were not different. NGAL correlated with eGFR (r = –0.2188, p = 0.01).

Conclusions

NGAL levels correlate with HF severity and hemodynamic improvement after VAD placement. Our findings suggest a role of this novel biomarker as a marker of severity and prognosis in patients with HF.

Section snippets

Methods

The Columbia University Medical Center Institutional Review Board approved this study. All patients provided written informed consent.

Baseline characteristics

Clinical characteristics of all patients are summarized in Table 1. Body mass index differed significantly among the groups. In patients with severe HF before VAD implantation, HF duration was a median of 1,637 days (range, 31–6,800). The duration of VAD support was a mean of 164 ± 123 days (range, 28–508 days). The VADs were pulsatile in 18 patients (45%) and continuous flow in 22 (55%). Table 2 summarizes laboratory examinations comparing controls, stable, and severe HF patients before and

Discussion

In the current study, we demonstrate that circulating levels of NGAL, a novel biomarker of renal dysfunction, increase in patients with HF, correlate with impairment of renal function in HF patients, and decrease after VAD implantation likely due to hemodynamic improvement. Cystatin C, another novel biomarker of renal function, shows a similar increase in patients with HF; however, a matched-pair analysis of patients before and after VAD placement failed to show a significant change in cystatin

Disclosure statement

This work was supported by grants from the National Heart, Lung and Blood Institute (K23-HL-095742-01, P30-HL-101272-01, UL1-RR-024156, HL-073029) and the Herbert and Florence Irving Scholar Award to Dr Schulze.

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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The increased risk is a result of aggravating renal venous congestion and lack of renal perfusion.26 The biomarker neutrophil gelatinase-associated lipocalin has also been used in patient selection.27 In most patients who receive an LVAD implant, B-type natriuretic peptide (BNP) levels decrease significantly postoperatively from LV unloading.
Left ventricular assist device (LVAD) implantation results in superior survival rates compared with optimal medical therapy in patients with end-stage heart failure. However, a potential complication of LVAD implantation is right heart failure (RHF), which can be devastating. Therefore, identifying preoperative risk factors for RHF and optimal management for these patients are critical for ensuring favorable postoperative outcomes. This review focuses on methods of assessing the risk factors for RHF before surgery, including evaluation of biomarkers, echocardiography, hemodynamics, risk-scoring systems, and existing conditions of right heart dysfunction. In addition, the review also explores the perioperative strategic approaches to reducing the likelihood of RHF.
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Neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin-C, and kidney injury molecule-1 have been suggested to predict the development of AKI.15,16 Of the aforementioned, only NGAL and cystatin-C have been assessed in the LVAD population.17 However, only NGAL showed a promising correlation with irreversible renal dysfunction.
Currently, an increasing number of patients with end-stage heart failure are being treated with left ventricular assist device (LVAD) therapy as bridge-to-transplantation, bridge-to-candidacy, or destination therapy (DT). Potential life-threatening complications may occur, specifically in the early post-operative phase, which positions LVAD implantation as a high-risk surgical procedure. Acute kidney injury (AKI) is a frequently observed complication after LVAD implantation and is associated with high morbidity and mortality. The rapidly growing number of LVAD implantations necessitates better approaches of identifying high-risk patients, optimizing peri-operative management, and preventing severe complications such as AKI. This holds especially true for those patients receiving an LVAD as DT, who are typically older (with higher burden of comorbidities) with impaired renal function and at increased post-operative risk. Herein we outline the definition, diagnosis, frequency, pathophysiology, and risk factors for AKI in patients with an LVAD. We also review possible strategies to prevent and manage AKI in this patient population.
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Citation Excerpt :
Siasos et al. [120] have shown that, in patients with HF, NGAL levels are associated with LVEF, as well as, biomarkers of inflammation and cardiac remodeling (cystatin C, BNP, TNFα, MMP-9), further suggesting a common pathogenetic mechanism of renal dysfunction, inflammation, and cardiac dysfunction. The role of NGAL, as a biomarker of severity and prognosis in patients with HF, is also supported by recent findings on correlation of serum NGAL levels with HF severity and hemodynamic improvement after ventricular assist device (VAD) placement in patients with advanced HF [146]. However, although significant association between serum NGAL levels and severity of HF, caused by idiopathic dilated cardiomyopathy (DCM), in children was confirmed, the relationship to indices of myocardial function was not observed [147].
Although substantial improvements have been made in majority of cardiac disorders, heart failure (HF) remains a major health problem, with both increasing incidence and prevalence over the past decades. For that reason, the number of potential biomarkers that could contribute to diagnosis and treatment of HF patients is, almost exponentially, increasing over the recent years. The biomarkers that are, at the moment, more or less ready for use in everyday clinical practice, reflect different pathophysiological processes present in HF.
In this review, seven groups of biomarkers associated to myocardial stretch (mid-regional proatrial natriuretic peptide, MR-proANP), myocyte injury (high-sensitive troponins, hs-cTn; heart-type fatty acid-binding protein, H-FABP; glutathione transferase P1, GSTP1), matrix remodeling (galectin-3; soluble isoform of suppression of tumorigenicity 2, sST2), inflammation (growth differentiation factor-15, GDF-15), renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL; kidney injury molecule-1, KIM-1), neurohumoral activation (adrenomedullin, MR-proADM; copeptin), and oxidative stress (ceruloplasmin; myeloperoxidase, MPO; 8-hydroxy-2′-deoxyguanosine, 8-OHdG; thioredoxin 1, Trx1) in HF will be overviewed.
It is important to note that clinical value of individual biomarkers within the single time points in both diagnosis and outcome prediction in HF is limited. Hence, the future of biomarker application in HF lies in the multimarker panel strategy, which would include specific combination of biomarkers that reflect different pathophysiological processes underlying HF.
Mean Arterial Pressure to Central Venous Pressure Ratio: A Novel Marker for Right Ventricular Failure After Left Ventricular Assist Device Placement
2017, Journal of Cardiac Failure
Early right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and often leads to increased morbidity and mortality. It is difficult to predict early RVF on the basis of clinical and hemodynamic parameters. We investigated the utility of mean arterial pressure (MAP) to central venous pressure (CVP) ratio in predicting early RVF.
We analyzed a retrospective cohort of 212 consecutive patients who underwent hemodynamic assessment before destination-therapy LVAD implantation. Patients were followed for early RVF and mortality. Receiver operating characteristic (ROC) analysis was used to determine discriminative capacity of MAP/CVP and tested the diagnostic and prognostic value of median MAP/CVP threshold. The ROC analysis demonstrated that pre-LVAD MAP/CVP was associated with an area under the ROC curve of 0.65 (95% confidence interval 0.58–0.73; P < .001). MAP/CVP threshold <7.5 (simple nearest-to-median value) was associated with 70% sensitivity and 56% specificity for early RV failure. Patients with MAP/CVP <7.5 had a higher incidence of post-LVAD RVF than those with a ratio ≥7.5 (44% vs 23%, respectively; P = .001). Right ventricular assist device requirement was higher in the MAP/CVP <7.5 group (11% vs 2%; P = .01). All-cause mortality was higher in the MAP/CVP <7.5 group (annualized mortality 26% vs 16%; log-rank P = .017). MAP-CVP ratio provided incremental prognostic value for RVF and all-cause mortality beyond established Heartmate II and RVF risk scores.
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Featured ArticlesNeutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement

Background

Methods

Results

Conclusions

Section snippets

Methods

Baseline characteristics

Discussion

Disclosure statement

Lancet

J Heart Lung Transplant

Heart Failure Society of America, HFSA 2010 comprehensive heart failure practice guideline

J Card Fail

Patient selection for left ventricular assist devices

Eur J Heart Fail

Cardiorenal syndrome: a literature review

Exp Clin Cardiol

Volume overload and cardiorenal syndromes

Congest Heart Fail

Biomarkers in heart failure

N Engl J Med

Cystatin C concentration as a risk factor for heart failure in older adults

Ann Intern Med

Relative performance of the MDRD and CKD-EPI equations for estimating glomerular filtration rate among patients with varied clinical presentations

Clin J Am Soc Nephrol

Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury

J Am Soc Nephrol

Featured Articles
Neutrophil gelatinase-associated lipocalin and cystatin C for the prediction of clinical events in patients with advanced heart failure and after ventricular assist device placement